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Combat-related mild traumatic brain injury (cmTBI) is a leading cause of sustained physical, cognitive, emotional, and behavioral disabilities in Veterans and active-duty military personnel. Accurate diagnosis of cmTBI is challenging since the symptom spectrum is broad and conventional neuroimaging techniques are insensitive to the underlying neuropathology. The present study developed a novel deep-learning neural network method, 3D-MEGNET, and applied it to resting-state magnetoencephalography (rs-MEG) source-magnitude imaging data from 59 symptomatic cmTBI individuals and 42 combat-deployed healthy controls (HCs). Analytic models of individual frequency bands and all bands together were tested. The All-frequency model, which combined delta-theta (1-7 Hz), alpha (8-12 Hz), beta (15-30 Hz), and gamma (30-80 Hz) frequency bands, outperformed models based on individual bands. The optimized 3D-MEGNET method distinguished cmTBI individuals from HCs with excellent sensitivity (99.9 ± 0.38%) and specificity (98.9 ± 1.54%). Receiver-operator-characteristic curve analysis showed that diagnostic accuracy was 0.99. The gamma and delta-theta band models outperformed alpha and beta band models. Among cmTBI individuals, but not controls, hyper delta-theta and gamma-band activity correlated with lower performance on neuropsychological tests, whereas hypo alpha and beta-band activity also correlated with lower neuropsychological test performance. This study provides an integrated framework for condensing large source-imaging variable sets into optimal combinations of regions and frequencies with high diagnostic accuracy and cognitive relevance in cmTBI. The all-frequency model offered more discriminative power than each frequency-band model alone. This approach offers an effective path for optimal characterization of behaviorally relevant neuroimaging features in neurological and psychiatric disorders.

Combat-related mild traumatic brain injury (mTBI) is a leading cause of sustained impairments in military service members and veterans. Recent animal studies show that GABA-ergic parvalbumin-positive interneurons are susceptible to brain injury, with damage causing abnormal increases in spontaneous gamma-band (30-80 Hz) activity. We investigated spontaneous gamma activity in individuals with mTBI using high-resolution resting-state magnetoencephalography source imaging. Participants included 25 symptomatic individuals with chronic combat-related blast mTBI and 35 healthy controls with similar combat experiences. Compared with controls, gamma activity was markedly elevated in mTBI participants throughout frontal, parietal, temporal, and occipital cortices, whereas gamma activity was reduced in ventromedial prefrontal cortex. Across groups, greater gamma activity correlated with poorer performances on tests of executive functioning and visuospatial processing. Many neurocognitive associations, however, were partly driven by the higher incidence of mTBI participants with both higher gamma activity and poorer cognition, suggesting that expansive upregulation of gamma has negative repercussions for cognition particularly in mTBI. This is the first human study to demonstrate abnormal resting-state gamma activity in mTBI. These novel findings suggest the possibility that abnormal gamma activities may be a proxy for GABA-ergic interneuron dysfunction and a promising neuroimaging marker of insidious mild head injuries.

Combat-related mild traumatic brain injury (mTBI) is a leading cause of sustained cognitive impairment in military service members and Veterans. However, the mechanism of persistent cognitive deficits including working memory (WM) dysfunction is not fully understood in mTBI. Few studies of WM deficits in mTBI have taken advantage of the temporal and frequency resolution afforded by electromagnetic measurements. Using magnetoencephalography (MEG) and an N-back WM task, we investigated functional abnormalities in combat-related mTBI. Study participants included 25 symptomatic active-duty service members or Veterans with combat-related mTBI and 20 healthy controls with similar combat experiences. MEG source-magnitude images were obtained for alpha (8-12 Hz), beta (15-30 Hz), gamma (30-90 Hz), and low-frequency (1-7 Hz) bands. Compared with healthy combat controls, mTBI participants showed increased MEG signals across frequency bands in frontal pole (FP), ventromedial prefrontal cortex, orbitofrontal cortex (OFC), and anterior dorsolateral prefrontal cortex (dlPFC), but decreased MEG signals in anterior cingulate cortex. Hyperactivations in FP, OFC, and anterior dlPFC were associated with slower reaction times. MEG activations in lateral FP also negatively correlated with performance on tests of letter sequencing, verbal fluency, and digit symbol coding. The profound hyperactivations from FP suggest that FP is particularly vulnerable to combat-related mTBI.

The present study developed a fast MEG source imaging technique based on Fast Vector-based Spatio-Temporal Analysis using a L1-minimum-norm (Fast-VESTAL) and then used the method to obtain the source amplitude images of resting-state magnetoencephalography (MEG) signals for different frequency bands. The Fast-VESTAL technique consists of two steps. First, L1-minimum-norm MEG source images were obtained for the dominant spatial modes of sensor-waveform covariance matrix. Next, accurate source time-courses with millisecond temporal resolution were obtained using an inverse operator constructed from the spatial source images of Step 1. Using simulations, Fast-VESTALs performance was assessed for its 1) ability to localize multiple correlated sources; 2) ability to faithfully recover source time-courses; 3) robustness to different SNR conditions including SNR with negative dB levels; 4) capability to handle correlated brain noise; and 5) statistical maps of MEG source images. An objective pre-whitening method was also developed and integrated with Fast-VESTAL to remove correlated brain noise. Fast-VESTALs performance was then examined in the analysis of human median-nerve MEG responses. The results demonstrated that this method easily distinguished sources in the entire somatosensory network. Next, Fast-VESTAL was applied to obtain the first whole-head MEG source-amplitude images from resting-state signals in 41 healthy control subjects, for all standard frequency bands. Comparisons between resting-state MEG sources images and known neurophysiology were provided. Additionally, in simulations and cases with MEG human responses, the results obtained from using conventional beamformer technique were compared with those from Fast-VESTAL, which highlighted the beamformers problems of signal leaking and distorted source time-courses.

Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild TBI (mTBI) can be difficult to detect using conventional MRI or CT. Injured brain tissues in mTBI patients generate abnormal slow-waves (1-4 Hz) that can be measured and localized by resting-state magnetoencephalography (MEG). In this study, we develop a voxel-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mTBI on a single-subject basis. A normative database of resting-state MEG source magnitude images (1-4 Hz) from 79 healthy control subjects was established for all brain voxels. The high-resolution MEG source magnitude images were obtained by our recent Fast-VESTAL method. In 84 mTBI patients with persistent post-concussive symptoms (36 from blasts, and 48 from non-blast causes), our method detected abnormalities at the positive detection rates of 84.5%, 86.1%, and 83.3% for the combined (blast-induced plus with non-blast causes), blast, and non-blast mTBI groups, respectively. We found that prefrontal, posterior parietal, inferior temporal, hippocampus, and cerebella areas were particularly vulnerable to head trauma. The result also showed that MEG slow-wave generation in prefrontal areas positively correlated with personality change, trouble concentrating, affective lability, and depression symptoms. Discussion is provided regarding the neuronal mechanisms of MEG slow-wave generation due to deafferentation caused by axonal injury and/or blockages/limitations of cholinergic transmission in TBI. This study provides an effective way for using MEG slow-wave source imaging to localize affected areas and supports MEG as a tool for assisting the diagnosis of mTBI.