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Approved VA Research with Sensitive Species that has been Completed (most recently completed protocols at the top)

Protocol

Funding Source

Protocol Status

Afferent Stimulation to Evoke Recto-Colonic Reflex for Colonic Motility (fully approved before the new review policy was established May 3, 2018)

VA

Closed 4/9/21

Cellular and Synaptic Basis of Cognitive Function in Prefrontal Cortical Networks (fully approved before new review policy was established October 25, 2018)

NIH

Approved but inactive since summer 2019;

Closed 4/8/2021

GABAergic Switches Control Wakefulness, NREM Sleep and REM Sleep (fully approved before new review policy was established May 3, 2018)

NIH

Closed 3/3/2021

Resolution of the Mechanisms Responsible for Atonia during REM Sleep (fully approved before new review policy was established May 3, 2018)

NIH

Closed 3/3/2021

Interventional Therapies after Spinal Cord Injury (fully approved before new review policy was established October 25, 2018)

VA and Yale University

Closed 9/1/2020

Training Effects on Recovery of Balance and Limb Accuracy in Cats (fully approved before new review policy was established May 3, 2018)

VA

Approved but inactive since at least 2016;

Closed 8/25/2020

High Frequency Spinal Cord Stimulation to Restore Cough

VA

Closed 10/11/19

Neuropharmacology of Pontine Control of Breathing Frequency

VA

Closed 6/25/19

VA Research with Current Secretary Approval for Work with Canines

Currently Approved VA Protocols for Research with Animals for the protocols with felines and NHPs




Protocol

Funding Source

VA Location

Afferent Stimulation to Evoke Recto-Colonic Reflex for Colonic Motility (fully approved before new review policy was established May 3, 2018)

Protocol Form and Feedback Document

VA

(protocol closed 4/9/21)

Cleveland

Purpose of Research: Millions of Americans, many of whom are veterans, struggle with fecal incontinence or chronic constipation due to conditions such as spinal cord injury, and currently available methods of managing bowel function are inadequate. This research was to learn more about the neurophysiological mechanisms involved, so that better therapeutic approaches can be developed. Cats are the smallest known species in which the control of bowel storage and emptying are managed as in humans, and are the appropriate size for the instrumentation available for stimulating the colon.

Value of the Results: It turned out to be possible to do this research with animals that had normal spinal cords, so none of the animals involved had spinal cord injuries, and the approved procedures for producing the injuries if necessary were not performed. Preliminary work with simulated stool in fully anesthetized animals established that other methods for measuring rectal pressures and volumes were better, so no further work was done with simulated stool. The results of this work, some of which has already been published in a peer-reviewed journal, established the appropriateness of proceeding now to further research with human subjects on new therapeutic approaches developed from these findings.

Selected Published Results:

Bourbeau D, Aamoth K, Brose S, Gustafson K. "Electrical Colon Stimulation Reflexively Increases Colonic Activity." Neuromodulation. 2020 Dec;23(8):1130-1136. PMID: 31418508 – reports on data collected through early 2018

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Cellular and Synaptic Basis of Cognitive Function in Prefrontal Cortical Networks (fully approved before new review policy was established October 25, 2018)

Protocol Form

NIH

(protocol has been approved but inactive since summer 2019; protocol closed 4/8/2021)

Minneapolis

Purpose of Research: It is estimated that one in every 150-400 people in the US (51,000 to 136,000 Veterans, and more than 25 million people in total) has schizophrenia, which is one of the leading causes of disability worldwide. This research was specifically to gain understanding of how brain cells that are involved in cognitive function communicate with each other, how interference with this communication can lead to cognitive deficits like those in patients with schizophrenia, and how electrical stimulation might help to restore cognitive function. Non-human primates are currently the only species for which those cognitive deficits can be measured and their relationship to specific features of the patterns of electrical activity within the brain can be evaluated.

Value of the Results:

This research revealed that cognitive deficits characteristic of schizophrenia appear when certain receptors in the brain are impaired and normally synchronous neural signals get disrupted. Specific neural circuits in the brain were also functionally disconnected. These results have been critically evaluated by scientific experts, published, and recognized as important to follow up on with a $25 million Conte Center grant from NIH, to support a multipronged approach involving research with transgenic mouse models, nonhuman primates, human patients with schizophrenia, and computational models. The goal is to gain further insight into the neural disruptions responsible for schizophrenia, so that interventions to restore normal function can be designed.

