Normalization of Blood Pressure With Spinal Cord Epidural Stimulation After Severe Spinal Cord Injury

Susan J Harkema, Siqi Wang, Claudia A Angeli, Yangsheng Chen, Maxwell Boakye, Beatrice Ugiliweneza, Glenn A Hirsch, Susan J Harkema, Siqi Wang, Claudia A Angeli, Yangsheng Chen, Maxwell Boakye, Beatrice Ugiliweneza, Glenn A Hirsch

Abstract

Chronic low blood pressure and orthostatic hypotension remain challenging clinical issues after severe spinal cord injury (SCI), affecting health, rehabilitation, and quality of life. We previously reported that targeted lumbosacral spinal cord epidural stimulation (scES) could promote stand and step functions and restore voluntary movement in patients with chronic motor complete SCI. This study addresses the effects of targeted scES for cardiovascular function (CV-scES) in individuals with severe SCI who suffer from chronic hypotension. We tested the hypothesis that CV-scES can increase resting blood pressure and attenuate chronic hypotension in individuals with chronic cervical SCI. Four research participants with chronic cervical SCI received an implant of a 16-electrode array on the dura (L1-S1 cord segments, T11-L1 vertebrae). Individual-specific CV-scES configurations (anode and cathode electrode selection, voltage, frequency, and pulse width) were identified to maintain systolic blood pressure within targeted normative ranges without skeletal muscle activity of the lower extremities as assessed by electromyography. These individuals completed five 2-h sessions using CV-scES in an upright, seated position during measurement of blood pressure and heart rate. Noninvasive continuous blood pressure was measured from a finger cuff by plethysmograph technique. For each research participant there were statistically significant increases in mean arterial pressure in response to CV-scES that was maintained within normative ranges. This result was reproducible over the five sessions with concomitant decreases or no changes in heart rate using individual-specific CV-scES that was modulated with modest amplitude changes throughout the session. Our study shows that stimulating dorsal lumbosacral spinal cord can effectively and safely activate mechanisms to elevate blood pressures to normal ranges from a chronic hypotensive state in humans with severe SCI with individual-specific CV-scES.

Keywords: cardiovascular system; epidural stimulation; heart rate; spinal cord injuries; systolic blood pressure.

