OHSU

Randomized Trial of Early Hemodynamic Management of Patients following Acute Spinal Cord Injury: TEMPLE
Miriam Treggiari, MD

Experiencing lower blood pressure is a common event following high spinal cord injury (SCI). Prevention of low blood pressure and early management in an Intensive Care Unit has saved lives and improved the functional results among survivors of SCI. When there is swelling of the spinal cord due to contusion, there is a window of opportunity to preserve some sections of the spinal cord near the level of injury, before they suffer irreversible damage. Today, it is unknown what blood pressure is optimal to help preserve these sections of the spinal cord at risk of ongoing damage. While it is known that managing blood pressure improves outcomes for patients, the best blood pressure range is not yet known. This study will provide guidance to care providers on how to manage blood pressure in the first week after the injury to achieve the best short- and long-term results to improve the life of victims of SCI. The objective of this study is to determine if targeted blood pressure manipulation will improve patient outcomes, including neurological function, functional independence, pain levels, and quality of life after SCI. The trial is currently enrolling participants in a multi-center, randomized, controlled study designed to assess the efficacy and safety of early targeted blood pressure management (TPM) in an intensive care unit (ICU) setting in adult patients with acute spinal cord injury involving the cervical and thoracic spine. Participating sites include Oregon Health and Science University (Clinical Site and Coordinating Center), University of Maryland, University of Pennsylvania, University of Cincinnati, and University of Washington.

Clinical Trials Identifier NCT02878850

Funding: Congressionally Directed Medical Research Program - US army – Department of Defense

An Assessor-Blinded, Randomized, Controlled, Single Center, Parallel Design Trial to Compare the Incidence of Postoperative Pulmonary Complications Associated with Rocuronium Neuromuscular Reversal with Sugammadex versus Neostigmine in Patients 70 Years of Age or Older Undergoing Surgery of at Least 3 Hours
Brandon Togioka, MD

Common practice throughout the world is to reverse neuromuscular blockade at the end of surgery with neostigmine. Residual neuromuscular blockade after reversal with neostigmine is quite common with an incidence in the range of 30-55%. Substantial respiratory morbidity has been associated with this postoperative residual paralysis. A new drug with evidence of more complete neuromuscular reversal has been developed, sugammadex. Sugammadex is unique from neostigmine in that it can reverse all depths of neuromuscular blockade in a dose-dependent manner and it has been shown to virtually eliminate residual paralysis in the PACU, when administered in appropriate doses. The objective of this study is to determine if a strategy of rocuronium neuromuscular reversal with sugammadex will reduce the proportion of adult patients that develop a postoperative pulmonary complication, as compared with neostigmine. This single center, double-blind, randomized, controlled trial is currently enrolling participants at Oregon Health and Science University.

Clinical Trials Identifier NCT02861131

Funding: Merck Sharp & Dohme Corp

Anesthetics and Post-Injury Hippocampal Neurogenesis
Eric Schnell, MD PhD

Our current research focuses on how synapses are formed in the brain by adult born neurons, how these neurons contribute to neuronal circuit function, and how they contribute to recovery from neurologic injury. Newly generated neurons must be integrated into existing neuronal circuits to contribute to information processing, and alterations in this process could have profound clinical implications. Our current focus is on understanding how adult-born neurons might contribute to the pathogenesis of post-traumatic epilepsy, and we have developed techniques to analyze synaptic transmission at synapses formed by these adult-born cells and to evaluate the behavioral consequences of activity in these adult-born neurons. Our scientific expertise lies in the study of neuronal structure and synaptic function, using electrophysiology, molecular biology, translational models and immunohistochemical/anatomical imaging techniques.

In recent studies, we have found that adult-born neurons contribute to the formation of recurrent circuits after injury, which might directly contribute to hippocampal hyperexcitability in epilepsy. Furthermore, although the brain has some capacity for regeneration after injury through the enhancement of adult neurogenesis, we have discovered that neurons born into an injured brain develop aberrantly and likely contribute to circuit dysfunction. Ongoing studies (unpublished) suggest that anesthetic drugs might modulate this aberrant neurogenesis, and might have therapeutic benefits if administered early after injury.

