A, Epidural spinal cord stimulation unit in combination with a 16-electrode array (red is cathode, blue is anode, white is inactive). B, Systolic blood pressure (SBP) responses during supine rest (minute 0) and 60° head-up tilt (minutes 1-5) with and without stimulation (data are presented as mean ± SEM across the 3 separate testing days); middle cerebral artery blood velocity (MCAv) response at rest and in response to 60° head-up tilt; and a raw steady state blood pressure (BP) tracing during 60° head-up tilt. The vertical dotted line indicates the start and end of stimulation. C, Changes in posterior cerebral artery velocity (PCAv) in response to cerebral activation (eyes open). D, End-diastolic volume (EDV), stroke volume (SV), cardiac output (CO), and heart rate (HR) responses during supine rest and 60° head-up tilt with and without stimulation. The gray arrowheads at the bottom of the panel indicate the direction and magnitude of the response. E, Trunk/lower-limb electromyography (EMG) recordings from the right/left rectus abdominis (RRA/LRA), right/left rectus femoris (RRF/LRF), and right/left soleus (RSOL/LSOL) during 60° head-up tilt with stimulation. RVLM indicates rostral ventrolateral medulla; Stim, stimulation.
A, Descending sympathetic pathways from the rostral ventrolateral medulla (RVLM) in an intact spinal cord, leading to efficacious action potentials (ie, depolarization) in sympathetic circuitry, allow for supraspinal control over vascular tone (ie, vasoconstriction) and blood pressure. B, Interrupted descending sympathetic pathways due to an anatomically discomplete spinal cord injury (SCI), in which a few preserved descending sympathetic fibers crossing the site of injury are not capable of eliciting action potentials in sympathetic circuitry caudal to injury. C, Epidural spinal electrical stimulation (Stim) may increase the resting membrane potential of sympathetic circuitry caudal to the spinal cord injury, allowing for the previously nonefficacious preserved descending sympathetic fibers crossing the site of injury to actively regulate caudal sympathetic circuits and thereby restore control of vascular tone and blood pressure. D, Epidural electrical stimulation stimulates dorsal afferent relays, which likely affect the membrane potential of intersegmental and intrasegmental neurons that (1) receive direct input from descending sympathetic pathways and (2) directly and indirectly lead to depolarization of sympathetic preganglionic neurons, leading to regulation of vascular tone. The dotted lines indicate the depolarization threshold and the arrowheads indicate the response in the blood vessel (ie, when depolarization occurs then constriction of the artery occurs).
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West CR, Phillips AA, Squair JW, et al. Association of Epidural Stimulation With Cardiovascular Function in an Individual With Spinal Cord Injury. JAMA Neurol. 2018;75(5):630–632. doi:10.1001/jamaneurol.2017.5055
The application of epidural electrical stimulation to the lumbosacral spinal cord in individuals with a spinal cord injury (SCI) facilitates supraspinal control of paralyzed limbs.1 There is a growing interest in studying whether epidural stimulation can be leveraged to also abrogate cardiovascular dysfunction, as evidenced by ongoing randomized clinical trials on this topic (NCT02037620; NCT03026816). Here, we investigated whether lumbosacral epidural stimulation could be optimized to control cardiovascular functions in the short term, a top health priority and primary cause of death,2 in 1 individual with a motor-complete cervical SCI.
A man in his early 30s with a chronic C5 motor-complete SCI (ASIA impairment scale B) who was previously (12 months prior) fitted with an epidural spinal cord stimulation unit and 16-electrode array (Restore-ADVANCED and Specify 5-6-5; Medtronic) at T11-L1 vertebral levels was assessed. The placement was confirmed via radiography (Figure 1A). The participant gave his written informed consent. This study was approved by the University of British Columbia Clinical Research Ethics Board.