Selected Published Results:

1: Kummerfeld E, Ma S, Blackman RK, DeNicola AL, Redish AD, Vinogradov S, Crowe DA, Chafee MV. Cognitive Control Errors in Nonhuman Primates Resembling Those in Schizophrenia Reflect Opposing Effects of NMDA Receptor Blockade on Causal Interactions Between Cells and Circuits in Prefrontal and Parietal Cortices. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Jul;5(7):705-714. doi: 10.1016/j.bpsc.2020.02.013. Epub 2020 Apr 8. PMID: 32513554; PMCID: PMC7874848.

2: DeNicola AL, Park MY, Crowe DA, MacDonald AW 3rd, Chafee MV. Differential Roles of Mediodorsal Nucleus of the Thalamus and Prefrontal Cortex in Decision-Making and State Representation in a Cognitive Control Task Measuring Deficits in Schizophrenia. J Neurosci. 2020 Feb 19;40(8):1650-1667. doi: 10.1523/JNEUROSCI.1703-19.2020. Epub 2020 Jan 15. PMID: 31941665; PMCID: PMC7046322.

3: Zick JL, Blackman RK, Crowe DA, Amirikian B, DeNicola AL, Netoff TI, Chafee MV. Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia. Neuron. 2018 Jun 27;98(6):1243-1255.e5. doi: 10.1016/j.neuron.2018.05.010. Epub 2018 May 31. PMID: 29861281; PMCID: PMC6085178.

4: Blackman RK, Crowe DA, DeNicola AL, Sakellaridi S, MacDonald AW 3rd, Chafee MV. Monkey Prefrontal Neurons Reflect Logical Operations for Cognitive Control in a Variant of the AX Continuous Performance Task (AX-CPT). J Neurosci. 2016 Apr 6;36(14):4067-79. doi: 10.1523/JNEUROSCI.3578-15.2016. PMID: 27053213; PMCID: PMC4821916.

5: Crowe DA, Goodwin SJ, Blackman RK, Sakellaridi S, Sponheim SR, MacDonald AW 3rd, Chafee MV. Prefrontal neurons transmit signals to parietal neurons that reflect executive control of cognition. Nat Neurosci. 2013 Oct;16(10):1484-91. doi: 10.1038/nn.3509. Epub 2013 Sep 1. PMID: 23995071; PMCID: PMC6379206.

6: Blackman RK, Macdonald AW 3rd, Chafee MV. Effects of ketamine on context-processing performance in monkeys: a new animal model of cognitive deficits in schizophrenia. Neuropsychopharmacology. 2013 Oct;38(11):2090-100. doi: 10.1038/npp.2013.118. Epub 2013 May 10. PMID: 23660706; PMCID: PMC3773669.

7: Goodwin SJ, Blackman RK, Sakellaridi S, Chafee MV. Executive control over cognition: stronger and earlier rule-based modulation of spatial category signals in prefrontal cortex relative to parietal cortex. J Neurosci. 2012 Mar 7;32(10):3499-515. doi: 10.1523/JNEUROSCI.3585-11.2012. PMID: 22399773; PMCID: PMC3712355.

8: Crowe DA, Averbeck BB, Chafee MV. Rapid sequences of population activity patterns dynamically encode task-critical spatial information in parietal cortex. J Neurosci. 2010 Sep 1;30(35):11640-53. doi: 10.1523/JNEUROSCI.0954-10.2010. PMID: 20810885; PMCID: PMC3020896.

9: Averbeck BB, Crowe DA, Chafee MV, Georgopoulos AP. Differential contribution of superior parietal and dorsal-lateral prefrontal cortices in copying. Cortex. 2009 Mar;45(3):432-41. doi: 10.1016/j.cortex.2008.02.007. Epub 2008 Jun 14. PMID: 18640669.

