Disruption of the ascending arousal network in acute traumatic disorders of consciousness

Abstract

Objective: To determine whether ascending arousal network (AAn) connectivity is reduced in patients presenting with traumatic coma.

Methods: We performed high-angular-resolution diffusion imaging in 16 patients with acute severe traumatic brain injury who were comatose on admission and in 16 matched controls. We used probabilistic tractography to measure the connectivity probability (CP) of AAn axonal pathways linking the brainstem tegmentum to the hypothalamus, thalamus, and basal forebrain. To assess the spatial specificity of CP differences between patients and controls, we also measured CP within 4 subcortical pathways outside the AAn.

Results: Compared to controls, patients showed a reduction in AAn pathways connecting the brainstem tegmentum to a region of interest encompassing the hypothalamus, thalamus, and basal forebrain. When each pathway was examined individually, brainstem-hypothalamus and brainstem-thalamus CPs, but not brainstem-forebrain CP, were significantly reduced in patients. Only 1 subcortical pathway outside the AAn showed reduced CP in patients.

Conclusions: We provide initial evidence for the reduced integrity of axonal pathways linking the brainstem tegmentum to the hypothalamus and thalamus in patients presenting with traumatic coma. Our findings support current conceptual models of coma as being caused by subcortical AAn injury. AAn connectivity mapping provides an opportunity to advance the study of human coma and consciousness.

Figure 1. AAn connectivity in patients and controls

(A) Sagittal (top row) and axial (bottom row) images of group median normalized tract numbers for pathways connecting the brainstem tegmentum (Teg) and a combined target including the hypothalamus (Hy), thalamus (Th), and basal forebrain (BF). In the third column, white voxels indicate regions with fewer normalized tracts in patients vs controls using a corrected p_c < 0.05 (after Benjamini-Hochberg false discovery rate adjustment). Red/yellow correspond to z scores of all voxels with fewer normalized tracts using an uncorrected p < 0.05. (B) Patients show reduced connectivity probability (CP) relative to controls in 2 of 3 ascending arousal network (AAn) pathways (tegmentum-hypothalamus, tegmentum-thalamus) and 1 of 4 non-AAn pathways (auditory). Points represent individual participant CP values; boxes show median and interquartile ranges; and whiskers extend from maximum to minimum values. Cereb = cerebellar pathway; Extrapyr = extrapyramidal pathway; P = pons. *Holm family-wise error adjusted p_c < 0.05, **p_c < 0.005.

Figure 2. Peak areas of tract disruption within the ascending arousal network

Blue shows 3D reconstruction of median normalized tracts in controls connecting the brainstem tegmentum seed to a combined target including the hypothalamus (Hy), thalamus (Th), and basal forebrain (BF) (binarized surface, median normalized tract count > 0.0005). Red shows voxels with significantly fewer normalized tracts in patients relative to controls (Benjamini-Hochberg false discovery rate–adjusted p_c < 0.05). DoC = disorders of consciousness; P = pons.