Resting-state fMRI: Algorithms and Applications to Brain Disorders

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Resting-state fMRIAlgorithms and Applications
to Brain Disorders
ZANG Yu-Feng ??? M.D. zangyf_at_gmail.com
YAN Chao-Gan ??? Ph. D. ycg.yan_at_gmail.com State
Key Laboratory of Cognitive Neuroscience and
Learning, Beijing Normal University, China
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Outline

• What is resting-state fMRI?
• Computational methodology
• Applications to brain disorders

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Functional MRI?

• Generally
• Blood oxygenation level dependent (BOLD)
• Perfusion
• Diffusion
• Magnetic resonance spectroscopy (MRS)

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Functional MRI?

• More Specifically
• BOLD-fMRI
• Perfusion
• Most Specifically
• BOLD-fMRI

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Functional MRI?
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Task-state fMRI?
Contrast within a scanning session is necessary!
T C T C T C
Design
Expected signal
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Task-state fMRI
What is activation?
activated
delta
baseline or control
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Task-state fMRI
What is abnormal activation for patients?
Abnormal activated level?
Abnormal delta
Abnormal baseline?
So, baseline is important!
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What is resting-state fMRI?

• Eyes closed or open with no task
• Continuously
• Quite a few minutes or more
• Not to fall asleep
• Not to think of anything in particular
• Low frequency fluctuation (LFF, 0.01 0.08 Hz)
  

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The nature of task BOLD

• the haemodynamic response seems to be better
  correlated with the LFPs, implying that
  activation in an area is often likely to reflect
  the incoming input and the local processing in a
  given area rather than the spiking activity.
• (Logothetis et al., 2001, Nature)

BOLD LFP
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The nature of spontaneous BOLD

• It was found that the impulse response function
  computed from LFP and BOLD under conditions of no
  stimulation can predict the response under
  stimulation conditions.
• (Logothetis et al., 2001, Nature)

Spontaneous BOLD spontaneous LFP
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Resting-state BOLD-fMRI signal reflects
However, also physiological noise (respiration,
cardiovascular pulsation, etc) (Cordes et al.,
2001 Birn et al., 2006)
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Outline

• What is resting-state fMRI?
• Computational methodology
• Applications to AD studies

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Task-state fMRI

• Functional segregation
• (activation detection)

• Functional integration
• (inter-regional relationship or connectivity)

1 gtgt 2
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Most of resting-state fMRI studiesintegration
(connectivity)

• Correlation (Biswal et al., 1995 )
• ICA (Kiviniemi et al., 2003 van de Ven et al.,
  2004 Greicius et al., 2004)
• Hierarchical Clustering (Cordes et al., 2000
  Salvador et al., 2005)
• Self Organization Map (Peltier et al., 2003)
• ....

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The first Resting-state fMRI study

• (Biswal et al., 1995)

Bilateral finger tapping (task vs. rest)
Resting-state correlation of low frequency
fluctuation (LFF, 0.01 0.08 Hz)
(Courtesy of Dr. WENG Xu-Chu)
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Linear Correlation

• Spontaneous LFF was highly synchronous among
• Bilateral motor cortices (Biswal et al., 1995)
• Bilateral visual cortices (Lowe et al., 1998
• Kiviniemi et al., 2004)
• Bilateral auditory cortices (Cordes et al., 2001)
• Bilateral amygdala (Lowe et al., 1998)
• Bilateral thalamus (Stein et al., 2000)
• Language cortices (Hampson et al., 2002)
• Default mode network (Greicius et al., 2003 Fox
  et al., 2005..)

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A default mode of brain function
(Raichle et al., 2001)
PCC, MPFC, IPL etc., 1) Consistently show
task-independent deactivation (TID) during a wide
range of tasks with cognitive demand 2) Highest
metabolic rate in the brain during resting state
1)
2)
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Functions of the default mode network

• Intrinsic activities (Fransson, 2005)
• Self-reflection, self-referential processing,
  self awareness
• Task-unrelated thought (TUT)
• Mind wandering or daydreaming
• Streams of consciousness
• Memory retrieval of autobiographic events

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Most of resting-state fMRI studiesintegration
(connectivity)

• Correlation (Biswal et al., 1995 )
• ICA (Kiviniemi et al., 2003 van de Ven et al.,
  2004 Greicius et al., 2004)
• Hierarchical Cluster (Cordes et al., 2000
  Salvador et al., 2005)
• Self Organization Map (Peltier et al., 2003)
• ....

