Neuromodulation: Technology at the Neural Interface Received: September 2, 2013
Revised: February 9, 2014
Accepted: February 13, 2014
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12177
Modulation of Cerebral Blood Flow With Transcutaneous Electrical Neurostimulation (TENS) in Patients With Cerebral Vasospasm After Subarachnoid Hemorrhage Mark ter Laan, MD, PhD*1; J. Marc C. van Dijk, MD, PhD*; Roy Stewart, PhD†; Michiel J. Staal, MD, PhD*; Jan-Willem J. Elting, MD, PhD‡ Objectives: Transcutaneous electrical neurostimulation (TENS) and spinal cord stimulation have been shown to increase peripheral and cerebral blood flow. We postulate that certain pathological conditions attenuate cerebral autoregulation, which may result in a relative increase of the importance of neurogenic regulation of cerebral blood flow, which could be decreased by electrical modulation. We therefore assess the effects of TENS on cerebral blood flow velocities (CBFVs) and cerebral saturation in patients with cerebral vasospasm after subarachnoid hemorrhage (SAH). Materials and Methods: Cervical TENS was applied in 10 SAH patients with transcranial Doppler (TCD)-proven cerebral vasospasm. Measurements included plethysmography, near-infrared spectroscopy, capnography, and CBFVs by TCD. After determining the optimal frequency and current, patients were treated with cervical TENS for two periods of three days, with a pause of one day in between. Results: The TENS electrodes were not always tolerated by the patients. Higher frequencies demonstrated the most prominent combined effects. ETCO2 was 0.19% lower with TENS off than with TENS on (p = 0.05). Mean arterial blood pressure and pulse were not significantly different over time. CBFV in MCA was decreased (p = 0.07) while cerebral oxygen saturation was increased (p = 0.01) after the use of TENS. Conclusions: Our data suggest improved cerebral blood flow when using cervical TENS in patients with cerebral vasospasm. Several factors could have attenuated the effects: the electrodes were poorly tolerated, ETCO2 increased during TENS, few vessels showed prolonged vasospasm, and overall flow velocities were low. Still, an on–off effect of TENS over time was detected. Keywords: Cerebral blood flow, electrical stimulation, subarachnoid hemorrhage, sympathetic nervous system, vasospasm Conflict of Interest: The authors reported no conflict of interest.
INTRODUCTION
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Address correspondence to: Mark ter Laan, MD, PhD, Department of Neurosurgery, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen 9700, The Netherlands. Email: [email protected] * Department of Neurosurgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands † Department of Health Sciences, Community & Occupational Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands ‡ Department of Neurophysiology and Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 1 Current Address: Mark ter Laan, MD, PhD, Department of Neurosurgery, Radboud University Medical Center, Nijmgen, The Netherlands. For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1 Clinical Trial Registration: Dutch Trial Registry: http://www.trialregister.nl/trialreg/ index.asp, unique identifier: NTR2358.
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Cervical spinal cord stimulation (SCS) has been reported to increase cerebral blood flow (CBF) (1–3). Studies with thoracic SCS in patients with coronary vasospasm showed increased coronary perfusion, as did studies using transcutaneous electrical nerve stimulation (TENS) (4–6). This effect may be partly mediated by the sympathetic nervous system (7,8). Indeed, inhibitory effects of TENS on sympathetically mediated reflexes have been shown (9). Because of the analogies of TENS with SCS and because of the proven effect on coronary perfusion and sympathetic tone, possibly, cervical TENS also increases CBF. Symptomatic delayed cerebral ischemia (DCI) occurs in up to 30% of patients with subarachnoid hemorrhage (SAH). Fifteen to 20% of them remain disabled or die as a result of progressive ischemia or stroke. Current treatment cannot prevent this morbidity (10). A previous study that showed that cervical TENS could be safely applied in healthy subjects failed to demonstrate an effect on CBF (11). This is thought to be due to the regulatory effects of the intact cerebral autoregulation. We hypothesize that after SAH, cerebral
TER LAAN ET AL.
Figure 1. Study protocol. TENS, transcutaneous electrical neurostimulation.
autoregulation is disrupted, which might open possibilities for TENS to influence CBF. If TENS increases CBF, it might decrease ischemia and could as such be a useful adjunct in the treatment or prevention of DCI SAH. In this pilot study, cervical TENS was applied in SAH patients with cerebral vasospasm.
