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Shinsaku Nishio, Masatoshi Yunoki, Zong-Fu Chen, Matthew J. Anzivino, and Kevin S. Lee

Object. Ischemic neuronal damage associated with neurological and other types of surgery can have severe consequences for functional recovery after surgery. Hypothermia administered during and/or after ischemia has proved to be clinically beneficial and its effects often rival or exceed those of other therapeutic strategies. In the present study the authors examined whether transient hypothermia is an effective preconditioning stimulus for inducing ischemic tolerance in the brain.

Methods. Adult rats were subjected to a 20-minute period of hypothermic preconditioning followed by an interval ranging from 6 hours to 7 days. At the end of this interval, the animals were subjected to transient focal ischemia induced by clamping one middle cerebral artery and both carotid arteries for 1 hour. The volume of cerebral infarction was assessed 1 or 7 days postischemia. In the first series of experiments, hypothermic preconditioning (28.5°C) with a postconditioning interval of 1 day reduced the extent of cerebral infarction measured 1 and 7 days postischemia. In the second series, hypothermic preconditioning (31.5°C) with postconditioning intervals of 6 hours, 1 day, or 2 days (but not 7 days) reduced the extent of cerebral infarction measured 1 day postischemia. Treatment with the protein synthesis inhibitor anisomycin blocked the protective effect of hypothermic preconditioning. In a final series of experiments, in vitro brain slices prepared from hypothermia-preconditioned (nonischemic) animals were shown to tolerate a hypoxic challenge better than slices prepared from unconditioned animals.

Conclusions. These findings indicate that hypothermic preconditioning induces a form of delayed tolerance to focal ischemic damage. The time course over which tolerance occurs and the ability of a protein synthesis inhibitor to block tolerance suggest that increased expression of one or more gene products is necessary to establish tissue tolerance following hypothermia. The attenuation of hypoxic injury in vitro following in vivo preconditioning indicates that tolerance is due, at least in part, to direct effects on the brain neuropil. Hypothermic preconditioning could provide a relatively low-risk approach for improving surgical outcome after invasive surgery, including high-risk neurological and cardiovascular procedures.

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Masatoshi Yunoki, Shinsaku Nishio, Naoya Ukita, Matthew J. Anzivino, and Kevin S. Lee

Object. A brief period of hypothermia has recently been shown to induce delayed tolerance to ischemic brain injury. This form of tolerance is initiated several hours after hypothermic preconditioning (HPC) and persists for a few days. Hypothermia-induced tolerance could provide a means for limiting cellular injury during predictable periods of ischemia, such as those that occur during many surgical procedures. The purpose of this study was to characterize the parameters of HPC that regulate the induction of delayed tolerance.

Methods. The general design of the experiments was to perform HPC or a sham procedure on adult Sprague-Dawley rats. Twenty-four hours later, the animals were subjected to a transient period of ischemia induced by a 1-hour period of three-vessel occlusion. Infarct volume was assessed 24 hours postischemia. In the first series of experiments, the depth of global (that is, whole-body) HPC was set at 25.5, 28.5, or 31.5°C, and the duration of HPC was fixed at 20 minutes. In the second series of experiments, the duration of global HPC was set at 20, 60, 120, or 180 minutes, and the depth of HPC was set at 33 or 34.5°C. In the third series of experiments, focal HPC was administered by selectively cooling the head to achieve a cortical temperature of 28.5 or 31.5°C for 20 minutes, with the duration of HPC fixed at 20 minutes.

The magnitude of tolerance induced by HPC was dependent on the depth and duration of the hypothermic stimulus. The parameters of hypothermia that are capable of inducing tolerance are similar to, or less severe than, those already in clinical use during intraoperative procedures. Focal cooling was as effective as global cooling for eliciting tolerance, indicating that it is possible to establish tolerance while limiting the potential complications of systemic hypothermia.

Conclusions. The results of these experiments indicate that HPC may provide an effective and safe means for limiting cellular injury resulting from predictable periods of central nervous system ischemia.

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Yi Wang, Matthew J. Anzivino, Yanrong Zhang, Edward H. Bertram, James Woznak, Alexander L. Klibanov, Erik Dumont, Max Wintermark, and Kevin S. Lee


Surgery can be highly effective for the treatment of medically intractable, neurological disorders, such as drug-resistant focal epilepsy. However, despite its benefits, surgery remains substantially underutilized due to both surgical concerns and nonsurgical impediments. In this work, the authors characterized a noninvasive, nonablative strategy to focally destroy neurons in the brain parenchyma with the goal of limiting collateral damage to nontarget structures, such as axons of passage.


Low-intensity MR-guided focused ultrasound (MRgFUS), together with intravenous microbubbles, was used to open the blood-brain barrier (BBB) in a transient and focal manner in rats. The period of BBB opening was exploited to focally deliver to the brain parenchyma a systemically administered neurotoxin (quinolinic acid) that is well tolerated peripherally and otherwise impermeable to the BBB.


Focal neuronal loss was observed in targeted areas of BBB opening, including brain regions that are prime objectives for epilepsy surgery. Notably, other structures in the area of neuronal loss, including axons of passage, glial cells, vasculature, and the ventricular wall, were spared with this procedure.


These findings identify a noninvasive, nonablative approach capable of disconnecting neural circuitry while limiting the neuropathological consequences that attend other surgical procedures. Moreover, this strategy allows conformal targeting, which could enhance the precision and expand the treatment envelope for treating irregularly shaped surgical objectives located in difficult-to-reach sites. Finally, if this strategy translates to the clinic, the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.