An electroencephalography connectomic profile of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a common and debilitating psychiatric condition, especially prevalent among combat veterans. PTSD may occur following the experience of, or exposure to, a life-threatening event, resulting in significantly deleterious behavioral effects and cognitive deficits. In healthy individuals, these cognitive capacities are associated with the functioning of large-scale cortical networks which functional magnetic resonance imaging (fMRI) studies have identified. Studies of PTSD have consistently noted abnormalities in functioning within and between these networks. Despite these pioneering insights into functional network interactions, fMRI remains a tool with limited clinical utility, as it is not directly translatable to the clinical setting of the practitioner. Electroencephalography (EEG), by contrast, is an economical and clinically-accessible neuroimaging modality providing sub-millisecond temporal resolution. However, EEG voltage, measured at the scalp, reflects the summation of many neuronal sources propagating current through tissues of inhomogeneous impedances. Thus, neural sources are attenuated and dispersed upon reaching the scalp, confounding whether scalp EEG channels are detecting unique or common sources. These effects of volume conduction limit the spatial resolution of EEG and contribute to making the determination of the neuronal sources' locations, or the inverse problem, ill-posed. The intractable nature of the inverse problem has stymied the EEG investigation of PTSD using resting-state source-space connectivity analyses for some time. However, considering the advances resting-state fMRI has made in understanding network structure, dynamics, and dysfunction across clinical populations, use of new methods that enable EEG-based resting-state connectivity research by mitigating volume conduction could make substantial inroads in achieving clinical deployability of connectomic research. Recently, a method has been reported for alleviating effects of volume conduction, which can reveal frequency-specific cortical connectivity networks similar to those observed with fMRI. This method correlates power envelopes time series using different frequency bands. Critically, prior to these connectivity analyses, analytical source-space signals are first orthogonalized to each other to remove zero phase lag correlation across regions, which is presumed to largely reflect volume conduction rather than physiological covariation. Using resting-state EEG data, I validated this novel method within a sample of healthy civilians, and then applied it to a large and demographically-homogenous sample of combat veterans with PTSD, compared to combat-exposed healthy veterans. This dissertation describes the first EEG connectomic profile of PTSD in veterans, providing an understanding of connectomic dysfunction in patients with respect to specific neurophysiological properties and the relationship of connectivity abnormalities to measures of cognition. By providing a framework for an empirical measure of the putative underlying neurophysiological processes giving rise to PTSD, existing diagnostics can be complimented, and the efficacy of therapies and treatments can be gauged. A grounding in EEG theories and methods as well as orthogonalization and source localization are first established in separate chapters. This dissertation also describes an automated neurotargeting pipeline which dovetails with native head model resting-state EEG connectivity analyses and transcranial magnetic stimulation (TMS) studies guided by neuronavigation. TMS has emerged as a potent connectomic research and treatment tool to treat depression, frequently comorbid with PTSD. Although a great deal of effort has been exerted in past decades to computationally extract, segment, and analyze the brain for MRI studies, modeling the scalp, hair, skull, and face accurately was not necessary for those types of investigation and therefore methods to accomplish this are underdeveloped. However, the more inchoate field of neuronavigated TMS and the generation of head models for source-space imaging kernels require a well-defined image of the brain and head. The scalp boundary must be precisely delineated, as clumps of hair can masquerade as scalp and significantly contaminate the accuracy of downstream analyses. I present a system that prepares structural MRI scans for the purpose of connectivity analyses, more accurate EEG electrode estimation, and a standardized means of region-of-interest-based neurostimulation target definition. Finally, this dissertation concludes with several lessons learned that will hopefully be of benefit to fellow scientists pursuing this field of study as well as the appendix of implemented algorithms for reference, adaptation, and expansion.

Keywords: Bioengineering.
Advisor: Etkin Amit
Deisseroth Karl 
Glover Gary H.