Funding: VA Merit Review Grant: Functional contribution of adult-born neurons to epileptogenesis

Publications:

Hendricks, W. D., Chen, Y., Bensen, A.L., Westbrook, G. L., and Schnell, E. (2017) Short-term Depression of Sprouted Mossy Fiber Synapses from Adult-born Granule Cells. Journal of Neuroscience, 37(23):5722-5735 and Cover Illustration.

Chatzi, C., Schnell, E., and Westbrook, G. L. (2015) Localized hypoxia within the SGZ determines the early survival of newborn hippocampal granule cells. eLife, 4:e08722.

Villasana, L. E., Kim, K. N., Westbrook, G. L., and Schnell, E. (2015) Functional integration of adult-born hippocampal neurons after traumatic brain injury. eNeuro, 2(5) e0056-15.

Villasana, L. E., Westbrook, G. L., and Schnell, E. (2014) Neurologic impairment following closed head injury predicts post-traumatic neurogenesis. Experimental Neurology, 261: 156-162.

Schnell, E., Long, T. H., Bensen, A. L., Washburn, E. K., and Westbrook, G. L. (2014) Neuroligin-1 knockdown reduces survival of adult-generated newborn hippocampal neurons. Frontiers in Neuroscience, 8(71): 1-7.

Perederiy, J. V., Luikart, B. W., Washburn, E. K., Schnell, E., and Westbrook, G. L. (2013) Neural injury alters proliferation and integration of adult-generated neurons in the dentate gyrus. Journal of Neuroscience, 33(11): 4754-4767 and Cover Illustration.

Schnell, E., Bensen, A. L., Washburn, E. K., and Westbrook, G. L. (2012) Neuroligin-1 overexpression in newborn granule cells in vivo. PLoS One, 7(10): e48045.

Investigating the Neural Circuits of Spinal Cord Stimulation
Andrei Sdrulla, MD PhD

Neuromodulation approaches such as spinal cord stimulation, peripheral nerve stimulation, and transcutaneous electrical nerve stimulation are employed for treating chronic pain conditions when other treatments have failed. These therapies are believed to relieve pain by electrical stimulation of Aβ fibers (Aβ-ES), resulting in modulation of nociceptive processing. Spinal cord stimulation (SCS) in particular has been shown to be an effective modality for the treatment of severe neuropathic pain, however many patients experience gradual loss of efficacy and suboptimal pain relief. Conventional SCS is believed to relieve pain by activating ascending branches of Aβ primary afferents in the dorsal columns, which in turn engage segmental and supraspinal inhibitory mechanisms. While “gate control” theory serves as the leading explanation for pain relieving effects of SCS, the underlying mechanisms in fact remain poorly understood. The goals of my research are to delineate the spinal mechanisms of SCS-induced analgesia, and thereby optimize its clinical implementation for the treatment of chronic pain.

We recently showed that Aβ-ES applied at the dorsal roots gives rise to a novel form of long-term depression of high-threshold (nociceptive), C-fiber evoked excitatory synaptic currents in superficial dorsal horn (SDH) neurons. Whether this synaptic depression influences SDH neuronal activity and nociceptive processing at the circuit level is unknown. Moreover, the SDH includes diverse populations of excitatory and inhibitory neurons with complex network interactions, and it is unknown if specific subpopulation(s) are critical for analgesic effects of SCS. My laboratory employs an integrated repertoire of state-of-the-art ex vivo and in vivo imaging coupled with optogenetic approaches to delineate the effects of Aβ-ES on defined neuronal populations in real-time over the entire SDH.

Funding: FAER: Foundation for Anesthesia Education and Research (FAER) Mentored Research Training Grant (July 2016).

