The role of biomarkers and MEG-based imaging markers in the diagnosis of post-traumatic stress disorder and blast-induced mild traumatic brain injury

Abstract

SummaryBackground: Pervasive use of improvised explosive devices (IEDs), rocket-propelled grenades, and land mines in the recent conflicts in Iraq and Afghanistan has brought traumatic brain injury (TBI) and its impact on health outcomes into public awareness. Blast injuries have been deemed signature wounds of these wars. War-related TBI is not new, having become prevalent during WWI and remaining medically relevant in WWII and beyond. Medicine's past attempts to accurately diagnose and disentangle the pathophysiology of war-related TBI parallels current lines of inquiry and highlights limitations in methodology and attribution of symptom etiology, be it organic, psychological, or behavioral. New approaches and biomarkers are needed. Preclinical: Serological biomarkers and biomarkers of injury obtained with imaging techniques represent cornerstones in the translation between experimental data and clinical observations. Experimental models for blast related TBI and PTSD can generate critical data on injury threshold, for example for white matter injury from acceleration. Carefully verified and validated models can be evaluated with gene expression arrays and proteomics to identify new candidates for serological biomarkers. Such models can also be analyzed with diffusion MRI and microscopy in order to identify criteria for detection of diffuse white matter injuries, such as DAI (diffuse axonal injury). The experimental models can also be analyzed with focus on injury outcome in brain stem regions, such as locus coeruleus or nucleus raphe magnus that can be involved in response to anxiety changes. * Corresponding author at: UCSD Radiology Imaging Laboratory, San Diego, CA 92121, USA. Tel.: +1 858 534 1254; fax: +1 8585346046. E-mail address: mxhuang@ucsd.edu (M. Huang). Clinical: Mild (and some moderate) TBI can be difficult to diagnose because the injuries are often not detectable on conventional MRI or CT. There is accumulating evidence that injured brain tissues in TBI patients generate abnormal low-frequency magnetic activity (ALFMA, peaked at 1-4 Hz) that can be measured and localized by magnetoencephalography (MEG). MEG imaging detects TBI abnormalities at the rates of 87% for the mild TBI, group (blast-induced plus non-blast causes) and 100% for the moderate group. Among the mild TBI patients, the rates of abnormalities are 96% and 77% for the blast and non-blast TBI groups, respectively. There is emerging evidence based on fMRI and MEG studies showing hyper-activity in the amygdala and hypo-activity in prefrontal cortex in individuals with PTSD. MEG signal may serve as a sensitive imaging marker for mTBI, distinguishable from abnormalities generated in association with PTSD. More work is needed to fully describe physiological mechanisms of post-concussive symptoms.Published by Elsevier Ltd. BackgroundBlast injuries are deemed the signature wounds of the first wars (Afghanistan and Iraq) of the 21st century (Lancet, 2007;Galarneau et al., 2008). According to a recent U.S. Department Veterans Affairs (DVA) ...

Resting-State Magnetoencephalography Reveals Different Patterns of Aberrant Functional Connectivity in Combat-Related Mild Traumatic Brain Injury

“…Unlike the more traditional method of spectral coherence, PLS separates the phase and amplitude components and can be directly interpreted in the framework of neural integration. 80 In the present study, the frequency increments used in the Morlet wavelet transformation were at 0.5 Hz for the low-frequency band (1-7 Hz) and alpha band (8-12 Hz), at 1 Hz for the beta band (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and at 2 Hz for the gamma band . Similar to the Xcorr approach, ROIglobal FC measures were obtained using the PLS approach as the ROI-global connectivity vector with 94 elements.…”

“…Red represents significant increases (correct p < 0.05), whereas blue represents significant decreases in FC. Top two rows: beta band (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Middle two rows: gamma band .…”

“…Extreme forces and their complex propagation characterize blast TBI. 15 Injury from blast can result from secondary, tertiary, and even quaternary effects as well as the primary supersonic pressure wave produced by the blast, all of which have been studied in brain injury models. Secondary effects, caused by the impact of flying objects, such as shrapnel fragments, can generate penetrating injuries.…”

Fear learning alterations after traumatic brain injury and their role in development of posttraumatic stress symptoms

“…The observed elevations in fear responding suggest that TBI may contribute to at least temporary alterations in the neural circuitry underlying fear acquisition and expression. TBI and chronic traumatic encephalopathy have been associated with disruption of cortical and limbic structures that make up the same fear circuit implicated in PTSD (Gavett et al, 2011;Huang, Risling, & Baker, 2016b;Stern et al, 2011). Another potential mechanism through which TBI may increase risk for PTSD is the postconcussive inflammatory cascade (Gyoneva & Ransohoff, 2015;Prasad & Bondy, 2015;Signoretti, Lazzarino, Tavazzi, & Vagnozzi, 2011).…”

Concerns Over Divergent Approaches in the Diagnostics of Posttraumatic Stress Disorder

“…Although there are no established diagnostic biomarkers for PTSD, biological investigations of PTSD have made progress identifying the pathophysiology of PTSD. 41,95,96 Given the biological and clinical complexity of PTSD, it is an accepted reality that no single biomarker of disease will be identified. Rather, investigations will more likely identify or model dynamics of different biomarkers or biosignatures that indicate the presence of clinically significant PTSD symptoms, associate with risk for PTSD after trauma exposure, and predict or identify recovery.…”