Brain Network Segregation and Integration is Altered in Soldiers with Post-traumatic Stress Disorder and Mild Traumatic Brain Injury
D Rangaprakash1, Gopikrishna Deshpande1,2,3, Jeffrey S Katz1,2,3, Thomas S Denney1,2,3, and Michael N Dretsch4,5

1AU MRI Research Center, Department of Electrical and Computer Engineering, Auburn University, Auburn, AL, United States, 2Department of Psychology, Auburn University, Auburn, AL, United States, 3Alabama Advanced Imaging Consortium, Auburn University and University of Alabama Birmingham, Birmingham, AL, United States, 4U.S. Army Aeromedical Research Laboratory, Fort Rucker, AL, United States, 5Human Dimension Division, HQ TRADOC, Fort Eustis, VA, United States

Synopsis

Brain functioning relies on various segregated/specialized neural regions functioning as an integrated-interconnected network. Psychiatric disorders are associated with altered functioning of these brain networks. Using resting-state fMRI, we assessed strength and variability of directional connectivity in brain-networks obtained from U.S. Army Soldiers with PTSD and mTBI. Employing graph-theoretic techniques in a novel framework, we show that PTSD and mTBI are associated with frontal disinhibition of key subcortical and visual regions, which leads to overdrive in parietal association areas, causing increased symptoms. This work is significant given that a mechanistic understanding of underlying network functioning in comorbid PTSD/mTBI has been elusive.

Introduction

The human brain is a highly interconnected system. Although connectivity modeling is popular, it can only characterize pair-wise relationships between brain regions. Complex network modeling1, using graph-theoretic measures, can inform us on how the ensemble of connections behave. Among such network properties, functional segregation informs about dense-connectedness within separate subnetworks, while functional integration captures the ease of interaction between subregions1. It has been shown that segregation and integration are altered in psychiatric disorders2,3. In this work, we study network-level alterations in the brains of Soldiers with posttraumatic stress disorder (PTSD) and post-concussion syndrome (PCS, a chronic outcome of mild traumatic brain injury [mTBI]).

Effective connectivity (EC) refers to directional influences among brain regions4. We constructed brain networks using strength (static-EC [SEC]) and temporal variability (dynamic-EC [DEC]) of directional connectivity. It has been shown that lower temporal variability of connectivity is associated with both neurologic and psychiatric conditions5, often presenting as a lack of cognitive flexibility. We hypothesized that PTSD and mTBI are characterized by altered strength and lower variability of segregation and integration in directional brain networks.

Methods

U.S. Army Soldiers (N=87) were recruited for the study, which included 17 with PTSD, 42 with both PTSD and PCS (PCS+PTSD) and 28 matched combat controls. Resting-state fMRI data was obtained in a 3T Verio Siemens scanner with TR=600ms, TE=30ms, voxel size=3×3×5mm3, 1000 volumes and 2 sessions (cerebellum was excluded). Standard pre-processing steps were performed including realignment, normalization to MNI space, detrending and regressing of white-matter, CSF, six-head motion parameters and global-mean signal. Each voxel time series were subjected to blind hemodynamic deconvolution6 to obtain underlying latent neuronal variables. Mean timeseries were obtained from 125 functionally homogenous brain regions (cc200 template7).

SEC was obtained (whole-brain) using Granger causality4. DEC was obtained using time-varying Granger causality evaluated in a Kalman filter framework8. Variance of DEC (vDEC) was taken as the measure of variability in connectivity. Segregation was obtained using transitivity (global measure, one value per subject) and clustering coefficient1 (local measure, one value per region per subject). Integration was obtained using global efficiency (global measure) and edge betweenness1 (local measure, one value per connection). Variability of segregation and integration were obtained by first evaluating the measures at each timepoint from DEC and then taking the variance of those values. Significant group differences (controlled for age, race, education and head-motion) were obtained (p<0.05, FDR-corrected) for both connectivity and network measures. Nodes and connections conforming to our hypothesis (see Fig.1) were obtained.

