Xiaowei Zhuang1, Virendra Mishra1, Zhengshi Yang1, Karthik Sreenivasan1, Sarah J Banks2, Lauren Bennett3, Bernick Charles1, and Dietmar Cordes1,4
1Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, United States, 2Department of Neuroscience, University of California, San Diego, La Jolla, CA, United States, 3Neuroscience Institute, Hoag Hospital, Irvine, CA, United States, 4University of Colorado, Boulder, Boulder, CO, United States
Synopsis
Both static and dynamic functional connectivity differences between
cognitively impaired and non-impaired active professional fighters were first explored.
Significant decreased static functional connections and trend-level increased
dynamic functional connections among regions involved in memory and executive
functions were found in cognitively impaired fighters, which adds brain
functional reorganizations to previously observed structural damages in brain
deficits related to repetitive head trauma. We further demonstrated that both
static and dynamic functional connectivity were sensitive to cognitive declines
in this fighter’s cohort, as both static and dynamic functional features can
reliably predict cognitive impairment status in fighters.
Introduction.
Repetitive exposures to head trauma is a risk factor for multiple
neuro-degenerative disorders1,2. Active professional fighters experiencing
repetitive head trauma in sanctioned competitions and daily trainings, are at
risks of potential brain damages. Previous neuroimaging studies have identified
abnormalities in brain regional volumes, cortical thickness and white-matter connections
in active professional fighters, which correlate with their cognitive task
performances3–5. In this study, in the same cohort of
active professional fighters, we investigated brain functional changes using
both static and dynamic functional connectivity analysis, which would provide
supplementary functional knowledge to brain deficits caused by repetitive head
trauma.Methods.
Subjects. 68 cognitively impaired fighters and 65 cognitively
non-impaired fighters from the Professional Fighters Brain Health Study6 were included in the analysis. Fighters’
cognitive impairment status was predefined using neuropsychological tests. Processing
speed (PSS) and psychomotor speed (PSY) were used to measure the cognitive
impairment status and subject full demographics are listed in Table. 1. Resting-state fMRI data were collected for
all subjects on a 3T Siemens scanner (TR/TE/resolution=2.8s/28ms/2x2x4mm3, 30
slices, axial acquisition, 137 time frames). A T1-weighted structural image was
also acquired with a standard MPRAGE sequence. Static and dynamic functional connectivity (FC) matrix. Each T1
image was input to the FreeSurfer pipeline7 and a subject-specific anatomical
segmentation was generated with 66 cortical regions of interest (ROIs) based on
Desikan-Killiany8 atlas and 12 sub-cortical ROIs. This
subject-specific parcellation was co-registered to fMRI native space using 12
parameters affine transformation. After standard preprocessing steps, average resting-state
fMRI time series were obtained for 78 ROIs in each fighter. Static FC matrix
was then computed using the Pearson’s correlation between average time series of
every ROI-pair. Dynamic FC matrix was estimated using a sliding-window
approach, with an optimum window-size computed at every time point9. Standard deviation over all windowed
functional connectivity matrices was used to quantify the temporal dynamics for
every ROI pair. Network-based statistical
analysis. Network based statistics10 was used to compare static and dynamic FC matrix
between cognitively impaired and non-impaired fighters, with age, gender, years
of education and fMRI root-mean-square motion as covariates. A threshold of
t=2.92 (puncorr=0.002) was applied to identify a set of
supra-threshold connections which showed significant differences (pcorr<0.05)
in network-based statistics. Classification.
Both static and dynamic FC matrix were used as features to predict
cognitive impairment status in fighters. An automated feature selection step
and a non-linear classifier were included in the classification framework. A
ten-fold cross validation was used to determine the classification accuracy and
the ten-fold division was repeated 100 times to avoid division bias.Results.
Static FC. 18 functional connections are significantly
stronger (pcorr<0.05) in cognitively non-impaired fighters, as
compared to cognitively impaired fighters (Fig. 1(A)). These paths comprise
both cortical and subcortical brain regions, including inferior frontal gyrus,
middle frontal gyrus, hippocampus, para-hippocampal gyrus, entorhinal cortex,
amygdala, precentral gyrus, temporal pole, superior temporal gyrus, banks of
superior temporal sulcus, and inferior parietal lobe. Most of these regions
form connections essential to executive and memory functions. Medium effect
sizes (Cohen’s d from 0.48 to 0.62) are observed for all connections (Table 2(A)).
Dynamic FC. No statistical
significant difference (pcorr<0.05) was observed between
cognitively non-impaired and impaired fighters in the network-based statistics
analysis. Only 6 paths showed a higher dynamic FC values in cognitively
impaired fighters at the trend level with pcorr=0.09 (Fig. 1(B)).
These connections depict higher temporal variations in impaired fighters corroborate
with regions showing lower static functional connections, and all 6 paths had a
medium effect sizes (Table 2 (B)). Classification.
Static FC alone can reliably predict cognitive status in fighters with an
accuracy 77.54% (Table 4). Adding dynamic FC to the feature set further
improves the prediction accuracy by 8% and reaches 84.11%. Discussion.
Our study identified a set of significant decreased static functional
connections and trend-level increased dynamic functional connections among
regions involved in memory and executive functions in cognitively impaired
fighters, as compared to cognitively nonimpaired fighters, which adds supplementary
knowledge of functional brain reorganizations to previous structural findings related
to repetitive head trauma. We further demonstrated that both static and dynamic
FCs are sensitive to cognitive declines in this fighter’s cohort, as both
static and dynamic FC features can reliably predict cognitive impairment status
in fighters.Acknowledgements
The study is
supported by the National Institutes of Health (grant number P20GM109025), a
private grant from the Peter and Angela Dal Pezzo funds, a private grant
from Lynn and William Weidner, a private grant from Stacie and Chuck Matthewson and the young scientist award at Cleveland
Clinic Lou Ruvo Center for Brain Health (Keep Memory Alive Foundation). The
PFBHS is supported by Belator, UFC, the August Rapone Family Foundation, Top
Rank, and Haymon Boxing.References
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