METHODS The local research ethical board approved the study protocol. Ten patients with cerebral vasospasm after confirmed aneurysmatic SAH were included. Cerebral vasospasm was defined as a middle cerebral artery (MCA) to internal carotid artery (ICA) flow velocity ratio of more than 3 (Lindegaard index). Inclusion and exclusion criteria were as follows:
In the first part of the study, the optimal frequency for the subject was determined. After a baseline data collection, stimulation took place for 10 min for each frequency. In the second part of the study, changes in study parameters were monitored during a seven-day period of stimulation, using the frequency determined in the first part of the study. Patients received continuous TENS treatment for three days (additional to regular SAH treatment), then it was stopped for one day, and again continued for three days. In this way, effects of TENS can be discerned from the physiological decrease of flow velocities over time in patients with vasospasm; for example, an increase of flow velocities after stopping TENS makes it more plausible that an observed decrease during TENS was indeed caused by TENS. Data were collected on day 0, day 3, day 4, and day 7 (Fig. 1).
• History of cervical spine or skull-base surgery • Known adverse reaction to TENS pads • The presence of any implanted electronic device (including pacemakers) • Preexisting disease that can obscure follow-up • Unacceptable interference with electrocardiography registration (in case intensive care is necessary) • Insufficient temporal bony windows • The use of sympathomimetic or sympatholytic agents
Data Collection and Integration An experimental setup was designed to indirectly determine CBF (represented by CBF velocity and cerebral oxygenation), as well as to continuously monitor as many factors that influence CBF as possible. Data were collected using a continuous TCD monitor (Nicolet Pioneer TC8080, Carefusion Corporation, San Diego, CA USA) to measure cerebral blood flow velocities (CBFVs) in the MCA on both sides. Each time the highest flow velocities were used in the first session (mostly found around 50 mm depth), and the subsequent measurements were taken at the same depth. A plethysmograph was used for assessing blood pressure and heart rate (HR) (Finometer-Pro, Finapress Medical Systems, Amsterdam, the Netherlands), a capnograph (CapnomacUltima, GE Healthcare, Chalfont St Giles, UK) to measure end tidal CO2, and a near-infrared spectroscope (Invos 5100C, Somanetics, Troy, MI, USA) to measure cerebral oxygenation (ScO2). The near-infrared spectroscopy (NIRS) electrodes were placed bilaterally on the forehead, covering mostly MCA territory, but also anterior cerebral artery (ACA) territory. The data were continuously registered using Labview 9.0 software (Labview, National Instruments, Austin, TX , USA). Raw data were sampled at 250 Hz. Beat-to-beat averages were calculated by using the arterial blood pressure curve for triggering (12).
The subjects were treated with conventional TENS, providing a continuous flow of symmetrical rectangular biphasic pulses (Schwa Medico, Pierenkemper GMBH, Ehringhausen, Germany). Stimulation was performed at 90% of the highest tolerated current (painful or motor response evoking), with a pulse width of 200 msec. Stimulation frequencies were 20, 50, 100, and 120 Hz. Subjects were positioned supine during the entire experiment. The TENS electrodes were applied cervically on both sides of the dorsal midline at the level of the mandibular angle.
Statistical Analysis In order to determine the optimal frequency of stimulation, an ad hoc analysis was performed (12). Stable sections of data of the same length with least artifacts were selected for analysis after visual inspection. In order to clean the data from artifacts, 5% of top and bottom of data were deleted, replacing those by linear interpolation using in-house written routines in the Matlab environment (Matlab 6.5, The Math Works, Inc., Natick, MA, USA). Recordings of data were
Inclusion Criteria • Confirmed aneurysmatic SAH • Cerebral vasospasm demonstrated by transcranial Doppler (TCD), defined as an MCA/ICA ratio >3 • Aneurysm secured with a surgical or endovascular procedure • Age >18 years • Treatment can be started promptly • Informed consent signed by patient or family Exclusion Criteria
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Table 1. Patient Characteristics.