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Independent Component Analysis (ICA)

• Spatial ICA for fMRI data separate a mixture
  of a 4D data into a set of spatially independent
  components (McKowen et al., 1998)

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Spatial ICA for resting-state fMRI
Vascular component
Visual component
(Kiviniemi et al., 2000)
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Integrative is really good, but

Decreased functional connectivity
Question Is A, B, C, orabnormal?
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Only A few resting-state fMRI studiesSegregation

• rms, power spectrum, ALFF (Biswal et al., 1995
  Li et al., 2000 Kiviniemi et al., 2000 Zang et
  al., 2007)
• TCA (Liu et al., 2000 Morgan et al., 2004)
• Regional Homogeneity (Zang et al., 2004)
• Multiple Regressors (Fransson, 2005)
• Autoregressive Noise Model (Cordes et al., 2005)
  
• Fractional Gaussian Noise (Maxim et al., 2005)

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rms, power, ALFF

• For a given frequency
• root mean square (rms)
• standard deviation
• amplitude
• rms white matter vs. gray matter 0.6 1
• (Biswal et al., 1995 Li
  et al., 2000)

Square root of the power
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rms, power, ALFF

• Power spectrum

Higher power at 0.033Hz in visual area (Kiviniemi
et al., 2000)
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Amplitude of Low Frequency Fluctuation
(ALFF) (Zang et al., 2007 Yang et al., 2007)
TR 400 ms
1.25 Hz
0.01-0.08 Hz
Steps square root, average of 0.01-0.08 Hz,
standardization by global mean
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ALFF
PET (Raichle et al., 2001)
ALFF (Zang et al., 2007)
noise
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Abnormal ALFF

• ADHD vs. controls
• (n13) (n12)
• (Zang et al., 2007)

• Early AD vs. controls
• (He Y et al., 2007) (Please see below for
  details)

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Improvement fractional ALFF
Suprasellar cistern
PCC
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Improvement fractional ALFF
(Zou et al., 2008)
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Regional Homogeneity (ReHo)
Similarity or coherence of the time courses
within a functional cluster
(Zang et al., 2004)
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ReHo motor task state vs. pure resting state
(Zang et al., 2004)
Rest gt Motor
Motor gt Rest
a) Higher ReHo in bilateral primary motor
cortices during motor task b) Higher ReHo in
default mode network (PCC, MPFC, IPL) during rest
(Raichle et al., 2001 Greicius et al., 2003)
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ReHo applications to brain disorders

• ADHD Zhu et al., 2005, 2007 Cao et al., 2006
• AD/MCI He et al., 2007 Bai et al., 2008
• Schizophrenia Liu et al., 2006, Shi et al., 2007
• Aging Wu et al., 2007
• PD Wu et al., 2008
• Depression Yuan et al., 2008

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Outline

• What is resting-state fMRI?
• Computational methodology
• Applications to brain disorders

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RESTing-state fMRI data analysis toolkit (REST)
By Song et al., http//www.restfmri.net
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Data Processing Assistant for Resting-State fMRI
(DPARSF)
Yan CG and Zang YF (2010) DPARSF a MATLAB
toolbox for "pipeline" data analysis of
resting-state fMRI. Frontiers in Systems
Neuroscience. 4(13) http//www.restfmri.net
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Outline

• What is resting-state fMRI?
• Computational methodology
• Applications to brain disorders

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Some issues about resting-state fMRI

• Definition and instruction?
• Sampling rates (TR)
• Length
• Standard method for data analysis?

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Definition and Instruction?

• Eyes closed or open with no cognitive task
• Continuously
• Not to fall asleep
• Not to think of anything particular

ill defined!
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Different resting conditions?
The functional connectivity patterns of the
default mode network was minimally disturbed
during different resting conditions with limited
cognitive demand (Greicius et al., 2003
Fransson, 2005 Fox et al., 2005)
Fox et al., 2005
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Different resting conditions?
Functional connectivity maps
Significantly different between different resting
conditions with limited cognitive demand
Yan et al., PLoS ONE 2009
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Different resting conditions?
Regional activity (ALFF)
Significantly different between different resting
conditions with limited cognitive demand
Yan et al., PLoS ONE 2009
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Different resting conditions?
Suggestion eyes closed for patients studies
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Is the resting block a resting-state?
In block design
Long resting
No study has compared directly between them yet
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Is the resting block a resting-state?
Stimulus
Peak 4-8 s
20 - 30 s
BOLD
Post undershoot gt 15 s
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Some issues about resting-state fMRI

• Definition and instruction?
• Sampling rates (TR)
• Length
• Standard method for data analysis?