Figures

FIGURE 1
FIGURE 1
Fluoroscopy showing electrode array location relative to thoracic and lumbar vertebrae. Large letters T11, T12, L1, and L2 identify thoracic and lumbar vertebrae; small letters L1–S1 identify the spinal cord levels estimated by mapping with motor-evoked potentials.
FIGURE 2
FIGURE 2
Electromyography, electrocardiography, and blood pressure during different epidural stimulation configurations exemplified in one research participant (B21). (A) Electromyography (EMG) of the soleurs (SOL), medial gastrocnemius (MG), tibialis anterior (TA), medial hamstrings (MH), vastus lateralis (VL), and rectus femoris (RF) during 2 min of no stimulation (left), using CV-scES, 30 Hz, Configuration No. 1 (middle) and using CV-scES, 60 Hz, configuration No. 2 (right) in one research participant B21. The electrode selections and stimulation frequency were indicated on the top right of each panel. Gray boxes are cathodes and black boxes are anodes, white boxes are inactive electrodes. (B) Amplitude of rectified mean EMG, systolic blood pressure, diastolic blood pressure, and heart rate averaged over 2 min of no stimulation (white bars), configuration No. 1 (gray bars) and configuration No. 2 (black bars) from the data shown in (A). Error bars represent standard error. (C) EMG, ECG, and continuous blood pressure in the 10-s windows depicted by the black boxes in (A).
FIGURE 3
FIGURE 3
Systolic blood pressure and heart rate responses to CV-scES in one research participant (A68). Systolic blood pressure gradually increased to target range and was maintained during 60 min of activation of stimulation (Stim ON) with minimal adjustment in stimulation amplitude, compared with baseline without stimulation (Stim OFF). Heart rate generally showed an inverse relationship with systolic blood pressure. Solid circles represent sitting systolic blood pressure (mmHg, top panel) and heart rate (beats per minute, bottom panel) averaged over every 3 min of beat-to-beat values (mean ± SE). Gray shading area represents the target range of systolic blood pressure (110–120 mmHg). Stimulation (Stim) amplitude is shown in the middle and was continuous throughout the 60 min. Frequency was constant at 50 Hz. The vertical dash line indicates the start of stimulation. Electrode configuration is represented on the top right; gray boxes are cathodes, black boxes are anodes, and white boxes are inactive electrodes.
FIGURE 4
FIGURE 4
Mean arterial pressure and heart rate response to CV-scES during their first session. (A) Mean arterial pressure was significantly higher during CV-scES when compared with Pre-CV-scES and Post-CV-scES in all of the four research participants A41 (left panel), A68 (second panel to the left), B21 (second panel to the right), and A80 (right). Mean arterial pressure was significantly lower during Post-CV-scES compared to Pre-CV-scES in research participant A68 (second panel to the left) and higher in research participant A80 (right panel). (B) Heart rate was significantly lower during CV-scES compared to Pre-CV-scES in research participant A41 (left panel). Heart rate was significantly higher during Post-CV-scES when compared with Pre-CV-scES and CV-scES in all four research participants. Data points are 1-min averages of mean arterial pressure and heart rate. Horizontal line, median; solid circle, mean; range of box, interquartile range (25th and 75th percentiles); whiskers, non-outliers maximum and minimum data points; open circles, outliers above or below 1.5× interquartile range. Electrode configurations are represented on the bottom left of the bottom graphs. Gray boxes are cathodes, black boxes are anodes, and white boxes are inactive electrodes. ∗p < 0.0001; #p < 0.003.
FIGURE 5
FIGURE 5
Changes in mean arterial pressure (delta mean arterial pressure, A) and heart rate (delta heart rate, B) during the first half an hour of active CV-scES from Pre-CV-scES, combined for four research participants averaged for five sessions. Mean arterial pressure increased, and heart rate decreased, from Pre-CV-scES to CV-scES in all five sessions. Data points are 1-min averages of mean arterial pressure and heart rate subtracted from mean values of Pre-CV-scES. Horizontal line, median; solid circle, mean; range of box, interquartile range (25th and 75th percentiles); whiskers, non-outliers maximum and minimum data points; open circles, outliers above or below 1.5× interquartile range. Delta of mean arterial pressure and heart rate of all sessions were significantly different from zero (p < 0.05).
FIGURE 6
FIGURE 6
Systolic blood pressure responses to optimal vs. non-optimal stimulation configurations in four research participants (A41: A and E; A68: B and F; B21: C and G; A80: D and H). Optimal stimulation configuration is important as other configurations failed to increase or maintain systolic blood pressure in the target range. Optimal stimulation configurations are shown on the left (A–D) while non-optimal stimulation configurations are shown on the right (E–H). Solid circles represent systolic blood pressure averaged over every 1 min of beat-to-beat values (mean ± SE, left axis). Stimulation was continuous throughout the 10 min, black lines represent stimulation amplitude (right black axis) and gray lines represent stimulation frequency (right gray axis). Participant A80 was stimulated with three programs (D and H). In D and H, thin black line with squares represents stimulation amplitude of program No. 1 (P1), thick black line represents stimulation amplitude of program No. 2 (P2), thin black line with crosses represents stimulation amplitude of program No. 3 (P3). The locations of the squares and crosses in H indicate amplitude changes. Pulse width was 450 μs in all sessions and experiments for all participants. Gray shading areas represent the target range of systolic blood pressure (110–120 mmHg for research participants A41, A68, and B21; 105–115 mmHg for research participant A80). Electrode configurations are represented on the top right of each graph; gray boxes are cathodes, black boxes are anodes, and white boxes are inactive electrodes.

