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sleeping and anesthetized states, and no difference in clearance between sleeping and anesthetized states. Since Ab clearance is partially mediated by receptor transport across the blood-brain barrier, the experiment was repeated with 14C-inulin, an inert tracer. Similar increases in clearance were noted during sleep and anesthetized states, thereby indicating that the majority of both substances were cleared by a common mechanism, likely the glymphatic system. In the final experiment, the authors sought to identify the modulator of glymphatic influx in the sleep-wake state. Since noradrenergic signaling has been implicated in arousal 3,4 as well as changes in cell volume in peripheral tissues,5 they hypothesized that increased norepinephrine in the awake state causes an increase in cell volume, thereby decreasing interstitial volume. To test this hypothesis, CSF influx was measured using the same method as in the first experiment, only this time the mice received either a cocktail of adrenergic receptor antagonists (prazosin, atipamezole, and propranolol) or vehicle 15 minutes prior to fluorescent tracers. The adrenergic antagonist group demonstrated an increase in CSF influx to the level of sleeping or anesthetized mice. Subsequently, interstitial volume was measured after infusion using the same TMA1 ionophoretic method as described above. Recordings showed an increase of interstitial volume from 14.3% to 22.6%, similar to previous recordings in the awake vs the sleeping or anesthetized states, respectively. After adrenergic antagonist infusion, ECoG confirmed an increase in slow-wave activity consistent with a sleep-like state. This study presents a compelling case that the state of arousal modulates interstitial volume, which in turn modulates CSF influx and convective exchange of metabolites. The universal “need for sleep” may represent a homeostatic demand on the organism to clear toxic metabolites. These data should be viewed in light of recent literature suggesting that the adverse consequences of sleep deprivation (common in neurosurgical training and practice) are serious. Though several studies have showed relatively minor or non-existent decrements in surgical performance following sleep deprivation 6,7 the long-term harm may be to the surgeon. Especially concerning are recent findings linking poor sleep in adults to accumulation of Ab.8 Further research will be needed to understand how the effects of sleep deprivation might be mitigated. These studies will be

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of interest to the entire neurosurgical community. KATHLEEN M. KELLY CHARLES B. MIKELL GUY M. MCKHANN, II

REFERENCES 1. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342 (6156):373-377. 2. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4 (147):147ra111. 3. Carter ME, Yizhar O, Chikahisa S, et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat Neurosci. 2010;13(12): 1526-1533. 4. Constantinople CM, Bruno RM. Effects and mechanisms of wakefulness on local cortical networks. Neuron. 2011;69(6):1061-1068. 5. O’Donnell J, Zeppenfeld D, McConnell E, Pena S, Nedergaard M. Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. Neurochem Res. 2012;37 (11):2496-2512. 6. Ellman PI, Law MG, Tache-Leon C, et al. Sleep deprivation does not affect operative results in cardiac surgery. Ann Thorac Surg. 2004;78(3):906-911. 7. Ganju A, Kahol K, Lee P, et al. The effect of call on neurosurgery residents’ skills: implications for policy regarding resident call periods. J Neurosurg. 2012;116 (3):478-482. 8. Spira AP, Gamaldo AA, An Y, et al. Self-reported sleep and beta-amyloid deposition in community-dwelling older adults. JAMA Neurol. 2013. doi: 10.1001/jamaneurol.2013.4258.

Deep Brain Stimulation for Locomotor Recovery Following Spinal Cord Injury

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n the 1960s, it was discovered that electrical stimulation of a brain region located at the junction between the midbrain and hindbrain, the mesencephalic locomotor region (MLR), could elicit controlled locomotion in the cat. In the human, the MLR corresponds to the area containing the pedunculopontine (PPN), cuneiform and subcuneiform nuclei, and projections from these nuclei are crucial for controlling movement. Human subjects asked to imagine they are walking demonstrate increased activity in these nuclei during fMRI studies. Consequently, deep brain stimulation (DBS) of the PPN in particular has been under investigation for the alleviation of gait