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Some issues about resting-state fMRI
Sampling rates (TR) Nyquist sampling theorem
Shorter TR (lt400 ms, gt2.5 Hz) for
heart beating (around 1.3 Hz)
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Sampling rate and physiological noise
But for respiration (around 0.3 Hz)? Is TR lt1.5 s
fast enough?
Courtesy of SONG Xiao-Wei
Simultaneous recording of respiration and heart
beat to remove physiological noise (Hu et al.,
1995, MRM)
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Some issues about resting-state fMRI

• Definition and instruction?
• Sampling rates (TR)
• Length
• Standard data analysis?

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Some issues about resting-state fMRI
Length? LFF 0.01-0.08 Hz Peak around 0.033 Hz
(Kiviniemi et al., 2000, MRM)
2/min
8 min, we used
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Some issues about resting-state fMRI

• Definition and instruction?
• Sampling rates (TR)
• Length
• Standard data analysis?

Not yet
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Applications to brain disorders

• Functional connectivity (integration)
• Linear correlation
• Independent component analysis
• Regional activity (functional segregation)
• Regional Homogeneity (ReHo)
• Amplitude of low frequency fluctuation
  (ALFF)

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Functional connectivity, linear correlation
analysis

• Multiple Sclerosis Low-Frequency Temporal
  Blood Oxygen LevelDependent Fluctuations
  Indicate Reduced Functional Connectivity -
  Initial Results
• (Lowe et al., 2002)

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Functional connectivity, linear correlation
analysis

• Data analysis and results
• MT the middle part of corpus callosum
  (connecting bilateral M1), lower in MS patients

(Lowe et al., 2002)
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Functional connectivity, linear correlation
analysis

• Decreased functional connectivity between
  bilateral sensorimotor cortex

(Lowe et al., 2002)
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Changes in hippocampal connectivity in the early
stages of Alzheimer's disease evidence from
resting state fMRI
Functional connectivity, linear correlation
analysis

• Pure resting state
• Subject-specific Seed ROIs in bilateral
  hippocampus
• Correlation analysis

• (Wang L et al., 2006)

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(Wang L et al., 2006)
AD decreased connectivity with the right
hippocampus
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Applications to brain disorders

• Functional connectivity (integration)
• Linear correlation
• Independent component analysis
• Regional activity (functional segregation)
• Regional Homogeneity (ReHo)
• Amplitude of low frequency fluctuation
  (ALFF)

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Default-mode network activity distinguishes
Alzheimer's disease from healthy aging evidence
from functional MRI
Functional connectivity, Independent component
analysis (ICA)

• (Greicius et al., 2004)

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Methods

• Data sensorimotor task in event-related design
• Independent component analysis (ICA)
• Define the default mode network component by
  goodness-of-fit with a PCC-template
• Between-group comparison on the Z maps
• Between-group comparison on the goodness-of-fit

(Greicius et al., 2004)
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Goodness-of-fit

• Increased functional connectivity in normal
  elderly

(Greicius et al., 2004)
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Applications to brain disorders

• Functional connectivity (integration)
• Linear correlation
• Independent component analysis
• Regional activity (functional segregation)
• Regional Homogeneity (ReHo)
• Amplitude of low frequency fluctuation
  (ALFF)

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Regional coherence changes in the early stages of
Alzheimer's disease a combined structural and
resting-state functional MRI study

(He Y et al., 2007)

• Pure resting state
• Regional homogeneity (ReHo)
• Amplitude of low frequency fluctuation (ALFF)

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• MCI decreased ReHo and ALFF in PCC, while
  increased in visual cortex (p lt 0.001, corrected)

(He Y et al., 2007)
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Correlated with MMSE
(He Y et al., 2007)
Consistent with PET studies (Reiman et al., 1996
Minoshima et al., 1994)
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Summary on the resting-state fMRI

• Mechanism needs further studies
• Application to clinical studies
• easy, cheap
• Combine with other MRI structure, perfusion
  (ASL), DTI

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Multiple MRI modalities
Computational Neuroanatomy
MRS
DTI
Others
fMRI Task, Rest
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Multiple Disciplines

• Neurology and Psychiatry
• Neuroradiology
• Computer Science
• Cognitive Neuroscience

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Thanks to

• ????
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• Kiviniemi, Vesa
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All the group members!
NSFC 30470575 30625024 30728017
30621130074
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• Thanks for your attention!