References

    1. Angeli C. A., Edgerton V. R., Gerasimenko Y. P., Harkema S. J. (2014). Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain 137(Pt 5) 1394–1409. 10.1093/brain/awu038
    1. Aslan S. C., Randall D. C., Krassioukov A. V., Phillips A., Ovechkin A. V. (2016). Respiratory training improves blood pressure regulation in individuals with chronic spinal cord injury. Arch. Phys. Med. Rehabil. 97 964–973. 10.1016/j.apmr.2015.11.018
    1. Beres-Jones J. A., Harkema S. J. (2004). The human spinal cord interprets velocity-dependent afferent input during stepping. Brain 127(Pt 10) 2232–2246. 10.1093/brain/awh252
    1. Carlozzi N. E., Fyffe D., Morin K. G., Byrne R., Tulsky D. S., Victorson D., et al. (2013). Impact of blood pressure dysregulation on health-related quality of life in persons with spinal cord injury: development of a conceptual model. Arch. Phys. Med. Rehabil. 94 1721–1730. 10.1016/j.apmr.2013.02.024
    1. Chao C. Y., Cheing G. L. (2005). The effects of lower-extremity functional electric stimulation on the orthostatic responses of people with tetraplegia. Arch. Phys. Med. Rehabil. 86 1427–1433. 10.1016/j.apmr.2004.12.033
    1. Croom J. E., Foreman R. D., Chandler M. J., Barron K. W. (1997). Cutaneous vasodilation during dorsal column stimulation is mediated by dorsal roots and CGRP. Am. J. Physiol. 272(2 Pt 2) H950–H957. 10.1152/ajpheart.1997.272.2.H950
    1. Ditor D. S., Macdonald M. J., Kamath M. V., Bugaresti J., Adams M., McCartney N., et al. (2005). The effects of body-weight supported treadmill training on cardiovascular regulation in individuals with motor-complete SCI. Spinal Cord 43 664–673. 10.1038/sj.sc.3101785
    1. Freeman R. (2008). Current pharmacologic treatment for orthostatic hypotension. Clin. Auton. Res. 18(Suppl. 1) 14–18. 10.1007/s10286-007-1003-1
    1. Gerasimenko Y., Gad P., Sayenko D., McKinney Z., Gorodnichev R., Puhov A., et al. (2016). Integration of sensory, spinal, and volitional descending inputs in regulation of human locomotion. J. Neurophysiol. 116 98–105. 10.1152/jn.00146.2016
    1. Gerasimenko Y. P., Lu D. C., Modaber M., Zdunowski S., Gad P., Sayenko D. G., et al. (2015). Noninvasive reactivation of motor descending control after paralysis. J. Neurotrauma 32 1968–1980. 10.1089/neu.2015.4008
    1. Grillner S., Wallen P. (2004). Innate versus learned movements–a false dichotomy? Prog. Brain Res. 143 3–12.
    1. Hainsworth R., Karim F. (1976). Responses of abdominal vascular capacitance in the anaesthetized dog to changes in carotid sinus pressure. J. Physiol. 262 659–677. 10.1113/jphysiol.1976.sp011614
    1. Harkema S., Gerasimenko Y., Hodes J., Burdick J., Angeli C., Chen Y., et al. (2011). Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet 377 1938–1947. 10.1016/S0140-6736(11)60547-3
    1. Harkema S. J., Ferreira C. K., van den Brand R. J., Krassioukov A. V. (2008). Improvements in orthostatic instability with stand locomotor training in individuals with spinal cord injury. J. Neurotrauma 25 1467–1475. 10.1089/neu.2008.0572
    1. Harkema S. J., Hillyer J., Schmidt-Read M., Ardolino E., Sisto S., Behrman A. (2012a). Locomotor training: as a treatment of spinal cord injury and in the progression of neurological rehabilitation. Arch. Phys. Med. Rehabil. 93 1588–1597. 10.1016/j.apmr.2012.04.032
    1. Harkema S. J., Hurley S. L., Patel U. K., Requejo P. S., Dobkin B. H., Edgerton V. R. (1997). Human lumbosacral spinal cord interprets loading during stepping. J. Neurophysiol. 77 797–811. 10.1152/jn.1997.77.2.797
    1. Harkema S. J., Schmidt-Read M., Lorenz D. J., Edgerton V. R., Behrman A. L. (2012b). Balance and ambulation improvements in individuals with chronic incomplete spinal cord injury using locomotor training-based rehabilitation. Arch. Phys. Med. Rehabil. 93 1508–1517. 10.1016/j.apmr.2011.01.024
    1. Krassioukov A., Claydon V. E. (2006). The clinical problems in cardiovascular control following spinal cord injury: an overview. Prog. Brain Res. 152 223–229. 10.1016/S0079-6123(05)52014-4