Results and Discussion

With global measures, we found significantly reduced strength and variability of segregation and integration in PTSD and PCS+PTSD compared to Controls, but no significant difference between the PTSD and PCS+PTSD groups, indicating that PTSD symptomatology might contribute to global brain alterations whereas the effect of mTBI is localized. Further granularity was obtained with local measures. Altered segregation was mainly observed in frontal and occipital regions (Fig.2). Altered local measures of integration could be found in fronto-visual (Fig.3) and parietal-overdrive (Fig.4) subnetworks. The fronto-visual subnetwork showed frontal under-modulation (lower strength/variance of connectivity) of secondary visual areas and lingual gyrus. This subnetwork was, however, not different between PTSD and PCS+PTSD, indicating that it might not be affected by mTBI (since one difference between these groups is history of significant prior mTBI(s) in the PCS group). The parietal-overdrive subnetwork showed that the visual areas affected in fronto-visual subnetwork drove two key parietal regions (precuneus, temporo-parietal-junction [TPJ]). Additionally there was fronto-subcortical disinhibition resulting in over-drive (increased strength but lower variance of connectivity) of key subcortical areas (anterior-insula, amygdala, hippocampus), which then resulted in over-drive of the same key parietal regions. Interestingly, this fronto-subcortical-parietal subnetwork was significantly altered between all groups, indicating that both PTSD and mTBI affect this subnetwork.

Schematic of the entire network (Fig.5) shows that the left middle-frontal gyrus (MFG) is the likely source of entire network disruption, whose under-modulation causes overdrive in subcortical and visual pathways, culminating in a parietal overdrive. Our results are significant given that regions affected here have been implicated (inconsistently) in earlier studies9, but a clear understanding of underlying mechanisms and network structure has not emerged from them. We show altered network segregation in frontal and visual areas, and altered integration along two pathways (fronto-visual and fronto-subcortical). The visual subnetwork might have a supporting role in traumatic memory retrieval process. The fronto-subcortical subnetwork, altered in both PTSD and mTBI, indicates emotion dysregulation with hyperactivated amygdala and hippocampus, which underpins compromised control over traumatic memories (evident from parietal overdrive). This characterization fits well with behavioral manifestations of co-occurring PTSD and mTBI.

Acknowledgements

The authors acknowledge financial support for this work from the U.S. Army Medical Research and Materials Command (MRMC) (Grant # 00007218). The views, opinions, and/or findings contained in this article are those of the authors and should not be interpreted as representing the official views or policies, either expressed or implied, of the U.S. Army or the Department of Defense (DoD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank the personnel at the TBI clinic and behavioral health clinic, Fort Benning, GA, USA and the US Army Aeromedical Research Laboratory, Fort Rucker, AL, USA, and most of all, the soldiers who participated in the study.

References

[1] Rubinov M. et al., Neuroimage,52(3):1059-69,2010

[2] Rocca et al., Brain Structure and Function, 2014 Sep (in press)

[3] Yu et al., Schizophrenia Research,150(2-3):450-8,2013

[4] Deshpande G. et al., IEEE Transactions on Biomedical Engineering,57(6):1446-56,2010

[5] Jia H. et al., Brain Connectivity,4(9):741-59,2014

[6] Wu et al., Medical Image Analysis,17(3):365-74,2013

[7] Craddock R.C. et al., Human Brain Mapping,33,1914–1928,2011

[8] Grant M.M. et al., Human Brain Mapping,35(9):4815-4826,2014

[9] Simmons A.N. et al., Neuropharmacology,62(2):598-606,2012

Figures

Fig.1.Illustration of our hypothesis showing reducing variability of segregation/integration, and either increasing or decreasing segregation/integration as we move from Control to PTSD to PCS+PTSD. Font sizes are symbolic of the increasing/decreasing trend. Some affected nodes/paths would have decreasing segregation/integration in disorders compared to controls while others would have the opposite.

Fig.2. Nodes which had altered functional segregation and lower variation of segregation over time in disease compared to controls. Red nodes were statistically significant only for control vs PTSD and Control vs PCS+PTSD comparisons (but not PTSD vs PCS+PTSD comparison). Yellow nodes were significantly different between all three groups.

Fig.3. The fronto-visual sub-network which had lower functional integration and lower temporal variation of integration, which was significant for control vs PTSD and control vs PCS+PTSD comparisons (but not PTSD vs PCS+PTSD comparison). This sub-network likely represents reduced frontal inhibition of visual memory processing and retrieval.

Fig.4.Parietal overdrive sub-network which had altered integration and lower temporal variation of integration. Yellow paths were significantly different for all group-wise comparisons. Green paths were altered except for the PTSD vs PCS+PTSD comparison. This sub-network showed parietal-overdrive caused by subcortical and visual network disruptions, which were in-turn caused by Left-MFG

Fig.5.Schematic of entire network: Yellow nodes/paths were significantly altered for all three comparisons. Green paths (and red nodes) were altered except for PTSD vs PCS+PTSD comparison. Thick lines correspond to inter-lobe connections. Disrupted Left-MFG causes under-modulation of subcortical emotion-memory regions and visual memory-retrieval regions, culminating in parietal-overdrive causing heightened symptoms.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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