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Carolina M. Maier, Guo Hua Sun, David Kunis, Midori A. Yenari and Gary K. Steinberg

Object. The goals of this study were to determine the effects of delaying induction of mild hypothermia (33°C) after transient focal cerebral ischemia and to ascertain whether the neuroprotective effects of mild hypothermia induced during the ischemic period are sustained over time.

Methods. In the first study, rats underwent 2 hours of middle cerebral artery (MCA) occlusion. Animals in one group were maintained under normothermic conditions (N group, 23 rats) throughout the period of ischemia and reperfusion. Rats in four additional groups were exposed to 2 hours of hypothermia, which commenced at ischemia onset (H0 group, 11 rats) or with delays of 90 (H90 group, 10 rats), 120 (H120 group, 10 rats), or 180 (H180 group, five rats) minutes, and allowed to survive for 3 days. In the second study, animals underwent 1.5 hours of MCA occlusion and were maintained under normothermic (48 rats) or hypothermic (44 rats) conditions during the ischemia period, after which they survived for 3 days, 1 week, or 2 months. All animals were evaluated for neurological findings at 24 hours and 48 hours postischemia and before they were killed. Regions of infarct were determined by examining hematoxylin and eosinstained brain slices obtained at six coronal levels.

Conclusions. Mild hypothermia conferred significant degrees of neuroprotection in terms of survival, behavioral deficits, and histopathological changes, even when its induction was delayed by 120 minutes after onset of MCA occlusion (p < 0.05) compared with normothermic conditions. Furthermore, the neuroprotective effect of mild hypothermia (2-hour duration) that was induced during the ischemia period was sustained over 2 months. These studies lend further support to the use of mild hypothermia in the treatment of stroke.

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Shervin R. Dashti, Aaron Spalding, Rob J. Kadner, Tom Yao, Arooshi Kumar, David A. Sun and Renato LaRocca

Radiation necrosis (RN) is a serious complication that can occur in up to 10% of brain radiotherapy cases, with the incidence dependent on both dose and brain location. Available medical treatment for RN includes steroids, vitamin E, pentoxifylline, and hyperbaric oxygen. In a significant number of patients, however, RN is medically refractory and the patients experience progressive neurological decline, disabling headaches, and decreased quality of life.

Vascular endothelial growth factor (VEGF) is a known mediator of cerebral edema in RN. Recent reports have shown successful treatment of RN with intravenous bevacizumab, a monoclonal antibody for VEGF. Bevacizumab, however, is associated with significant systemic complications including sinus thrombosis, pulmonary embolus, gastrointestinal tract perforation, wound dehiscence, and severe hypertension. Using lower drug doses may decrease systemic exposure and reduce complication rates. By using an intraarterial route for drug administration following blood-brain barrier disruption (BBBD), the authors aim to lower the bevacizumab dose while increasing target delivery.

In the present report, the authors present the cases of 2 pediatric patients with cerebral arteriovenous malformations, who presented with medically intractable RN following stereotactic radiosurgery. They received a single intraarterial infusion of 2.5 mg/kg bevacizumab after hyperosmotic BBBD.

At mean follow-up duration of 8.5 months, the patients had significant and durable clinical and radiographic response. Both patients experienced resolution of their previously intractable headaches and reversal of cushingoid features as they were successfully weaned off steroids. One of the patients regained significant motor strength. There was an associated greater than 70% reduction in cerebral edema.

Intraarterial administration of a single low dose of bevacizumab after BBBD was safe and resulted in durable clinical and radiographic improvements at concentrations well below those required for the typical systemic intravenous route. Advantages over the intravenous route may include higher concentration of drug delivery to the affected brain, decreased systemic toxicity, and a significantly lower cost.

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Gary K. Steinberg, Nariman Panahian, Go-Hua Sun, Carolina M. Maier and David Kunis

✓ Temporary intracranial arterial occlusion is often utilized during the surgical treatment of intracranial aneurysms. Although numerous experimental studies have suggested that repetitive, brief periods of global ischemia cause more severe cerebral injury than a similar single period of global ischemia, this issue has not been extensively studied in relation to focal ischemia. It remains controversial whether it is safer to use brief periods of interrupted, temporary occlusion separated by reperfusion periods, or a more prolonged, single temporary occlusion. This question is addressed in studies on a rabbit model of transient, focal cerebral ischemia.

Sixteen anesthetized rabbits underwent transorbital occlusion of the left internal carotid, middle cerebral, and anterior cerebral arteries, with one of two paradigms: uninterrupted occlusion (1 hour of temporary occlusion followed by 5 hours of reperfusion in eight rabbits), or interrupted occlusion (three separate 20-minute periods of occlusion, with 10 minutes of reperfusion between occlusions, followed by 4 hours, 40 minutes of reperfusion in eight rabbits). Histopathological evaluation for ischemic neuronal damage and magnetic resonance imaging studies for ischemic edema were conducted 6 hours after the initial arterial occlusion.

The animals in the interrupted, repeated occlusion group showed a 59% decrease in the area of cortical ischemic neuronal damage (mean ± standard error of the mean 10.0% ± 1.7%) compared with the uninterrupted occlusion group (24.4% ± 5%, p = 0.016). There was no difference between the groups in the extent of striatal ischemic damage or area of ischemic edema. These results suggest that interrupted, repeated focal ischemia causes less cortical ischemic injury than uninterrupted transient ischemia of a similar total duration. Although caution should be exercised in extrapolating from these results to the clinical situation, they may have important implications for temporary arterial occlusion during intracranial surgery.