10: Crowe DA, Averbeck BB, Chafee MV. Neural ensemble decoding reveals a correlate of viewer- to object-centered spatial transformation in monkey parietal cortex. J Neurosci. 2008 May 14;28(20):5218-28. doi: 10.1523/JNEUROSCI.5105-07.2008. PMID: 18480278; PMCID: PMC3844802.

11: Chafee MV, Averbeck BB, Crowe DA. Representing spatial relationships in posterior parietal cortex: single neurons code object-referenced position. Cereb Cortex. 2007 Dec;17(12):2914-32. doi: 10.1093/cercor/bhm017. Epub 2007 Mar 26. PMID: 17389630.

12: Crowe DA, Averbeck BB, Chafee MV, Georgopoulos AP. Dynamics of parietal neural activity during spatial cognitive processing. Neuron. 2005 Sep 15;47(6):885-91. doi: 10.1016/j.neuron.2005.08.005. PMID: 16157282.

13: Chafee MV, Crowe DA, Averbeck BB, Georgopoulos AP. Neural correlates of spatial judgement during object construction in parietal cortex. Cereb Cortex. 2005 Sep;15(9):1393-413. doi: 10.1093/cercor/bhi021. Epub 2005 Jan 5. PMID: 15635058.

14: Crowe DA, Chafee MV, Averbeck BB, Georgopoulos AP. Neural activity in primate parietal area 7a related to spatial analysis of visual mazes. Cereb Cortex. 2004 Jan;14(1):23-34. doi: 10.1093/cercor/bhg088. PMID: 14654454.

15: Averbeck BB, Crowe DA, Chafee MV, Georgopoulos AP. Neural activity in prefrontal cortex during copying geometrical shapes. II. Decoding shape segments from neural ensembles. Exp Brain Res. 2003 May;150(2):142-53. doi: 10.1007/s00221-003-1417-5. Epub 2003 Apr 1. PMID: 12669171.

16: Averbeck BB, Chafee MV, Crowe DA, Georgopoulos AP. Neural activity in prefrontal cortex during copying geometrical shapes. I. Single cells encode shape, sequence, and metric parameters. Exp Brain Res. 2003 May;150(2):127-41. doi: 10.1007/s00221-003-1416-6. Epub 2003 Apr 1. PMID: 12669170.

17: Averbeck BB, Chafee MV, Crowe DA, Georgopoulos AP. Parallel processing of serial movements in prefrontal cortex. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13172-7. doi: 10.1073/pnas.162485599. Epub 2002 Sep 19. PMID: 12242330; PMCID: PMC130605.

18: Chafee MV, Averbeck BB, Crowe DA, Georgopoulos AP. Impact of path parameters on maze solution time. Arch Ital Biol. 2002 Jul;140(3):247-51. PMID: 12173528.

19: Crowe DA, Averbeck BB, Chafee MV, Anderson JH, Georgopoulos AP. Mental maze solving. J Cogn Neurosci. 2000 Sep;12(5):813-27. doi: 10.1162/089892900562426. PMID: 11054923.

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GABAergic Switches Control Wakefulness, NREM Sleep and REM Sleep (fully approved before new review policy was established May 3, 2018)

Protocal Form

NIH

(protocol closed 3/3/21)

Los Angeles

Purpose of Research: Many people have trouble falling or staying asleep, or suffer frequent nightmares, especially if they have PTSD, which is a problem for many US combat veterans. Current sleep medications can lead to daytime drowsiness, drug dependence, and other problems. This research is to increase understanding of the brain mechanisms involved in the transitions between different stages of sleep and wakefulness, which can then inform the development of better ways to treat sleep disorders.Cats are the only species in which it has been possible to study individual neurons during naturally occurring states of wakefulness, REM sleep, and non-REM sleep.

Value of the Results: It is key that this research could only be done with cats that were so completely comfortable, physically and emotionally, that they could be observed while they slept, transitioning naturally between wakefulness and sleep, and among the various stages of sleep. This made it possible to examine the brain mechanisms involved in these spontaneous transitions. The results have been presented at numerous national scientific meetings, and data analysis continues, which is expected to contribute to identifying better ways to treat sleep disorders.

