Funded Grants

Brainstem modulation of human consciousness

Cognition is predicated on consciousness. For a comatose patient to recover cognition, the brainstem must first generate ascending arousal signals to reactivate the cerebral cortex and establish conscious awareness. When brainstem arousal nuclei or their axonal connections are disrupted, the cortex is quiescent and cognition cannot occur, even if the cortex itself is uninjured. Cortical regions critical to cognition remain dormant until brainstem arousal inputs are restored.

Despite the essential role of the brainstem in consciousness and cognition, the neuroanatomic connections that link the brainstem to the cortex have not been mapped in the human brain. Current models of human brainstem connectivity are almost entirely based upon extrapolations from animal studies, which are inherently limited due to evolutionary differences in human neuroanatomy. Moreover, the specific brainstem neurons and axonal connections that are necessary for recovery of cognitive function in patients with brainstem injury are unknown.

For over one million civilians worldwide who experience a coma each year due to traumatic brain injury, and for thousands of military personnel who have experienced a traumatic coma since 2001, this gap in knowledge significantly impairs clinical care. Clinicians are unable to detect preserved brainstem connections capable of supporting recovery, which leads to inaccurate prognostication and creates uncertainty for families facing decisions about goals of care. Furthermore, with recent studies showing that pharmacologic and electrophysiologic therapies can reactivate the cortex in selected patients, a brainstem connectivity map is needed to identify patients who may benefit from stimulant therapy.

My laboratory is creating personalized connectivity maps of the brainstem arousal network in civilians and military personnel with traumatic coma to elucidate the mechanisms by which the brainstem modulates human consciousness and to test the efficacy of stimulant therapies that promote recovery of consciousness. We have developed ultra-high resolution magnetic resonance imaging methods to map brainstem connectivity in ex vivo human brain specimens, and we have translated these methods to the intensive care unit for brainstem connectivity mapping in patients with acute traumatic coma. We now aim to develop a quantitative, network-based model of brainstem modulation of consciousness that will predict recovery from coma and predict individual patient responses to stimulant therapy. The rationale for a network-based approach is that our preliminary studies indicate that no single brainstem nucleus (i.e. network node) or axonal pathway (i.e. network connection) is essential for consciousness. Rather, there appear to be emergent properties of the brainstem arousal network’s entire set of connections that enable recovery from coma.

Over the next six years, I will build a translational research program to identify the connectivity properties of the brainstem arousal network that are essential for human consciousness and cognition. This research program will use graph theoretical analysis to create a quantitative, clinically useful network model for how the brainstem reactivates the cortex after traumatic coma. The development of this network model will improve acute care for civilians and military personnel with traumatic coma and is a crucial step towards the discovery of novel treatments that promote recovery of consciousness and cognition.