    1. Krassioukov A., Eng J. J., Warburton D. E., Teasell R. (2009). A systematic review of the management of orthostatic hypotension after spinal cord injury. Arch. Phys. Med. Rehabil. 90 876–885. 10.1016/j.apmr.2009.01.009
    1. Liu Y., Yue W. S., Liao S. Y., Zhang Y., Au K. W., Shuto C., et al. (2012). Thoracic spinal cord stimulation improves cardiac contractile function and myocardial oxygen consumption in a porcine model of ischemic heart failure. J. Cardiovasc. Electrophysiol. 23 534–540. 10.1111/j.1540-8167.2011.02230.x
    1. Mathias C. J., Kimber J. R. (1998). Treatment of postural hypotension. J. Neurol. Neurosurg. Psychiatry 65 285–289. 10.1136/jnnp.65.3.285
    1. Minson C. T., Wladkowski S. L., Pawelczyk J. A., Kenney W. L. (1999). Age, splanchnic vasoconstriction, and heat stress during tilting. Am. J. Physiol. 276(1 Pt 2) R203–R212. 10.1152/ajpregu.1999.276.1.R203
    1. Mitchell J. M., Dzerdzeevskii B., Flohn H., Hofmeyr W. L., Lamb H. H., Rao K. N., et al. (1966). Technical note No. 79. climatic change. (Report of a working group of the commission for climatology). World Meteorol. Organ. 195:179.
    1. Rejc E., Angeli C., Harkema S. (2015). Effects of lumbosacral spinal cord epidural stimulation for standing after chronic complete paralysis in humans. PLoS One 10:e0133998. 10.1371/journal.pone.0133998
    1. Rejc E., Angeli C. A., Bryant N., Harkema S. J. (2017). Effects of stand and step training with epidural stimulation on motor function for standing in chronic complete paraplegics. J. Neurotrauma 34 1787–1802. 10.1089/neu.2016.4516
    1. Sato T., Kawada T., Sugimachi M., Sunagawa K. (2002). Bionic technology revitalizes native baroreflex function in rats with baroreflex failure. Circulation 106 730–734. 10.1161/01.CIR.0000024101.77521.4D
    1. Schultz D. M., Musley S., Beltrand P., Christensen J., Euler D., Warman E. (2007). Acute cardiovascular effects of epidural spinal cord stimulation. Pain Physician 10 677–685.
    1. Schultz D. M., Zhou X., Singal A., Musley S. (2011). Cardiovascular effects of spinal cord stimulation in hypertensive patients. Pain Physician 14 1–14.
    1. Schutte A. E., Huisman H. W., Van Rooyen J. M., Oosthuizen W., Jerling J. C. (2003). Sensitivity of the Finometer device in detecting acute and medium-term changes in cardiovascular function. Blood Press. Monit. 8 195–201. 10.1097/01.mbp.0000103280.95050.f7
    1. Tanaka S., Barron K. W., Chandler M. J., Linderoth B., Foreman R. D. (2001). Low intensity spinal cord stimulation may induce cutaneous vasodilation via CGRP release. Brain Res. 896 183–187. 10.1016/S0006-8993(01)02144-8
    1. Tanaka S., Komori N., Barron K. W., Chandler M. J., Linderoth B., Foreman R. D. (2004). Mechanisms of sustained cutaneous vasodilation induced by spinal cord stimulation. Auton. Neurosci. 114 55–60. 10.1016/j.autneu.2004.07.004
    1. Tse H. F., Turner S., Sanders P., Okuyama Y., Fujiu K., Cheung C. W., et al. (2015). Thoracic spinal cord stimulation for heart failure as a restorative treatment (SCS HEART study): first-in-man experience. Heart Rhythm 12 588–595. 10.1016/j.hrthm.2014.12.014
    1. Wecht J. M., Bauman W. A. (2017). Implication of altered autonomic control for orthostatic tolerance in SCI. Auton. Neurosci. 209 51–58. 10.1016/j.autneu.2017.04.004
    1. Yamasaki F., Ushida T., Yokoyama T., Ando M., Yamashita K., Sato T. (2006). Artificial baroreflex: clinical application of a bionic baroreflex system. Circulation 113 634–639. 10.1161/circulationaha.105.587915
    1. Yanagiya Y., Sato T., Kawada T., Inagaki M., Tatewaki T., Zheng C., et al. (2004). Bionic epidural stimulation restores arterial pressure regulation during orthostasis. J Appl. Physiol. 97 984–990. 10.1152/japplphysiol.00162.2004
    1. Zipes D. P., Neuzil P., Theres H., Caraway D., Mann D. L., Mannheimer C., et al. (2016). Determining the feasibility of spinal cord neuromodulation for the treatment of chronic systolic heart failure: the DEFEAT-HF study. JACC Heart Fail 4 129–136. 10.1016/j.jchf.2015.10.006
    1. Zwiers F. W., Storch H. V. (1995). Taking serial correlation into account in tests of the mean. J. Clim. 8 336–351. 10.1175/1520-0442(1995)008<0336:TSCIAI>;2

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