We first conducted a series of tests (over 2 weeks) to determine the optimum stimulation parameters to increase blood pressure (BP) in the seated position, ultimately selecting a wide-field stimulation configuration (Figure 1A; frequency, 35 Hz; pulse width, 300 milliseconds; intensity, 3.5 V). On the main experimental day, we assessed beat-by-beat BP via finger photoplethysmography (Finometer PRO; Finapres Medical Systems) corrected to brachial BP (Dinamap Pro 300V2; General Electric), cardiac function using transthoracic echocardiography (Vivid7; General Electric Healthcare), cerebral blood flow/neurovascular coupling by transcranial Doppler (ST3; Spencer Technologies), and trunk/lower-limb electromyography (Bagnoli; Delsys Inc). All procedures were initially assessed in the supine position and then in response to a 60° head-up tilt, with and without epidural stimulation. To confirm the reliability of our findings, we reassessed the blood pressure response to a 60° head-up tilt (with and without stimulation) on 3 separate days.
The stimulation resolved the orthostatic hypotension (Figure 1B), which is a debilitating and prevalent condition in SCI.3 The rise in BP in response to stimulation was well-controlled and did not increase uncontrollably, as it does during autonomic dysreflexia (Figure 1B).4 In the brain, the stimulation prevented the orthostatic-induced 30% decrease in middle cerebral artery blood flow (Figure 1B), improved neurovascular coupling (Figure 1C), and resolved orthostatic-induced symptoms, including light-headedness, dizziness, and poor concentration, that were self-reported without stimulation. The stimulation also prevented the reduction in cardiac filling (ie, end-diastolic volume) during tilt (Figure 1D), thereby preserving stroke volume and cardiac output. The general lack of lower-limb electromyography during stimulation indicates that the skeletal muscle contraction was not leading to venous pump-mediated increases in BP and venous return (Figure 1E).
To our knowledge, this study is one of the first to demonstrate the acute cardiovascular benefits of lumbosacral epidural stimulation in an individual with SCI that spanned the systemic vasculature, heart, and brain. That we found an immediate benefit in integrated cardiovascular responses raises the possibility that epidural stimulation can excite sympathetic circuitry and instantaneously modulate cardiovascular function in individuals with SCI. The possibility of using electrical spinal cord stimulation to modulate hemodynamics in isolated vascular beds and/or organs has been investigated in various settings and species, with the primary intent of alleviating pain,5 but to our knowledge, this is one of the first demonstrations that acute lumbosacral epidural stimulation modulates multiple facets of the cardiovascular system concomitantly, following motor-complete cervical SCI. We postulate that epidural stimulation can specifically modulate cardiovascular function by increasing the resting membrane potential of sympathetic circuitry via the stimulation of dorsal afferent relays (Figure 2).6
These preliminary data suggest that epidural neuroprosthetics may be a viable approach to manage cardiovascular dysfunction in individuals with chronic SCI and provide an important complement to pharmacological agents that are often slow-acting with undesirable adverse effects.
Corresponding Author: Andrei V. Krassioukov, MD, PhD, Division of Physical Medication & Rehabilitation, Department of Medicine, International Collaboration on Repair Discoveries-Blusson Spinal Cord Centre, University of British Columbia, 818 W 10th Ave, Vancouver, BC V5Z 1M9, Canada (firstname.lastname@example.org).
Accepted for Publication: November 19, 2017.
Published Online: February 19, 2018. doi:10.1001/jamaneurol.2017.5055
Open Access: This article is published under the JN-OA license and is free to read on the day of publication.
Correction: This article was corrected online November 5, 2018, to correct the affiliation of Dr Phillips.
Author Contributions: Drs West and Phillips contributed equally to this work and share first authorship. Drs West and Phillips had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: West, Phillips, Walter, Krassioukov.
Acquisition, analysis, or interpretation of data: West, Phillips, Squair, Williams, Walter, Lam.
Drafting of the manuscript: West, Phillips, Krassioukov.
Critical revision of the manuscript for important intellectual content: West, Phillips, Squair, Williams, Walter, Lam.
Statistical analysis: Squair.
Obtained funding: Krassioukov.
Administrative, technical, or material support: West, Phillips, Williams, Walter, Lam, Krassioukov.
Supervision: Walter, Lam, Krassioukov.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was funded by grant 2015-31 from the Rick Hansen Institute.
Role of the Funder/Sponsor: The Rick Hansen Institute had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Alison M. M. Williams, BKIN, and Amanda H. X. Lee, BS (International Collaboration on Repair Discoveries), for their assistance with the collection and analyses of electromyography and transcranial Doppler data, respectively. They were not compensated for their contributions.
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