Selected Published Results:

1. Xi M, Fung SJ, Sampogna S, Chase MH. Differential C-Fos expression in GABAergic neurons of the nucleus pontis oralis during wakefulness and carbachol-induced active sleep. Sleep. 40:A51, 2017.

2. Zhang J, Sampogna S, Xi M, Fung SJ, Chase MH. Anatomical evidence of direct hypocretinergic control of GABAergic neurons in the nucleus pontis oralis. Sleep. 41:A29, 2018.

3. Xi M, Fung SJ, Sampogna S, Chase MH. An intracellular study of GABAergic processes in the control of activity of neurons in the pontine reticular formation of the cat. Program No. 597.14. 2018 Neuroscience Meeting Planner. San Diego, CA: Soc Neurosci. Online, 2018.

4. Zhang J, Sampogna S, Xi M, Fung SJ, Tobin C, Chase MH. Direct Projections of GABAergic neurons in the Nucleus Pontis Oralis to the Dorsal Raphe Nucleus. Sleep. 42:A51, 2019.

5. Zhang J, Sampogna S, Xi M, Fung SJ, Tobin C, Chase MH. An anatomic substrate for GABAergic processes to suppress active sleep and promote wakefulness in the nucleus pontis oralis. Sleep. 43:A27, 2020.

6. Zhang J, Xi M, Fung SJ, Tobin C, Sampogna S, Chase MH. GABAergic neurons in the dorsal raphe nucleus are under the influence of GABAergic inputs from the nucleus pontis oralis. Accepted for Sleep 2021.

7. Xi M, Fung SJ, Tobin C, Sampogna S, Chase MH. The activity of GABAergic neurons in the nucleus pontis oralis during wakefulness, quiet sleep and active sleep. Manuscript in preparation.

8. Zhang J, Xi M, Fung SJ, Tobin C, Sampogna S, Chase MH. An anatomic study of GABAergic processes to suppress active sleep and promote wakefulness in the nucleus pontis oralis. Manuscript in preparation.

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Resolution of the Mechanisms Responsible for Atonia during REM Sleep (fully approved before new review policy was established May 3, 2018)

Protoocal Form

NIH

(protocol closed 3/3/21)

Los Angeles

Purpose of Research: Veterans are four times as likely as other Americans to suffer from sleep apnea, with about 20% of veterans affected and 63,000 receiving VA benefits to address it. Current ways of treating this (such as using CPAP machines) are not tolerable for many, so better treatments are needed. This research is focused on the special neurons that keep the throat open for airflow to the lungs, and on drugs that might make them more active without disrupting normal sleep. The cat is the only species in which anyone has been able to study individual neurons during naturally-occurring states of sleep and wakefulness.

Value of the Results: It is key that this research could only be done with cats that were so completely comfortable, physically and emotionally, that they could be observed while they slept, transitioning naturally between wakefulness and sleep, and among the various stages of sleep. This made it possible to examine the mechanisms involved in controlling the muscles responsible for keeping the throat open, even as other muscles in the body relaxed completely. The results have been presented at numerous national scientific meetings, and data analysis continues, which is expected to contribute to identifying better ways to treat sleep apnea.

Selected Published Results:

1. Chase M, Fung S, Xi M. Neurochemical mechanisms responsible for atonia during REM sleep. Sleep 39: A29 2016.

2. Xi M, Fung SJ, Chase MH. A chronic animal model to study the neuromechanisms that control hypoglossal motoneuron activity during hypoxic REM sleep. Sleep. 41: A29, 2018.

3. Tobin C, Fung SJ, Xi M, Chase MH. Glycinergic postsynaptic inhibition is responsible for the suppression of hypoglossal motoneuron activity during naturally-occurring REM sleep. Sleep. 43: A27, 2020.

4. Tobin C, Fung SJ, Xi M, Chase MH. The effects of hypoxia on the activity of hypoglossal motoneurons during non-REM and REM sleep. Control/Tracking No: 2021-S-1092-SfN, Society for Neuroscience Global Connectome, 2021

5. Fung SJ, Xi M, Tobin C, Chase MH. A chronic animal model to examine neural mechanisms that control the activity of hypoglossal motoneurons under hypoxic conditions during REM and non-REM sleep. Manuscript in preparation.

