Neuroanatomic Connectivity of the Human Ascending Arousal System Critical to Consciousness and Its Disorders

Abstract

The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. HARDI tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, hypothalamus, and basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may impact the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.

Aneurysmal Subarachnoid Hemorrhage Causes Injury of the Ascending Reticular Activating System: Relation to Consciousness

“…8,[37][38][39][40][41] Since the introduction of DTI, several studies have reported on the lower portion of the ARAS in healthy subjects and patients with brain injury. 5,6,12,13 In 2012, Edlow et al 6 reconstructed the ARAS connecting the brain stem to the thalamus, hypothalamus, and the basal forebrain in healthy subjects. In 2013, Yeo et al 5 reported a method for reconstruction of the lower portion of the ARAS from the pontine reticular formation to the thalamus in healthy subjects.…”

“…[9][10][11] By contrast, diffusion tensor tractography, which is derived from diffusion tensor imaging, has enabled 3D reconstruction and estima-tion of the ARAS in the healthy human brain. 5,6 In addition, a few studies have reported injury of the ARAS in patients with traumatic brain injury and hypoxic-ischemic brain injury by using diffusion tensor tractography. 12,13 However, no study on injury of the ARAS in patients with SAH has been reported, to our knowledge.…”

“…4 Human consciousness consists of arousal and awareness, which is accomplished by action of the pathway known as the ascending reticular activating system (ARAS). [5][6][7] The ARAS is a complex neural network connecting from the reticular formation of the brain stem to the cerebral cortex via excitatory relays in the intralaminar nuclei of the thalamus; therefore, accurate assessment of the ARAS plays an important role in the diagnosis and management of patients with impaired consciousness. [5][6][7][8] Successful evaluation of the ARAS has been limited despite many attempts by using conventional MR imaging, functional neuroimaging, electrophysiologic assessments, MR spectroscopy, and positron-emission tomography.…”

“…[5][6][7] The ARAS is a complex neural network connecting from the reticular formation of the brain stem to the cerebral cortex via excitatory relays in the intralaminar nuclei of the thalamus; therefore, accurate assessment of the ARAS plays an important role in the diagnosis and management of patients with impaired consciousness. [5][6][7][8] Successful evaluation of the ARAS has been limited despite many attempts by using conventional MR imaging, functional neuroimaging, electrophysiologic assessments, MR spectroscopy, and positron-emission tomography. [9][10][11] By contrast, diffusion tensor tractography, which is derived from diffusion tensor imaging, has enabled 3D reconstruction and estima-tion of the ARAS in the healthy human brain.…”

Frontal Networks Associated With Command Following After Hemorrhagic Stroke

“…We first assessed whether structural injury to the pons, midbrain, and thalamus accounted for unresponsiveness in our population, as these structures are known to be critical for arousal. 27,28 Second, we used resting-state fMRI to identify from a screen of multiple standard networks those that were disrupted in unresponsive patients. We then directly interrogated the DMN and its relationship to TPN in our study group.…”