Neuroimaging Biomarkers of New-Onset Psychiatric Disorders Following Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) has traditionally been associated with cognitive and behavioral changes during both the acute and chronic phases of injury. Because of its noninvasive nature, neuroimaging has the potential to provide unique information on underlying macroscopic and microscopic biological mechanisms that may serve as causative agents for these neuropsychiatric sequelae. This broad scoping review identifies at least 4 common macroscopic pathways that exist between TBI and new-onset psychiatric disorders, as well as several examples of how neuroimaging is currently being utilized in clinical research. The review then critically examines the strengths and limitations of neuroimaging for elucidating TBI-related microscopic pathology, such as microstructural changes, neuroinflammation, proteinopathies, blood-brain barrier damage, and disruptions in cellular signaling. A summary is then provided for how neuroimaging is currently being used to investigate TBI-related pathology in new-onset neurocognitive disorders, depression, and posttraumatic stress disorder. Identified gaps in the literature include a lack of prospective studies to definitively associate imaging findings with the development of new-onset psychiatric disorders, as well as antemortem imaging studies subsequently confirmed with postmortem correlates in the same study cohort. Although the spatial resolution and specificity of imaging biomarkers has greatly improved over the last 2 decades, we conclude that neuroimaging biomarkers do not yet exist for the definitive in vivo diagnosis of cellular pathology. This represents a necessary next step for further elucidating causal relationships between TBI and new-onset psychiatric disorders.

Keywords: Depression; Mindboggle; Neurocognitive disorders; Neuroimaging; Posttraumatic stress disorder; Traumatic brain injury.

Figure 1:. Macroscopic depiction of circuits involved in traumatic brain injury (TBI), depression and post-traumatic stress disorder (PTSD).

Literature searches were conducted for highly cited articles that explicitly discussed regions implicated in TBI pathology (11,24,26), depression without co-morbid TBI (Dep Only; 27,28,29) and PTSD without co-morbid TBI (PTSD Only; 30,31,32). Study-specific brain region labels from each review article were independently extracted by at least two individuals (see acknowledgment section), entered into a spreadsheet and sorted by major region type. Non-specific or overly broad labels (e.g., frontal lobe, white matter) and laterality (i.e., right vs. left) were not extracted. The variable neuroanatomical nomenclature utilized in each review article was “translated” into common neuroanatomical labels using the Mindboggle (boundaries preserved in Figure) and Johns Hopkins White Matter Atlas through author consensus (see Supplemental Table 1 for consensus extracted labels and for consensus transformation to atlas labels). The temporal pole label (displayed in ventral view) had to be hand-drawn using a subset of other labels (the most anterior aspects of the superior, middle and inferior gyri from Mindboggle). Each label from each atlas could receive a maximum of one vote from each review article. Voting results (cool colors: dark blue = vote from 1 article; light blue = votes from 2 articles; cyan = votes from 3 articles) amongst the three individual TBI review articles are presented in Panel A, for Dep articles in Panel B, and for PTSD articles in Panel C In subsequent panels, cool colors represent TBI Only articles, whereas the intersection between TBI and Dep (Panel D), as well as TBI and PTSD (Panel E), are represented using warm colors (red = 2–3 total articles; burnt orange = 4–5 articles; mustard yellow = 6 articles). Unique areas for new-onset psychiatric disorders are colored in green (lawn green in Panel E only for the basal forebrain). A high degree of intersection between TBI and individual psychiatric disorders without TBI co-morbidity was observed in mesocortical and mesolimbic circuity, including the diencephalon and brainstem. White matter regions were more specifically implicated in TBI pathology. Although pronounced overlap existed between prefrontal, basal ganglia and brain stem circuitry, neurocognitive disorders were not explicitly included in the figure due to variable reliance on different circuitry for each cognitive domain.

Figure 2:. Microscopic injury cascade following traumatic brain injury (TBI) and relevance to selected imaging modalities.

The center inset of Panel A (adapted from 16) depicts the prototypical and complex pathophysiologies of TBI (red-colored font) that occur within the cellular milieu during both acute and chronic injury phases. Each injury cascade is associated with a numbered circle/red font that roughly corresponds to the temporal progression of injury from initial impact through cellular death. Additional abbreviations for cellular physiology and pathology include adenosine triphosphate (ATP), blood-brain barrier (BBB), calcium ion (C^a2+), damage associated molecular patterns (DAMP), sodium ion (N^a+), pattern recognition receptors (PRR), red blood cells (RBC), reactive nitrogen species (RNS), and reactive oxygen species (ROS). The outlying graphics of Panel A depict selected imaging modalities including structural magnetic resonance imaging (sMRI), diffusion imaging (dMRI), blood oxygen level dependent (BOLD) techniques including functional near infrared spectroscopy (fNIRS), magnetic resonance angiography (MRA) and cerebral blood flow (CBF), positron emission tomography (PET; adapted from 73), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS). The putative cellular injury cascades that each imaging modality is capable of measuring is listed directly under each imaging modality, along with a brief description of each modality in Panel B.