disturbances in Parkinson disease. Could stimulation of this target area aid in locomotor recovery from spinal cord injury? In most cases of spinal cord injury, some nerve fibers remain intact, including some of those descending from the MLR, providing residual connections from the brain to the spinal cord below the level of injury. Bachmann et al (Deep Brain Stimulation of the Midbrain Locomotor Region Improves Paretic Hindlimb Function After Spinal Cord Injury in Rats. Sci Transl Med. 2013;23;5 (208):208ra146.) recently showed that DBS of the MLR in rats with incomplete spinal cord sectioning improved their ability to walk and swim. First, however, the authors used retrograde axonal tracing from the lumbar spinal cord to demonstrate that brainstem reticular nuclei dominate the input to the spinal cord and are driven by the MLR. MLR stimulation was then shown to modulate the strength of locomotor output in intact, awake animals, using 0.5-ms cathodal pulses at 50 Hz. Remarkably, at 4 weeks after T10 spinal cord injury destroying 75% to 88% of the white matter, DBS of the MLR restored walking in spinal cord– injured rats close to prelesional performance, almost fully restored hindlimb function during swimming, and allowed functionally paralyzed animals to regain basic movements. Further investigations, using targeted injections of the GABAA receptor agonist muscimol, demonstrated that neurons of the MLR and not motor cortex were responsible for MLR DBS-induced stepping. Lastly, complete hemisection experiments showed that MLR BDS-induced stepping depended on the integrity of ipsilaterally descending reticulospinal fibers. This new work suggests that MLR stimulation may be useful for improving gait in patients with spinal cord injury, particularly those who have been living with the injury for some time. That varying results on locomotion have been reported in patients undergoing PPN DBS for Parkinson disease, however, is a reminder that the functional anatomy of the human MLR is complex and not fully understood. Attempting to reproduce the results of Bachmann et al in a nonhuman primate spinal cord injury model would be a reasonable next step. Nonetheless, these results in the rat do suggest the potential for neuromodulation of midbrain locomotor control nuclei to treat patients with incomplete spinal cord injury. MARK RICHARDSON

www.neurosurgery-online.com

Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

SCIENCE TIMES

Figure. MLR stimulation improves swimming in animals with subtotal spinal cord injuries (,10% remaining white matter). A-E, individual animals with sever, 91% to 97.5% lesions of the T10 spinal cord are color-coded according to the amount of spared white matter from blue (least spared) to red (most spared). F, estimation of remaining fibers of the major descending tracts from the brain in these animals. G, walking speed without stimulation was fully compensated by the forelimbs and increased with increasing MLR DBS intensity. H, occasional, nonfunctional step-like twitches were scarce, illustrating the sever hindlimb deficits. Despite a slight increase of stepping frequency, no functional steps with MLR DBS were seen. I, under weight-released conditions, swimming speed increased with increasing stimulation intensity. J, Hindlimb stroke frequency increased slightly with stimulation. K and L, representative joint trajectories of the swimming animal show in (D) without MLR DBS (K) and with 100% MLR DBS (L). Joint trajectories are shown at 20-ms intervals. X axis, intensity of MLR BDS as a percent of maximal stimulation (123 6 47.1 mA). *P , .05, **P , .01, ***P , .001, 1-way ANOVA with Dunnett’s multiple comparison to 0% stimulation. Dashed horizontal line indicates the mean intact baseline performance. (From [Bachmann LC, Matis A, Lindau NT, Felder P, Gullo M, Schwab ME. Deep Brain Stimulation of the Midbrain Locomotor Region Improves Paretic Hindlimb Function After Spinal Cord Injury in Rats. Sci Transl Med. 2013;23;5(208):208ra146]. Reprinted with permission from AAAS).

Traumatic Brain Injury at Your Fingertips!

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rguably the greatest functional feature of today’s most popular portable/handheld smart devices is specific application software. There is a cornucopia of “apps” to aid for any task available for download at finger length. There are more than 900 000 iPhone apps currently available, and the number of smart phone app downloads is expected to increase to 40 billion in 2014 alone.1,2 The significance of these apps lies in their functionality:

NEUROSURGERY

they serve as interactive tools that, if designed appropriately, can play effective roles in assessing or reviewing information at a moment’s notice to help one make the best possible judgment in almost any situation. Unbeknownst to most neurosurgeons and the public, neurosurgery is no exception. As of September 10, 2013, there are more than 50 neurosurgery related apps in the iTunes store. Currently, there are more than 20 apps related to traumatic brain injury (TBI) (Table 1) for the iPhone. In addition to serving as educational resources, these apps contain a range of medical assessments including various algorithms, scales,

and calculators for use by health care professionals and caretakers alike. There are also apps that attempt to provide lifestyle modifications for patients with communication ailments. Although there are several TBI-related apps in the market, a few may be considered particularly useful for neurosurgeons or as a recommendation for use by patients, and this paper is a brief review of some of these useful apps. Traumatic Brain Injury (by Fuze.cc) (Figure A): This is an educational app developed by physicians and neurosurgeons in Brazil designed to serve as an aid to learn or review the general topics in TBI. Currently, it appears to be the most

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Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

Deep brain stimulation for locomotor recovery following spinal cord injury.

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