6. Tobin C, Fung SJ, Xi M, Chase MH. The effects of hypoxia on the activity of hypoglossal motoneurons during naturally-occurring sleep and wakefulness. Manuscript in preparation.

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Interventional Therapies after Spinal Cord Injury (fully approved before new review policy was established October 25, 2018)

Protocol Form

VA and Yale University

(protocol closed 9/1/20)

West Haven

Purpose of Research:The purpose of this research is to improve restoration of function after spinal cord injury by injecting a specialized protein into the space around the spinal cord to support the growth of nerve fibers within the spinal cord. Results to date show improved functional outcomes and development of axons (nerve fibers) below the level of the lesion. This work was done with non-human primates because of the importance of evaluating the recovery of behaviors common to humans and non-human primates, but not displayed by rodents.

Value of the Results: The results of this work, demonstrating the safety of the specialized protein and the improvements in function achieved by its administration, have been published and are the basis for now studying its effects in human subjects with chronic spinal cord injuries. For these people, recovery of hand function is a very high priority, so the promise that this new treatment option offers is of great interest.

Selected Published Results:

Wang X, Zhou T, Maynard GD, Terse PS, Cafferty WB, Kocsis JD, Strittmatter SM. Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury. Brain 2020 Jun 1;143(6):1697-1713. doi: 10.1093/brain/awaa116.

Bradbury EJ, Oliveira R. Scientific Commentaries: Inhibiting an inhibitor: a decoy to recover dexterity after spinal cord injury. Brain 2020: 143; 1618–1631. doi:10.1093/brain/awaa175.

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Training Effects on Recovery of Balance and Limb Accuracy in Cats (fully approved before new review policy was established May 3, 2018)

VA

(no work has been done with animals on this protocol since at least 2016; protocol closed 8/25/20)

Louisville

Purpose of Research: Veterans with incomplete spinal cord injury (SCI) may have sensation and be able to use muscles below the level of the injury, but still lack the finer control needed for balance and accurate foot placement when walking in environments common in the community. This research compared the effectiveness oftwo potential treatment approaches for restoring skilled gait after SCI: (1)infusion into the site of the injury of an agent that promotes repair of the damaged neural circuitry, and (2) a training strategy focused on improving accuracy of foot placements and maintenance of balance. Felines are the best model currently available for this translational research because of their size, particularly as size relates to the growth that is needed for re-connection across the injury to be accomplished, and because they are more similar to humans than rodents are in certain key biological processes related to how nerve cells grow (sulfation patterns). Felines also exhibit much finer control of balance and individual foot placement than other species do, which is crucial to research into restoring the ability to navigate locomotion across the uneven surfaces common to ordinary communities.

Value of the Results: The information gained from this work has deepened understanding of the role of the spinal cord in the fine control of balance and foot placement that is needed to navigate safely and smoothly over uneven and unpredictable surfaces that are common in community settings. The publications below report on details of how incomplete injuries of the spinal cord interfere with that control, and how an agent that promotes repair impacts it. The results of this work are foundational to the follow-up research needed to improve the recovery of gait after spinal cord injury.

Selected Published Results – reporting on data collected through 2015

1. Doperalski AE, Montgomery LR, Mondello SE, Howland DR. Anatomical Plasticity of Rostrally Terminating Axons as a Possible Bridging Substrate across a Spinal Injury. J Neurotrauma. 2020 Mar 15;37(6):877-888. doi: 10.1089/neu.2018.6193. Epub 2019 Dec 23

2. Niazi IF, Lyle MA, Rising A, Howland DR, Nichols TR. Redistribution of inhibitory force feedback between a long toe flexor and the major ankle extensor muscles following spinal cord injury. J Neurosci Res. 2020 Aug;98(8):1646-1661. doi: 10.1002/jnr.24630. Epub 2020 Jun 14.

