These authors contributed equally for this work

## **References**

a relatively permanent occlusion [152]. This heterogeneity is likely a large source of conflicting findings, and surely prevents investigators from coming to an agreement on TH mechanisms. Another issue with present research is the goal of hypotheses. While there have been innumerable studies on the mechanisms of hypothermia-mediated neuroprotection, these reports are usually correlative rather than causative, which makes it difficult to derive any concrete, widely applicable mechanisms from the literature. This overall lack of research has hindered publicization of the procedure; given that LEVI was only developed in 2002, many groups are simply unaware that such a procedure has been proposed. For instance, a highly cited 2012 review on the topic discussed numerous problems with global cooling, but failed to mention LEVI to any extent despite the fact that the procedure remedies every problem highlighted in the paper [58]. However, as the body of research on LEVI grows, so too will

Overall, the picture of therapeutic hypothermia-mediated neuroprotection is favorable and encouraging. TH consistently decreases infarct volumes and facilitates short- and long-term preservation of function to an unprecedented degree. Although there is little widespread consensus as to how this is accomplished, a review of the literature is scarce with detrimental effects of TH. While many questions remain to be answered before TH can be consistently implemented in humans, such a promising therapy to such a ubiquitously disastrous disease

This work was partially supported by the American Heart Association Grant-in-Aid (14GRNT20460246), Merit Review Award (I01RX-001964-01) from the US Department of Veterans Affairs Rehabilitation R&D Service, the National Natural Science Foundation of China (81501141), and the Beijing New-Star Plan of Science and Technology (xx2016061).

1 Department of Neurological Surgery, Wayne State University School of Medicine, Detroit,

2 Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China 3 China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University,

, Fengwu Li2

, Longfei Wu<sup>3</sup>

, Longfei

its clinical acceptance.

198 Hypoxia and Human Diseases

**Acknowledgements**

**Author details**

Guan2

MI, USA

Beijing, China

warrants a significant time investment going forward.

Mitchell Huber1#, Hong Lian Duan2#, Ankush Chandra<sup>1</sup>

, Xiaokun Geng1,2\* and Yuchuan Ding1,2 \*Address all correspondence to: xgeng@ccmu.edu.cn