1 2 3 4 5 6 7 8 9 10
Age
WFNS
Fisher
HC
Aneurysm
Aneurysm treatment
Day first spasm
Day inclusion
55 51 51 53 40 65 55 69 23 55
5 1 1 1 1 2 1 2 1 2
4 3 2 2 1 4 1 2 1 2
Y Y N Y N Y N N N Y
Acom MCA-L Pcom-R Acom MCA-L Acom Pcom-L Pcom-R ICA-R MCA-L
Coil Coil Coil Coil Clip Coil Coil Coil Coil Clip
5 5 5 3 7 7 3 7 7 7
6 7 8 4 8 8 4 10 8 9
Acom, anterior communicating artery; Fisher, Fisher grade; HC, hydrocephalus; ICA, internal carotid artery; L, left; MCA, middle cerebral artery; Pcom, posterior communicating artery; R, right; WFNS, World Federation of Neurological Surgeons grading.
compared with baseline using the Student’s t-test. An effect size was calculated for the significant differences over time (with baseline as anchor point) in order to determine the frequency with the greatest amount of change from the baseline. If none of the frequencies showed an effect of more than 20% of the pooled standard deviation, no superiority was assumed (13). A multilevel model was used for the analysis of the frequency data of all patients for left and right side using SAS 9.2 software (SAS 9.2, SAS Institute Inc, Raleigh, NC, USA). Measurements were nested in patient, and data were adjusted for variance of the confounders mean arterial blood pressure (MAP), HR, and ETCO2. For analyzing the CBFV in the MCA and the ScO2, data were extracted at the left and right side, at four different days (0, 3, 4, and 7). A multilevel model was designed where side was nested within patient, day was nested within side, and measurement was nested within day. The computer software MLwin 2.28 (Centre of Multilevel Modelling, University of Bristol, UK) was used for calculating these models.
RESULTS Between July 2010 and November 2011, 10 patients could be included. One patient refused to continue TENS a few hours after the first data collection (subject nr. 5, Table 1). All other included subjects (N = 9) completed TENS treatment for seven days, or until vasospasm disappeared. Characteristics of patients are shown in Table 1. In five patients, dislodged electrodes had to be replaced at least once. Main causes of dislodged electrodes were disease-related restlessness and the fact that poorly cooperating patients could not tolerate the paresthesias. All patients developed a slight burning of the skin around the sites of TENS application, although this never led to stopping the TENS application.
TENS FREQUENCIES
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Differences in MAP, HR, and ETCO2 over time were not significant (Fig. 2a). ETCO2 was 0.19% lower with TENS off than with TENS on (p = 0.05). MCA blood flow velocities and cerebral oxygenation (ScO2 by NIRS) are shown in Figure 2b, corrected for variability in MAP, HR, and ETCO2 (in a multilevel analysis). When comparing CBFV and ScO2 at days 0 and 4 (TENS off) with days 3 and 7 (TENS on), CBFV was 8.72 m/sec slower when TENS was on (p = 0.07) and saturation improved by 2.66% (p = 0.01). We analyzed spastic and non-spastic vessels separately in a fourlevel model. Spasm was determined as an ICA/MCA ratio >3 on two or more occasions (because not all included patients showed spasm after inclusion). Differences in MCA flow velocities were not statistically significant, but a trend toward an on–off effect was found. Significant differences were found in ScO2 between days 0 and 3 in the non-spastic vessels and between days 3 and 4 and 4 and 7 in the spastic vessels (Fig. 3). When comparing CBFV and ScO2 at days 0 and 4 (TENS off) with days 3 and 7 (TENS on), CBFV did not significantly change for neither non-spastic nor spastic vessels. ScO2 increased 3.35% when TENS was on in non-spastic vessels (p = 0.07) and ScO2 increased 2.40% in spastic vessels (p = 0.06).
DISCUSSION Interpretation of TCD and NIRS Data During the measurements at day 0, the higher frequencies showed more convincing effects than the lower frequencies. Therefore, stimulation frequencies of 100 and 120 Hz were used. Our data showed a trend toward decreased MCA flow velocities, while oxygenation of the frontal lobe significantly increased during TENS treatment. This is suggestive of decreased vasospasm and increased CBF. Because ETCO2 increased during TENS, the measured effects on CBFV may have been attenuated, while effects on ScO2 could be overestimated. Even though few effects reached statistical significance in the small study population, there is an on–off effect over time. These results comply with previous findings of increased CBF in patients treated with cervical SCS (1–3). Especially, the non-spastic vessels seem to contribute to the significant increase of cerebral saturation during TENS treatment, while the changes in flow velocities are more prominent in spastic vessels.