Publications:

  1. Sdrulla A and Chen G. (2016) Minimally invasive procedures for neuropathic pain. Pain Manag. 6(2):103-9.
  2. Sdrulla AD, Xu Q, He SQ, Tiwari V, Yang F, Zhang C, Shu B, Shechter R, Raja SN, Wang Y, Dong X, Guan Y. (2015) Electrical stimulation of low-threshold afferent fibers induces a prolonged synaptic depression in lamina II dorsal horn neurons to high threshold afferent inputs in mice. Pain. 156(6):1008-17.
  3. Yang F, Xu Q, Cheong YK, Shechter R, Sdrulla A, He SQ, Tiwari V, Dong X, Wacnik PW, Meyer R, Raja SN, Guan Y. (2014) Comparison of intensity-dependent inhibition of spinal wide-dynamic range neurons by dorsal column and peripheral nerve stimulation in a rat model of neuropathic pain. Eur J Pain. 18(7):978-88.
  4. Shechter R, Yang F, Xu Q, Cheong YK, He SQ, Sdrulla A, Carteret AF, Wacnik PW, Dong X, Meyer RA, Raja SN, Guan Y. (2013) Conventional and kilohertz frequency spinal cord stimulation produces intensity- and frequency-dependent inhibition of mechanical hypersensitivity in a rat model of neuropathic pain. Anesthesiology. 119(2):422-32.

Defining the role of glymphatic pathway dysfunction in the development of development of Alzheimer’s disease and post-traumatic neurodegeneration
Jeffrey Iliff, PhD

Neurodegenerative diseases such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE) are characterized by the mis-aggregation of different proteins in the form of senile plaques (amyloid beta) and neurofibrillary tangles (tau). The changes in the aging and post-traumatic brain that promote this protein mis-aggregation remain unclear. Our group has recently defined the ‘glymphatic’ system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal fluid through the brain extracellular compartment, facilitating the clearance of interstitial wastes including amyloid beta and tau. Glymphatic function is greatest during sleep compared to waking, and is impaired in the aging and post-traumatic brain, suggesting that glymphatic disruption may be a critical link underlying the clinical association between aging, traumatic brain injury (TBI), sleep disruption, and neurodegeneration.

Work within my group follows three paths. First, we utilize cellular and molecular approaches to define the role that changes in astroglial water and solute homeostasis play in the impairment of glymphatic function. This work includes in vivo imaging in rodents, including 2-photon microscopy and dynamic contrast-enhanced MRI, as well as experimental mouse models of AD and TBI. Second, we are conducting histopathological, transcriptomic, and genetic studies in human datasets to evaluate whether changes in astroglial function are associated with the development or course of human AD. Lastly, we are developing novel MRI-based imaging approaches in human subjects to define glymphatic function in the human brain, and evaluate whether impairment of glymphatic function occurs in the clinical setting of aging, AD and TBI.

Funding: National Institutes of Aging (R01), National Institutes of Neurological Disease and Stroke (R01), Paul G. Allen Family Foundation (human neuroimaging study), GlaxoSmithKline.

Publications:

  1. Iliff JJ, Wang M, Liao Y, Plog BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M*. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4, 147ra111. 2012.
  2. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep initiated fluid flux drives metabolite clearance from the adult brain. Science Oct 18;342(6156):373-7 2013.
  3. Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, Singh I, Deane R, Nedergaard M. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci Dec 3;34(49):16180-93 2014.
  4. Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol Sep 10 2014.
  5. Zeppenfeld DM, Simon M, Haswell JD, D’Abreo D, Murchison C, Quinn JF, Grafe MR, Woltjer RL, Kaye J, Iliff JJ. Preservation of perivascular aquaporin-4 localization in the cognitively heathy elderly. JAMA Neurol 74(1):91-99 2017.
  6. Burfeind KG, Murchison CF, Westaway SK, Simon MJ, Erten-Lyons D, Kaye JA, Quinn JF, Iliff JJ. The effects of noncoding aquaporin-4 (AQP4) single nucleotide polymorphisms on cognition and functional progression of Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research & Clinical Interventions Vol 3:3 348-359 2017