To awake the unawakened:Deciphering the “Single-unit” of Neurovascular

Coupling to Switch the Coma State in Rats

Xin YuGrant proposal (step 1)

ERC starting grant (March 2014)

The reversible coma: a self-adaptive strategy of the brain to heal itself

• Coma is a state of brain inactivation leading to propound nonresponsiveness. – Invertebres (locust, spiders) enter coma to survive from the

noxious environment.• Reducing neural activity and slowing down brain

metabolism can avoid irreversible consequences of energy exhaustion due to the lack of blood flow and intracranial hypertension following severe brain injuries.– Medically induced coma: physical trauma, meningitis, rabies

or status epilepticus.

The uncontrollable outcomes of the coma state

• Different levels of brain injuries lead to the patients in coma in hours, days, weeks, years, or forever before regain the conciousness.

• The question is how we can develop a strategy to awake the unawakened at the right time, or can we do it?

Central thalamic DBS waked up a patient in the minimal conscious state

(MCS)

Six years of MCS

Reticular formation and thalamic intralaminar nuclei for arousal and coma

De Lecea et al. 2012

Shah et al. 2010

Shirvalkar et al. 2006

Not all VS/MSC patients can be awakened with DBS.

• VS (21 cases) and MCS (5 cases).

• 3-6 month after brain injury.

• 8 of the 21 emerges from VS (only 1 recover)

• 4 of 5 MCS patients wake up.

Yamamoto et al. 2005

Challenges

• Neural underpinnings of coma are little understood.– Multiple causes of brain injuries

• Little neural specificity

– Lack of the functional information during the emergence period from coma state

– Limited accessibility to human patients

Questions

• Is there a “core switch” to manipulate the coma state in the brain?

• What is the right time to introduce the functional intervention?

• What will be the good indicate to estimate the brain state emerging from the coma?

Objective of this proposal

Hypothsis: Restoration of the neurovascular coupling can be modulated to control the switch of coma state in the brain. • Identify the dynamics of neurovascular coupling

during the emergence from the coma.• Control the functional neurovascular coupling by

targeting candidate arousal centers.• Improve the rate of recovery from coma by

modifying neurovascular coupling

Single-unit of the neurovascular coupling

Badaut et al. 2013; Zhang et al. 2012