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In four subjects, 100 Hz demonstrated the most prominent combined effects (t-test, data not shown), while in other four, 120 Hz was superior. In two patients, no differences could be demonstrated and 100 Hz was used on pragmatic grounds. When comparing the frequencies used in all patients, no significant differences were found in flow velocities. There was a small but significantly higher cerebral oxygenation (5%) though when using TENS in the highest frequencies.
ANALYSIS OF TENS TREATMENT
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Figure 2. a. Cerebral blood flow velocity (CBFV in centimeter per second) in middle cerebral arteries of all patients (18 arteries) and cerebral oxygen saturation (ScO2 in %). p values are indicated. b. Mean arterial blood pressure (MAP) and heart rate (HR) during the seven-day period of treatment showed no significant changes. c. End tidal CO2 showed a slight increase when TENS was on. Subjects 3, 7, and 8 had no vasospasm anymore on day 4. In these patients, only the measurements of days 1, 3, and 4 are included. All means on day 7 were calculated from the remaining six subjects.
TCD alone is not reliable for estimating CBF, especially when vessel diameters change. It is impossible to determine with sufficient certainty if proximal or distal diameter changes have occurred. We have used NIRS to measure distal cerebral oxygenation to facilitate this. Provided that brain metabolism, oxygen extraction, blood pressure, and PaCO2 remain unaltered during the measurement, an increase in oxygenation indicates vasodilatation and an increase in CBF, while a decrease indicates vasoconstriction and a decrease in CBF. Still, even though a raised ETCO2 or MAP can also explain an increase in CBFV, a decrease in CBFV under these circumstances cannot be disregarded and could be caused by an increased vessel diameter.
Physiological Basis of Neurogenic Control The anatomical and physiological bases of neurogenic control of CBF have been extensively studied and reviewed (14–18). While overruled by stronger mechanisms in normal resting state, we postulate that in pathological conditions such as SAH, sympathetic regulation becomes more important because cerebral autoregulation is (focally) decreased (12). Electrical modulation of the sympathetic nerve activity could then be of therapeutic importance. Our data suggest that if TENS increases CBF, it does so by means of a peripheral vasodilation, because the increase in ScO2 was more convincing than the decrease in CBFV. Possibly locally increased sympathetic tone causes decreased peripheral CBF (leading to DCI), which can be reversed by TENS.
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Limitations of This Study Because this was not a blinded study, bias cannot be ruled out. Our population is small because it concerns a pilot study. We did measure confounding factors like MAP, HR, and ETCO2, but we were not technically able to correct them during the measurements. The average changes in these confounders were very small though www.neuromodulationjournal.com
(Fig. 2). Another problem is that we have chosen to include patients when an ICA/MCA ratio of 3 or higher was detected; some patients only reached this once and therefore fewer spastic vessels were studied than was aimed for. Overall, the flow velocities in our population were not very high. Another factor that could lead to an underestimation of the effects of TENS on CBFV is the fact that ETCO2 was slightly higher when TENS was on than when it was off, which would increase MCA flow velocities. On the other hand, this can cause an overestimation of the effects on ScO2. A technical limitation is the fact that NIRS in our study detects the combined cerebral saturation of (part of ) both ACA and MCA territories. Theoretically, an increased saturation in ACA territory could mask a decreased saturation in MCA territory. Finally, TENS was tolerated far less than expected in this patient group. Several patients did not tolerate the TENS treatment very well, complaining of local paresthesias. Of course, headache after SAH could have sensitized patients. Some patients were too restless to keep the electrodes in place, even though the cutaneous injuries were mild.
Implications for Clinical Practice Our data show that high-frequency cervical TENS has the potential to increase CBF in SAH patients with cerebral vasospasm. The largest effects (in the on–off analysis) on MCA flow velocity and cerebral oxygenation were around 15% and 10%, respectively, which is hardly clinically relevant. The clinical feasibility is low because patients poorly tolerated the electrodes. All in all, we postulate that based on our results, further research toward more invasive kinds of electrical neurostimulation at the cervical level in SAH patients is warranted. Possibly, subcutaneous or epidural electrical stimulation will achieve higher electrical currents, resulting in better effects on CBF. Also, SAH patients might better tolerate these methods.