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Chris Kao, Jonathan A. Forbes, Walter J. Jermakowicz, David A. Sun, Brandon Davis, Jiepei Zhu, Andre H. Lagrange and Peter E. Konrad

Object

Traumatic brain injury (TBI) often causes an encephalopathic state, corresponding amplitude suppression, and disorganization of electroencephalographic activity. Clinical recovery in patients who have suffered TBI varies, and identification of patients with a poor likelihood of functional recovery is not always straightforward. The authors sought to investigate temporal patterns of electrophysiological recovery of neuronal networks in an animal model of TBI. Because thalamocortical circuit function is a critical determinant of arousal state, as well as electroencephalography organization, these studies were performed using a thalamocortical brain slice preparation.

Methods

Adult rats received a moderate parietal fluid-percussion injury and were allowed to survive for 1 hour, 2 days, 7 days, or 15 days prior to in vitro electrophysiological recording. Thalamocortical brain slices, 450-μm thick, were prepared using a cutting angle that preserved reciprocal connections between the somatosensory cortex and the ventrobasal thalamic complex.

Results

Extracellular recordings in the cortex of uninjured control brain slices revealed spontaneous slow cortical oscillations (SCOs) that are blocked by (2R)-amino-5-phosphonovaleric acid (50 μM) and augmented in low [Mg2+]o. These oscillations have been shown to involve simultaneous bursts of activity in both the cortex and thalamus and are used here as a metric of thalamocortical circuit integrity. They were absent in 84% of slices recorded at 1 hour postinjury, and activity slowly recovered to approximate control levels by Day 15. The authors next used electrically evoked SCO-like potentials to determine neuronal excitability and found that the maximum depression occurred slightly later, on Day 2 following TBI, with only 28% of slices showing evoked activity. In addition, stimulus intensities needed to create evoked SCO activity were elevated at 1 hour, 2 days, and 7 days following TBI, and eventually returned to control levels by Day 15. The SCO frequency remained low throughout the 15 days following TBI (40% of control by Day 15).

Conclusions

The suppression of cortical oscillatory activity following TBI observed in the rat model suggests an injury-induced functional disruption of thalamocortical networks that gradually recovers to baseline at approximately 15 days postinjury. The authors speculate that understanding the processes underlying disrupted thalamocortical circuit function may provide important insights into the biological basis of altered consciousness following severe head injury. Moreover, understanding the physiological basis for this process may allow us to develop new therapies to enhance the rate and extent of neurological recovery following TBI.

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Hai-Ying Shen, Hai Sun, Marissa M. Hanthorn, Zhongwei Zhi, Jing-Quan Lan, David J. Poulsen, Ruikang K. Wang and Detlev Boison

Object

New experimental models and diagnostic methods are needed to better understand the pathophysiology of focal neocortical epilepsies in a search for improved epilepsy treatment options. The authors hypothesized that a focal disruption of adenosine homeostasis in the neocortex might be sufficient to trigger electrographic seizures. They further hypothesized that a focal disruption of adenosine homeostasis might affect microcirculation and thus offer a diagnostic opportunity for the detection of a seizure focus located in the neocortex.

Methods

Focal disruption of adenosine homeostasis was achieved by injecting an adeno-associated virus (AAV) engineered to overexpress adenosine kinase (ADK), the major metabolic clearance enzyme for the brain's endogenous anticonvulsant adenosine, into the neocortex of mice. Eight weeks following virus injection, the affected brain area was imaged via optical microangiography (OMAG) to detect changes in microcirculation. After completion of imaging, cortical electroencephalography (EEG) recordings were obtained from the imaged brain area.

Results

Viral expression of the Adk cDNA in astrocytes generated a focal area (~ 2 mm in diameter) of ADK overexpression within the neocortex. OMAG scanning revealed a reduction in vessel density within the affected brain area of approximately 23% and 29% compared with control animals and the contralateral hemisphere, respectively. EEG recordings revealed electrographic seizures within the focal area of ADK overexpression at a rate of 1.3 ± 0.2 seizures per hour (mean ± SEM).

Conclusions

The findings of this study suggest that focal adenosine deficiency is sufficient to generate a neocortical focus of hyperexcitability, which is also characterized by reduced vessel density. The authors conclude that their model constitutes a useful tool to study neocortical epilepsies and that OMAG constitutes a noninvasive diagnostic tool for the imaging of seizure foci with disrupted adenosine homeostasis.

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David A. Sun, Hong Yu, John Spooner, Armanda D. Tatsas, Thomas Davis, Ty W. Abel, Chris Kao and Peter E. Konrad

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a clinically effective neurosurgical treatment for Parkinson disease. Tissue reaction to chronic DBS therapy and the definitive location of active stimulation contacts are best studied on a postmortem basis in patients who have undergone DBS. The authors report the postmortem analysis of STN DBS following 5 years and 11 months of effective chronic stimulation including the histologically verified location of the active contacts associated with bilateral implants. They also describe tissue response to intraoperative test passes with recording microelectrodes and stimulating semimacroelectrodes. The results indicated that 1) the neural tissue surrounding active and nonactive contacts responds similarly, with a thin glial capsule and foreign-body giant cell reaction surrounding the leads as well as piloid gliosis, hemosiderin-laden macrophages, scattered lymphocytes, and Rosenthal fibers; 2) there was evidence of separate tracts in the adjacent tissue for intraoperative microelectrode and semimacroelectrode passes together with reactive gliosis, microcystic degeneration, and scattered hemosiderin deposition; and 3) the active contacts used for ~ 6 years of effective bilateral DBS therapy lie in the zona incerta, just dorsal to the rostral STN. To the authors' knowledge, the period of STN DBS therapy herein described for Parkinson disease and subjected to postmortem analysis is the longest to date.

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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010