Challenges and demand for modeling disorders of consciousness following traumatic brain injury

Abstract

Following severe traumatic brain injury (TBI), many patients experience coma - an unresponsive state lacking wakefulness or awareness. Coma rarely lasts more than two weeks, and emergence involves passing through a state of wakefulness without awareness of self or environment. Patients that linger in these Disorders of Consciousness (DoC) undergo clinical assessments of awareness for diagnosis into Unresponsive Wakefulness Syndrome (no awareness, also called vegetative state) or Minimally Conscious State (periodic increases in awareness). These diagnoses are notoriously inaccurate, offering little prognostic value. Recovery of awareness is unpredictable, returning within weeks, years, or never. This leaves patients' families with difficult decisions and little information on which to base them. Clinical studies have made significant advancements, but remain encumbered by high variability, limited data output, and a lack of necessary controls. Herein we discuss the clear and present need to establish a preclinical model of TBI-induced DoC, the significant challenges involved, and how such a model can be applied to support DoC research.

Keywords: Coma; Disorders of consciousness; Large animal models; Minimally conscious state; Porcine; Rotational acceleration; Swine; Traumatic brain injury; Unresponsive wakefulness syndrome; Vegetative state.

Figure 1.. Rotational acceleration injury in swine.

Head rotational acceleration in different anatomical planes is facilitated by customized bite plates. Rotation in the sagittal or axial plane preferentially deforms the brainstem, while coronal rotation does not. Figure adapted with permission from Cullen et al., 2016.

Figure 2.. Neuropathology in the porcine brain following rapid head rotational acceleration in the sagittal plane.

Coronal brain sections were stained with a primary antibody for amyloid precursor protein (APP) and secondary antibody conjugated to 3,3′-Diaminobenzidine (DAB), with a hematoxylin counterstain. (A) APP accumulation – the hallmark pathological feature of diffuse axonal injury (DAI) – was evident throughout the brain in damaged axons as well as in neuronal cell bodies, generally an indication of stressed neurons. (B) Pontine lesions highlighted via APP accumulation. (C) High magnification in the pons providing examples of APP buildup in the somata of stressed cells (white arrows) and in axonal retraction bulbs (black arrows) indicative of axonal pathology.

Figure 3.. Sagittal cross-sections of a porcine brain with simplified depictions of circuits associated with wakefulness and awareness.

(A) Aspects of the Ascending Reticular Activating System (ARAS) and its cortical connections. The parabrachial nucleus of the pons (P) sends projections (thick white arrows) to the thalamus (T), basal forebrain (BF), and hypothalamus (HT). BF synchronizes activity in T via high frequency GABAergic signaling (pink arrow); BF projects mixed excitatory and modulatory afferents throughout cortex (yellow arrows). T projects excitatory afferents throughout cortex (slim white arrows). (B) Aspects of the mesocircuit model. Striatum (St) projects inhibitory afferents (flat red arrows) to Globus Pallidus (GP), which projects inhibitory afferents to Thalamus (T). Excitatory afferents (white arrows) project from T throughout cortex, and also from cortex back to St. Excitation of St inhibits GP, thereby disinhibiting T. Frames A and B are of the same scale, with a smaller brain section in B due to greater distance from midline. Mapped magnetic resonance images of swine brain are courtesy of 3D Slicer (http://www.slicer.org) (Fedorov et al., 2012; Saikali et al., 2010).

Figure 4.

Summary of Major Challenges and Possible Solutions