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Figure 3. Cerebral blood flow velocities and cerebral saturation in spastic and non-spastic vessels (territories). Middle cerebral artery flow velocity (MCAv) in centimeter per second; cerebral oxygen saturation in %. Results of day 7 were calculated based on the data of the six remaining patients. Only eight vessels were considered spastic (see text). No statistically significant differences were found in MCA. p values for ScO2 are shown.
CONCLUSIONS
How to Cite this Article:
Despite its limitations, cervical TENS increases cerebral oxygenation and shows a trend toward decreased MCA flow velocities in the presence of cerebral vasospasm after SAH. The beneficial changes found in our study are clinically not relevant though. More invasive methods of electrical stimulation are probably better tolerated and can as such be expected to achieve better and more relevant clinical results.
ter Laan M., van Dijk J.M.C., Stewart R., Staal M.J., Elting J.-W.J. 2014. Modulation of Cerebral Blood Flow With Transcutaneous Electrical Neurostimulation (TENS) in Patients With Cerebral Vasospasm After Subarachnoid Hemorrhage. Neuromodulation 2014; 17: 431–437
Authorship Statements
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1. Clavo B, Robaina F, Catala L et al. Increased locoregional blood flow in brain tumors after cervical spinal cord stimulation. J Neurosurg 2003;98:1263–1270. 2. Takanashi Y, Shinonaga M. Spinal cord stimulation for cerebral vasospasm as prophylaxis. Neurol Med Chir (Tokyo) 2000;40:352–356. 3. Clavo B, Robaina F, Catala L et al. Effect of cervical spinal cord stimulation on regional blood flow and oxygenation in advanced head and neck tumours. Ann Oncol 2004;15:802–807.
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Drs. ter Laan, van Dijk, Staal, and Elting contributed to the conception and design of the study. Drs. Elting and ter Laan performed experiments and data collection. Analysis of data was performed by Drs. Stewart and ter Laan. Dr. ter Laan drafted the manuscript, with important intellectual input from all other authors. All authors have read and approved the submitted manuscript.
REFERENCES
TER LAAN ET AL. 4. Sanderson JE, Woo KS, Chung HK, Chan WW, Tse LK, White HD. The effect of transcutaneous electrical nerve stimulation on coronary and systemic haemodynamics in syndrome X. Coron Artery Dis 1996;7:547–552. 5. Hautvast RW, Ter Horst GJ, DeJong BM et al. Relative changes in regional cerebral blood flow during spinal cord stimulation in patients with refractory angina pectoris. Eur J Neurosci 1997;9:1178–1183. 6. Jessurun GA, Hautvast RW, Tio RA, DeJongste MJ. Electrical neuromodulation improves myocardial perfusion and ameliorates refractory angina pectoris in patients with syndrome X: fad or future? Eur J Pain 2003;7:507–512. 7. Goellner E, Slavin KV. Cervical spinal cord stimulation may prevent cerebral vasospasm by modulating sympathetic activity of the superior cervical ganglion at lower cervical spinal level. Med Hypotheses 2009;73:410–413. 8. Linderoth B, Herregodts P, Meyerson BA. Sympathetic mediation of peripheral vasodilation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes. Neurosurgery 1994;35:711–719. 9. Sanderson JE, Tomlinson B, Lau MS et al. The effect of transcutaneous electrical nerve stimulation (TENS) on autonomic cardiovascular reflexes. Clin Auton Res 1995;5:81–84. 10. Weyer GW, Nolan CP, Macdonald RL. Evidence-based cerebral vasospasm management. Neurosurg Focus 2006;21:E8. 11. Ter Laan M, van Dijk JMC, Elting JWJ, Fidler V, Staal MJ. The influence of transcutaneous electrical neurostimulation (TENS) on human cerebral blood flow velocities. Acta Neurochir (Wien) 2010;152:1367–1373. 12. Ter Laan M, van Dijk JMC, Staal MJ, Elting JWJ. Electrical modulation of the sympathetic nervous system in order to augment cerebral blood flow: a protocol for an experimental study. BMJ Open 2011;1:e000120. 13. Middel B, Stewart R, Bouma J, Van Sonderen E, Van den Heuvel WJ. How to validate clinically important change in health-related functional status. Is the magnitude of the effect size consistently related to magnitude of change as indicated by a global question rating? J Eval Clin Pract 2001;7:399–410. 14. Edvinsson L, Hamel E.Perivascular nerves in brain vessels.In: Edvinsson L, Krause DN, eds. Cerebral blood flow and metabolism, Vol. 2nd. Philadelphia, PA: Lippincott, Williams and Wilkins, 2002:43–67. 15. Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol 2006;100:1059–1064. 16. Goadsby PJ, Edvinsson L. Neurovascular control of the cerebral circulation. In: Edvinsson L, Krause DN, eds. Cerebral blood flow and metabolism, Vol. 2nd. Philadelphia, PA: Lippincott, Williams & Wilkins, 2002:172–188. 17. Sandor P. Nervous control of the cerebrovascular system: doubts and facts. Neurochem Int 1999;35:237–259. 18. Ter Laan M, van Dijk JM, Elting JW, Staal MJ, Absalom AR. Sympathetic regulation of cerebral blood flow in humans: a review. Br J Anaesth 2013;111:361–367.