3. Brown NP, Bertocci GE, Cheffer KA, Howland DR. A three dimensional multiplane kinematic model for bilateral hind limb gait analysis in cats. PLoS One. 2018 Aug 6;13(8):e0197837. doi: 10.1371/journal.pone.0197837. eCollection 2018.PMID: 30080884

4. Mondello SE, Jefferson SC, O'Steen WA, Howland DR. Enhancing Fluorogold-based neural tract tracing. J Neurosci Methods. 2016 Sep 1;270:85-91. doi: 10.1016/j.jneumeth.2016.06.004. Epub 2016 Jun 7.PMID: 27288218

5. Mondello SE, Jefferson SC, Tester NJ, Howland DR. Impact of treatment duration and lesion size on effectiveness of chondroitinase treatment post-SCI. Exp Neurol. 2015 May;267:64-77. doi: 10.1016/j.expneurol.2015.02.028. Epub 2015 Feb 26.PMID: 25725355

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High Frequency Spinal Cord Stimulation to Restore Cough

Protocol Form, Feedback Document, and Summary of the Literature

VA

(protocol closed 10/11/19)

Cleveland

Purpose of Research: Cough is a normal defensive reflex that functions to protect the airway. Cough is automatically triggered by the body’s need to expel irritants and mucus from the airway passages. Without effective coughing, those things can stay in the airways and result in recurrent respiratory tract infections. Losing the ability to cough effectively is a consequence of weakness or paralysis of expiratory muscles, mainly the abdominal muscles, so restoring the function of those muscles may allow patients with various neuromuscular disorders to effectively clear secretions, reducing their risks of illness and even death related to the respiratory complications. The main goal of this research was to demonstrate that high frequency spinal cord stimulation (HF-SCS), which can work with low stimulus amplitudes, can activate the most important muscles to generate an effective cough. This work was designed to allow the most direct translation to humans as possible. Dogs and humans share many anatomical and physiological similarities, including how individual respiratory muscles are coordinated in coughing. Dogs were the best animal species appropriate for this research.

Value of the Results: Patients with neuromuscular disorders, such as spinal cord injury (SCI), stroke, and amyotrophic lateral sclerosis (ALS), suffer from severe weakness or paralysis of the expiratory muscles, the muscles we depend on to generate an effective cough. This makes them prone to severe respiratory complications such as pneumonia, a major cause of disability and death. In fact, patients with SCI are ~150 times more likely to die from pneumonia compared to the general population. Approximately 42,000 Veterans are living with SCI, an estimated 15,000 Veterans suffer a stroke each year, and those who served in the military are at greater risk of developing ALS. Spinal cord stimulation is a useful method to restore an effective cough in persons with SCI. However, the high stimulus amplitudes that have been required can activate pain fibers, and this significantly limits this application in individuals who have intact sensation. The purpose of this work was to evaluate a novel method to restore the expiratory muscle function needed to generate an effective normal cough in patients with intact sensation. This method involves HF-SCS at low stimulus amplitudes to electrically activate the expiratory muscle muscles, in an animal model. Our results suggest that this novel method can generate the positive airway pressures needed to restore an effective cough, without also causing pain in those with sensation. This technique holds promise as a method to restore the ability to cough productively and has the potential to be useful in all individuals who would benefit from that, including not only those with spinal cord injuries that interfere with sensation, but also those with disorders like stroke and amyotrophic lateral sclerosis, who have sensation. To date, results are encouraging, and we are planning the next steps needed to take this method to clinical trials. Ultimately, this method may become an important clinical tool in the routine pulmonary management of patients with neurological disorders. When extrapolated more broadly to eligible patients, use of this device would significantly impact the overall costs of care (estimated ~$1 billion/year).

Selected Published Results:

1. Kowalski KE, Romaniuk JR, Brose S, Richmond MA, Kowalski T, DiMarco AF. High Frequency Spinal Cord Stimulation – New Method to Restore Cough. Respir Physiol Neurobiol 232:54-56, 2016. PMID: 27395446.

2. Romaniuk JR, Dick TE, Bruce EN, DiMarco AF, and Kowalski KE. Bifurcation of the Respiratory Response to Lung Inflation in Anesthetized Dogs. Respiratory Physiology & Neurobiology 244:26–31, 2017. PMCID: PMC5567807.

3. Kowalski KE, Romaniuk JR, Kowalski T and DiMarco AF. Effects of Expiratory Muscle Activation via  High Frequency Spinal Cord Stimulation. J Appl Physiol 123:1525-1531, 2017. PMID: 28935824.

