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Disconnection of the ascending arousal system in traumatic coma.

ABSTRACT: Traumatic coma is associated with disruption of axonal pathways throughout the brain, but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness-arousal and awareness-in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. High angular resolution diffusion imaging tractography guided tissue sampling in the neuropathologic analysis. High angular resolution diffusion imaging tractography demonstrated complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic intralaminar and reticular nuclei. In contrast, hemispheric arousal pathways connecting the thalamus and basal forebrain to the cerebral cortex were only partially disrupted, as were the cortical "awareness pathways." Neuropathologic examination, which used ?-amyloid precursor protein and fractin immunomarkers, revealed axonal injury in the white matter of the brainstem and cerebral hemispheres that corresponded to sites of high angular resolution diffusion imaging tract disruption. Axonal injury was also present within the gray matter of the hypothalamus, thalamus, basal forebrain, and cerebral cortex. We propose that traumatic coma may be a subcortical disconnection syndrome related to the disconnection of specific brainstem arousal nuclei from the thalamus and basal forebrain.

SUBMITTER: Edlow BL

PROVIDER: S-EPMC3761353 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Disconnection of the ascending arousal system in traumatic coma.

Edlow Brian L BL Haynes Robin L RL Takahashi Emi E Klein Joshua P JP Cummings Peter P Benner Thomas T Greer David M DM Greenberg Steven M SM Wu Ona O Kinney Hannah C HC Folkerth Rebecca D RD

Journal of neuropathology and experimental neurology 20130601 6

Traumatic coma is associated with disruption of axonal pathways throughout the brain, but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness-arousal and awareness-in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. High angular resolution diffusion imaging tractography g ...[more]

PMID: 23656993

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Project description:BackgroundIt is not currently possible to predict which patients will develop chronic disorders of consciousness (DoC) after severe traumatic brain injury (TBI). Although the ascending arousal network (AAN) supports human consciousness, it is unknown which AAN pathways must be preserved for patients to recover consciousness.MethodsSixteen patients with acute traumatic coma and 16 matched healthy controls were scanned with high angular resolution diffusion imaging (HARDI). All patients recovered consciousness (Recovery Cohort). Nine were scanned longitudinally: first in the ICU (Acute), then at ≥5 months post-injury (Follow-up). Six separate patients with post-traumatic DoC were scanned ≥5 months post-injury (Chronic DoC Cohort). For each AAN pathway, we computed the median relative change in Acute-to-Follow-up Connectivity Probability (CP) in the Recovery Cohort. We then used Wilcoxon tests with Bonferroni correction to compare CP in each AAN pathway in the Recovery Cohort at Follow-up versus the Chronic DoC Cohort. In an exploratory analysis, we used principal component analysis (PCA) to determine whether linear combinations of AAN CP values could separate the Chronic DoC Cohort from the Recovery Cohort and the healthy controls.ResultsIn the Recovery Cohort, the largest relative AAN CP changes were in the brainstem-to-thalamus (median [IQR] = 0.7 [0.09, 0.9]) and forebrain-to-occipital lobe (-0.8 [-0.9, -0.8]) pathways. The AAN connections that differed in the cross-sectional analysis between the Recovery Cohort at Follow-up and the Chronic DoC Cohort included brainstem-to-hypothalamus (W = 53, PBonf = 0.02), brainstem-to-temporal lobe (W = 52, PBonf = 0.04), and thalamus-to-temporal lobe (W = 54, PBonf = 0.009). Plotting the first two principal components of AAN connectivity resulted in a linear separation of Chronic DoC patients from other study groups.ConclusionsWe provide evidence for a longitudinal increase in brainstem-thalamic connectivity during recovery of consciousness after traumatic coma. Cross-sectional analyses revealed that brainstem-hypothalamus, brainstem-temporal lobe, and thalamus-temporal lobe connectivity differed between patients who recovered consciousness and those with a chronic DoC. These observations provide the basis for further investigation into AAN connectivity as a biomarker for recovery of consciousness after traumatic coma.

Project description:Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORXA) treatment will enhance arousal from coma and decrease the production of proinflammatory cytokines resulting in improved functional outcome after resuscitation. We used a highly validated CA rat model to determine the effects of intranasal ORXA treatment 30-minute post resuscitation. At 4hrs post-CA, the mRNA levels of proinflammatory markers (IL1?, iNOS, TNF-?, GFAP, CD11b) and orexin receptors (ORX1R and ORX2R) were examined in different brain regions. CA dramatically increased proinflammatory markers in all brain regions particularly in the prefrontal cortex, hippocampus and hypothalamus. Post-CA intranasal ORXA treatment significantly ameliorated the CA-induced neuroinflammatory markers in the hypothalamus. ORXA administration increased production of orexin receptors (ORX1R and ORX2R) particularly in hypothalamus. In addition, ORXA also resulted in early arousal as measured by quantitative electroencephalogram (EEG) markers, and recovery of the associated behavioral neurologic deficit scale score (NDS). Our results indicate that intranasal delivery of ORXA post-CA has an anti-inflammatory effect and accelerates cortical EEG and behavioral recovery. Beneficial outcomes from intranasal ORXA treatment lay the groundwork for therapeutic clinical approach to treating post-CA coma.

Project description:Traumatic brain injury affects brain connectivity by producing traumatic axonal injury. This disrupts the function of large-scale networks that support cognition. The best way to describe this relationship is unclear, but one elegant approach is to view networks as graphs. Brain regions become nodes in the graph, and white matter tracts the connections. The overall effect of an injury can then be estimated by calculating graph metrics of network structure and function. Here we test which graph metrics best predict the presence of traumatic axonal injury, as well as which are most highly associated with cognitive impairment. A comprehensive range of graph metrics was calculated from structural connectivity measures for 52 patients with traumatic brain injury, 21 of whom had microbleed evidence of traumatic axonal injury, and 25 age-matched controls. White matter connections between 165 grey matter brain regions were defined using tractography, and structural connectivity matrices calculated from skeletonized diffusion tensor imaging data. This technique estimates injury at the centre of tract, but is insensitive to damage at tract edges. Graph metrics were calculated from the resulting connectivity matrices and machine-learning techniques used to select the metrics that best predicted the presence of traumatic brain injury. In addition, we used regularization and variable selection via the elastic net to predict patient behaviour on tests of information processing speed, executive function and associative memory. Support vector machines trained with graph metrics of white matter connectivity matrices from the microbleed group were able to identify patients with a history of traumatic brain injury with 93.4% accuracy, a result robust to different ways of sampling the data. Graph metrics were significantly associated with cognitive performance: information processing speed (R(2) = 0.64), executive function (R(2) = 0.56) and associative memory (R(2) = 0.25). These results were then replicated in a separate group of patients without microbleeds. The most influential graph metrics were betweenness centrality and eigenvector centrality, which provide measures of the extent to which a given brain region connects other regions in the network. Reductions in betweenness centrality and eigenvector centrality were particularly evident within hub regions including the cingulate cortex and caudate. Our results demonstrate that betweenness centrality and eigenvector centrality are reduced within network hubs, due to the impact of traumatic axonal injury on network connections. The dominance of betweenness centrality and eigenvector centrality suggests that cognitive impairment after traumatic brain injury results from the disconnection of network hubs by traumatic axonal injury.

Dataset Information

Disconnection of the ascending arousal system in traumatic coma.

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Disconnection of the ascending arousal system in traumatic coma.

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