COMMENTS
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The authors of this study are to be congratulated with an attempt to eliminate a dangerous and potentially deadly complication of aneurysmal subarachnoid hemorrhage (aSAH) with a non-invasive neuromodulation approach. The practical implications of this concept have a huge clinical potential, mainly because there is still no reliable way to prevent, or treat, for that matter, the cerebral arterial vasospasm that develops in up to a half of aSAH patients. The choice of neuromodulation approach is remarkable. The first clinical observations of spinal cord stimulation (SCS) effects on cerebral flow took place almost 30 years ago (1). Following this, SCS was shown to be effective in relief of arterial vasospasm in various animal models (2–4). This was then tested in humans—initially in Japan by Takanashi and Shinonaga (5), and then in the US by our group (6). A hypothesis was proposed to explain the SCS action (7), but it appears that clinical effects we discovered were, at least in part, opposite to the hypothesized mechanism of vasospasm-relieving effect. The limited clinical experience is insufficient to draw any meaningful conclusions or come up with any practical recommendations. It is clear, however, that a larger prospective study may be able to define optimal stimulation parameters, best electrode location, most effective timing of stimulation, the rest of the so far unanswered questions, and perhaps make this modality an acceptable treatment of vasospasm after aSAH. In the meantime, transcutaneous electrical nerve stimulation (TENS) remains a much more attractive way to modulate neural activity, mainly because it is cheaper, safer and easier than SCS—and these advantages make the efforts of the authors of this study worthwhile. www.neuromodulationjournal.com
Even though the results presented here are not clinically impressive, the research should continue. As the authors mention in their article, the ultimate goal is to use this in “treatment and prevention of delayed cerebral ischemia.” If TENS, with proper optimization, turns out to be an effective approach to reach this goal, millions of patients and families will appreciate the investigators’ efforts. With this, I feel that research should gradually shift from attempts to treat ischemia to a reliable way to prevent it. Konstantin Slavin, MD Chicago, IL, USA REFERENCES 1. Hosobuchi Y. Electrical stimulation of the cervical spinal cord increases cerebral blood flow in humans. Stereotact Funct Neurosurg 1985;48:372–376. 2. Vicocchi M, Argiolas L, Meglio M, Cioni B, Dal Basso P, Rollo M, Cabezas D. Spinal cord stimulation and early experimental cerebral spasm: the “functional monitoring” and the “preventing effect”. Acta Neurochir (Wien) 2001;143:177–185. 3. Karadağ Ö, Erdoğlu E, Gürelik M, Göksel HM, Kiliç E, Gültürk S. Cervical spinal cord stimulation increases cerebral cortical blood flow in an experimental cerebral vasospasm model. Acta Neurochir (Wien) 2005;147:79–84. 4. Lee JY, Huang DL, Keep R, Sagher O. Effect of electrical stimulation of the cervical spinal cord on blood flow following subarachnoid hemorrhage. J Neurosurg 2008;109:1148– 1154. 5. Takanashi Y, Shinonaga M. Spinal cord stimulation for cerebral vasospasm as prophylaxis. Neurol Med Chir (Tokyo) 2000;40:352–357. 6. Slavin KV, Vannemreddy PSSV, Goellner E, Alaraj AM, Aydin S, Eboli P, Mlinarevich N, Watson KS, Walters LE, Amin-Hanjani S, Deveshwar R, Aletich V, Charbel FT. Use of cervical spinal cord stimulation in treatment and prevention of arterial vasospasm after aneurysmal subarachnoid hemorrhage: Technical details. Neuroradiology J 2011;24:131– 135. 7. Goellner E, Slavin KV. Cervical spinal cord stimulation may prevent cerebral vasospasm by modulating sympathetic activity of the superior cervical ganglion at lower cervical spinal level. Med Hypothes 2009;73:410–413.