4. Kirkwood PA, Romaniuk JR and Kowalski KE. Further observations on cardiac modulation of thoracic motoneuron discharges. Neurosci Lett. 2018 Nov 20. pii: S0304-3940(18)30813-9. doi: 10.1016/j.neulet.2018.11.026. PMID: 30468888.

5. Kowalski KE. Romaniuk JR, Kirkwood PA, and DiMarco AF. Inspiratory Muscle Activation via Ventral Lower Thoracic High Frequency Spinal Cord Stimulation. J Appl Physiol. PMID: 30763163 DOI: 10.1152/japplphysiol.01054.2018. Feb 14, 2019. PMID: 30763163.

Abstracts

1. Kowalski KE, Romaniuk, JR, Brose, S, Richmond MA, Kowalski T, DiMarco AF. High Frequency Spinal Cord Stimulation (HF-SCS) to Restore Cough in a Dog Model. Presented at the National VA Research Week; Cleveland, OH, May 2015.

2. Kowalski KE, Romaniuk JR, Brose S, Richmond MA, Kowalski T, DiMarco AF. High Frequency Spinal Cord Stimulation (HF-SCS) to Restore Cough in a Dog Model. Presented at the Research ShowCASE; Cleveland, OH, April, 2016.

3. Kowalski KE, Romaniuk JR, Brose S, Richmond MA, Kowalski T, DiMarco AF. Expiratory Muscle Activation via High Frequency Spinal Cord Stimulation to Restore Cough in a Dog Model. Presented at the Joint Meeting of the American Physiological Society and the Physiological Society; Dublin, Ireland, July, 2016.

4. Kowalski KE, Romaniuk JR, Brose S, Richmond MA, Kowalski T, DiMarco AF. High Frequency Spinal Cord Stimulation – New Method to Restore Cough. Presented at the Annual Conference of the Academy of Spinal Cord Injury Professionals; Nashville, TN, September 2016.

5. Kowalski KE, Romaniuk JR, Brose S, Richmond MA, Kowalski T, DiMarco AF. Expiratory Muscle Activation via High Frequency Spinal Cord Stimulation. Experimental Biology Annual Meeting; Chicago, IL, April 2017. FASEB J April 2017 31:lb831.

6. Kowalski KE, Romaniuk JR, Pawlowski G, DiMarco AF. High frequency spinal cord stimulation of expiratory muscle activation: potential new method to restore cough. Annual Conference of the International Functional Electrical Stimulation Society; Nottwil, Switzerland, August 2018.

7. Kowalski KE, Romaniuk JR, Pawlowski G, DiMarco AF. Differential Activation of Respiratory Muscles during Lower Thoracic High Frequency Spinal Cord Stimulation (HF-SCS). Experimental Biology Annual Meeting; San Diego, CA, April 2018. FASEB J April 2018.

8. Kowalski KE, Romaniuk JR, Kirkwood PA and DiMarco AF. Effects of High Frequency Spinal Cord Stimulation (HF-SCS) Applied to the Ventral Surface of the Spinal Cord. Aberdeen, UK, July 8-10, 2019.

9. Zander HJ, Kowalski KE, DiMarco AF, Lempka SF. Model-Based Analysis of Lower Thoracic High-Frequency Spinal Cord Stimulation (HF-SCS) to Restore Effective Cough. Experimental Biology Annual Meeting; San Diego, CA. April 2020.

Invited Presentations

1. High frequency spinal cord stimulation of expiratory muscle activation: potential new method to restore cough. Annual Conference of the International Functional Electrical Stimulation Society; Nottwil, Switzerland, August 2018.

2. Complete Restoration of Respiratory Muscle Function from Bench to Bedside.  Academic Partnership Committee. CWRU-VAMC February 19th, 2019.

