Synopsis
Dynamic functional connectivity (dFC) uses
region-of-interest or data driven methods to elucidate temporally-varying
changes in resting-state brain networks. Challenges are the lack of a gold
standard for dFC, the difficulty in discriminating signal from non-neurally generated
BOLD fluctuations, and the tradeoffs between temporal resolution of the neural dynamics
and the statistical significance of the resulting networks. This talk will
describe the methods and pitfalls to be avoided in applying these techniques,
as well as results that correlate with independently acquired measures of
behavior and psychometrics.Since
the discovery of networks of brain regions whose members have correlated
fluctuations in BOLD timeseries signals during periods when the subject is not
performing an intentional cognitive task (Biswal,
Yetkin et al. 1995), a large number of such “resting-state”
analyses have been performed both to extend basic underpinnings of brain
function as well as to study neurological disorders. Until recently, these
analyses have tacitly assumed that the networks are static, and a single map of
Functional Connectivity (FC) is typically calculated from the full scan using
either region-of-interest (ROI) correlation methods as in Biswal, or a
data-driven method such as Independent Components Analysis (ICA) (Beckmann
and Smith 2004). However, more recently FC has been observed
to vary across typical scan time scales of 5-10 minutes (Chang and
Glover 2010), and considerable interest in the reasons for
non-stationarity and methods for elucidating such changes has been demonstrated
(see (Hutchison,
Womelsdorf et al. 2013) for a review). Here
we discuss the methods of observing dynamic FC (dFC), the pitfalls and issues
associated with drawing inferences from dynamic changes in the FC maps, and
attempts to correlate dFC with measures of behavior or psychometric dynamics.
The simplest method of observing dFC is to temporally segment
the scan using a sliding window of time frames (Chang and Glover 2010), calculating FC with either
an ROI or ICA-based method that produces multiple maps depicting apparently
varying brain states such as CAPS (Liu and Duyn 2013) and/or quantitative measures of the dynamics (Chen, Chang et al. 2015). Both intra-network and inter-network
dynamics have been observed. An alternative method uses temporally
restricted basis functions such as wavelets to demonstrate continuously
evolving network patterns within a series of temporal scales commensurate with
the temporal extent of the basis functions (Chang and Glover 2010).
There are several intrinsic problems with extracting FC in
the resting brain experiment. The first is the lack of “ground truth”, i.e. there
is no hypothesis for how to model the timeseries in any given voxel, unless
independently collected measures of some psychometric or behavioral construct
have been collected that could be reasonably expected to reflect changes in brain
state. The second significant problem with FC and especially dFC is the low
signal-to-noise ratio of the BOLD response in the resting state. The “noise” in
FC is any variance in the timeseries that is non-neural and not related to the
specific network under study. Since this
noise is often not distinguishable from signal of interest, false connectivity
can be generated by correlations that are caused by non-neural signals common
to many voxels, such as BOLD modulations caused by respiration (Birn, Diamond et al. 2006)and the significance of any
observed correlations can be reduced by the spurious variance. The third
problem in using sliding window correlations is the tradeoff between short
windows for good temporal resolution and poor statistics. It is important to verify the null hypothesis
to avoid false connectivity.(Chang and Glover 2010, Hindriks, Adhikari et al. 2016).
Therefore, it is important to remove any known sources of spurious
fluctuations in the timeseries data before attempting to identify networks with
any form of FC. The usual motion
co-registration must be employed and motion regressors projected from the
timeseries. However, additional care must be taken to remove other sources of
noise. Typically the frame repetition time (TR) employed in resting state
scanning with conventional acquisitions is ~2s. While respiration may be
correctly sampled at this TR, cardiovascular pulsation is undersampled and may be
temporally aliased to low frequencies where it can pose as true neural signal.
One approach is to use a retrospective sorting algorithm like RETROICOR(Glover, Li et al. 2000) to correctly identify and
remove such aliased pseudo-periodic signals. Another source of spurious signal
is due to modulation of CO2 content from variations in heart-rate and respiration
leading to slow, non-cyclic BOLD modulations. It has been found that a
respiration response function (Birn, Smith et al. 2008) and cardiac response function
(Chang, Cunningham et al. 2009) can be used to form nuisance
regressors to remove these sources of noise. Alternatively, rapid scanning methods
using Simultaneous Multi-Slice acquisitions (Feinberg and Setsompop 2013) have been recently introduced
that can reduce the TR to a few hundred ms, allowing cardiac-related signals to
be faithfully sampled and removed by low-pass or notch filtering.
When combined with other
independently collected metrics such as heart-rate variability (Chang, Metzger et al. 2013), galvanic skin response (Buchel, Morris et al. 1998), or EEG (Goldman, Stern et al. 2000), dFC can provide valuable
insights into brain networks by hypothesizing connections between these
measures, brain state variations and fluctuations in dFC within and between
different networks. When thus confirmed, it has also been observed that dFC can
demonstrated differences between healthy
and diseased populations, potentially allowing resting state fMRI to be used as
a biomarker.
Acknowledgements
The author is indebted to Catherine E. Chang for helpful discussions, and to the NIH NIBIB for financial support through P41 EB015891.References
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