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Peter J. Grahn, Kendall H. Lee, Aimen Kasasbeh, Grant W. Mallory, Jan T. Hachmann, John R. Dube, Christopher J. Kimble, Darlene A. Lobel, Allan Bieber, Ju Ho Jeong, Kevin E. Bennet and J. Luis Lujan

OBJECT

Despite a promising outlook, existing intraspinal microstimulation (ISMS) techniques for restoring functional motor control after spinal cord injury are not yet suitable for use outside a controlled laboratory environment. Thus, successful application of ISMS therapy in humans will require the use of versatile chronic neurostimulation systems. The objective of this study was to establish proof of principle for wireless control of ISMS to evoke controlled motor function in a rodent model of complete spinal cord injury.

METHODS

The lumbar spinal cord in each of 17 fully anesthetized Sprague-Dawley rats was stimulated via ISMS electrodes to evoke hindlimb function. Nine subjects underwent complete surgical transection of the spinal cord at the T-4 level 7 days before stimulation. Targeting for both groups (spinalized and control) was performed under visual inspection via dorsal spinal cord landmarks such as the dorsal root entry zone and the dorsal median fissure. Teflon-insulated stimulating platinum-iridium microwire electrodes (50 μm in diameter, with a 30- to 60-μm exposed tip) were implanted within the ventral gray matter to an approximate depth of 1.8 mm. Electrode implantation was performed using a free-hand delivery technique (n = 12) or a Kopf spinal frame system (n = 5) to compare the efficacy of these 2 commonly used targeting techniques. Stimulation was controlled remotely using a wireless neurostimulation control system. Hindlimb movements evoked by stimulation were tracked via kinematic markers placed on the hips, knees, ankles, and paws. Postmortem fixation and staining of the spinal cord tissue were conducted to determine the final positions of the stimulating electrodes within the spinal cord tissue.

RESULTS

The results show that wireless ISMS was capable of evoking controlled and sustained activation of ankle, knee, and hip muscles in 90% of the spinalized rats (n = 9) and 100% of the healthy control rats (n = 8). No functional differences between movements evoked by either of the 2 targeting techniques were revealed. However, frame-based targeting required fewer electrode penetrations to evoke target movements.

CONCLUSIONS

Clinical restoration of functional movement via ISMS remains a distant goal. However, the technology presented herein represents the first step toward restoring functional independence for individuals with chronic spinal cord injury.

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Bartosz T. Grobelny, Andrew F. Ducruet, Peter A. DeRosa, Ivan S. Kotchetkov, Brad E. Zacharia, Zachary L. Hickman, Luis Fernandez, Reshma Narula, Jan Claassen, Kiwon Lee, Neeraj Badjatia, Stephan A. Mayer and E. Sander Connolly Jr.

Object

Cystathionine β-synthase (CBS) is an enzyme that metabolizes homocysteine to form H2S in the brain. Hydrogen sulfide functions as a vasodilator as well as a regulator of neuronal ion channels and multiple intracellular signaling pathways. Given the myriad effects of H2S, the authors hypothesized that patients possessing gain-of-function polymorphisms of the CBS gene will experience a decreased incidence of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH).

Methods

Patients were enrolled in a prospective observational database of aSAH outcomes. DNA was extracted from buccal swabs and sequenced for 3 functional polymorphisms of the CBS gene (699C→T, 844ins68, and 1080C→T) by polymerase chain reaction. Serum homocysteine levels (μmol/L) were assayed. Multivariate analysis was used to determine the relationship between CBS genotype and occurrence of both angiographic vasospasm and DCI.

Results

There were 87 patients included in the study. None of the polymorphisms investigated were significantly associated with the incidence of angiographic vasospasm. However, after controlling for admission hypertension, patients with the gain-of-function 844 WT/ins genotypes were less likely to experience DCI relative to those with the 844 WT/WT genotype (86 patients, p = 0.050), while the decrease-in-function genotype 1080 TT was more likely to experience DCI relative to those with 1080 CC and CT genotypes (84 patients, p = 0.042). Serum homocysteine levels did not correlate with the extent of either angiographic vasospasm or DCI in this analysis.

Conclusions

Polymorphisms of the CBS gene that impart gain-of-function may be associated with a reduced risk of DCI after aSAH, independent of serum homocysteine. Signaling through H2S may mediate protection from DCI following aSAH through a mechanism that does not involve macrovascular vasodilation.

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Oral Presentations

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