3. Senate Staff Briefing – VA Translational Research. Washington DC, June 28th, 2019.

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Neuropharmacology of Pontine Control of Breathing Frequency

Protocol Form, Feedback Document, and Summary of the Literature

VA

(protocol closed 6/25/19)

Milwaukee

Purpose of Research: The many Veterans who are administered potent analgesics to control pain, as well as those with certain head or neck injuries, are at risk of respiratory depression that can result in brain damage or death. Finding ways to prevent this depends on understanding how the specific brain cells that control breathing work and how they are impacted by the analgesics. This work was to increase understanding of that control, which is fundamental to developing better ways to help these veterans. This involved recording the electrical activity of individual brain cells under conditions that could be expected to be stable for hours, so that changes in that activity could be observed as the cells were exposed to opioids and other drugs. It was crucial for this work to be done with animals in which the brain structures are large enough for the clusters of neurons involved to be distinct from other neurons, so that it was possible to know which neurons were being observed. Dogs were the best animal species available for this.

Value of the Results: This research identified within the brainstem a particular subregion that appears to be the main controller of breathing rate. This subregion interacts with other parts of the brainstem that generate the rhythmic character of breathing. It also modifies the strength of reflexes triggered by stretch receptors in the lungs, which modify the depth and rate of breathing. These components together are responsible for the timing and pattern of inspiration and expiration that make up normal breathing. Opioids depress the neurons in this subregion, which can dramatically slow or even stop the breathing rate. But the neurons also have receptors for a number of other neurotransmitters and modulators, which are then potential targets for therapeutic drugs to counter the depressive effects of analgesics.

Selected Published Results:

1. Mustapic S, Radocaj T, Sanchez A, Dogas Z, Stucke AG, Hopp FA, and Stuth EA, and Zuperku EJ. Clinically relevant infusion rates of μ-opioid agonist remifentanil causes bradypnea in decerebrate dogs but not via direct effects on the pre-Bötzinger Complex.J.Neurophysiol. 103: 409-418, 2010.

2. Stuth EA, Stucke AG, and Zuperku, EJ. Effects of Anesthetics, Sedatives and Opioids on Ventilatory Control. 2012 American Physiological Society. Compr Physiol 2:1-87, 2012. (Review with 792 references).

3. Prkic I, Mustapic S, Radocaj T, Stucke AG, Stuth EAE, Hopp FA, Dean C, and Zuperku EJ. Pontine μ-opioid receptors mediate bradypnea caused by intravenous remifentanil infusions at clinically relevant concentrations in dogs. J Neurophysiol 108: 2430–2441, 2012. First published August 8, 2012; doi:10.1152/jn.00185.2012.

4. Lalley PM, Pilowsky PM, Forster HV, and Zuperku EJ. Opposing View: The pre-Bötzinger Complex is not essential for respiratory depression following systemic administration of opioid analgesics.J Physiol. 592(6): 1163-1166, 2014.

5. Zuperku EJ, Prkic I, Stucke AG, Miller JR, Hopp FA and Stuth EA.Automatic classification of canine PRG neuronal discharge patterns using K-means clustering.Resp Physiol and Neurobiol207: 28-39, 2015.

6. Radocaj T, Mustapic S, Prkic I, Stucke AG, Hopp FA, Stuth EA, and Zuperku EJ. Activation of 5-HT1A receptors in the preBötzinger region has little impact on the respiratory pattern.Resp Physiol and Neurobiol 212-214: 9-19,2015.

7. Zuperku EJ, Stucke AG, Hopp FA, Stuth EA. Characteristics of breathing rate control mediated by a subregion within the pontine parabrachial complex. J Neurophysiol 117: 1030–1042, 2017. First published December 14, 2016; doi:10.1152/jn.00591.2016.

8. Zuperku EJ, Stucke AG, Krolikowski JG, Tomlinson J, Hopp FA & Stuth EA. (2019). Inputs to medullary respiratory neurons from a pontine subregion that controls breathing frequency. Respir Physiol Neurobiol. 265: 127-140; First published June 28, 2018; doi: 10.1016/j.resp.2018.06.011.

9. Zuperku EJ, Hopp FA, Stuth EA, and Stucke AG.Interaction between the pulmonary stretch receptor and pontine control of expiratory duration.Respir Physiol Neurobiol 2021 Nov;293:103715. doi: 10.1016/j.resp.2021.103715. Epub 2021 Jun 11.

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