*** The quest to enhance blood flow with SCS is almost as old as the therapy itself. Even as far back as 1976, investigators noted that SCS resulted in potentially important improvements in tissue perfusion (1). While the question of whether the same effect could be seen for cerebral blood flow wasn’t raised until 1985, it has been investigated in a number of animal models and occasional clinical reports since then (2–4). Experimental work has shown fairly convincingly that SCS could result in increases in CBF, when applied to the high cervical spine. In addition, there is evidence that the mechanism for this effect involves modulation of vasomotor centers in the rostral ventral lateral medulla and cerebellum (5–7). Clinical reports of the potentially salubrious effect of SCS have lagged behind, however (8,9). Despite a few promising small studies in humans, electrical stimulation for the treatment or prevention of stroke still remains on the “to-do list” of neuromodulation. One of principal hurdles to clinical investigation of electrical stimulation therapy for the treatment of cerebral ischemia is the invasiveness of this modality. Spinal cord stimulation requires the placement of an electrode into the spinal canal—a non-trivial consideration in a patient who may be a candidate for thrombolytic therapy in a time-critical window. In the case of subarachnoid hemorrhagerelated vasospasm, the implantation of a SCS lead in a patient who is critically ill, and who may be undergoing systemic anticoagulation, also presents a significant logistical challenge. The study of these modalities is therefore curtailed by the apparent conflict with established acute therapies. In light of the challenges presented by invasive electrical stimulation therapies, ter Laan et al. take a step back and examine the effect of noninvasive stimulation on cerebral perfusion in the setting of cerebral vasospasm (10). The clear advantage of this approach is the ability to study its efficacy with little to no risk. The potential disadvantage of using TENS to study therapeutic benefit to cerebral blood flow is the
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TENS FOR VASOSPASM AFTER SAH increased likelihood that this treatment would be ineffective. Since the presumed goal is the modulation of vasomotor centers within the brainstem, it is entirely possible that TENS would lack sufficient power to modulate a target so far centrally. The modest central vasomotor effects seen in this study are therefore not surprising. It is also not surprising that the authors found that the most consistent effect of TENS was patient discomfort. It is likely that the amplitude of stimulation required for any vasoactive changes to be appreciated would be high enough to be intolerable. It is important that we continue our efforts to harness the nervous system’s natural protective mechanisms. Doing so is the core of neuromodulation. Inasmuch as delivering these therapies in the least invasive way possible is our goal, approaches like the one undertaken by ter Laan are to be encouraged. Perhaps we will eventually have the technology to deliver such modulation more centrally without being invasive. For now, however, we are still fighting the limits of peripheral stimulation when attempting to do so without any invasion whatsoever. Oren Sagher, MD Ann Arbor, MI, USA
2. Hosobuchi Y. Electrical stimulation of the cervical spinal cord increases cerebral blood flow in humans. Applied Neurophysiology 1985;48(1–6):372–376. 3. Meglio M, Cioni B, Visocchi M, Nobili F, Rodriguez G, Rosadini G, et al. Spinal cord stimulation and cerebral haemodynamics. Acta Neurochirurgica 1991;111(1–2):43–48. 4. Visocchi M, Cioni B, Vergari S, Marano G, Pentimalli L, Meglio M. Spinal cord stimulation and cerebral blood flow: an experimental study. Stereotactic and Functional Neurosurgery 1994;62(1–4):186–190. 5. Reis DJ, Golanov EV, Galea E, Feinstein DL. Central neurogenic neuroprotection: central neural systems that protect the brain from hypoxia and ischemia. Annals of the New York Academy of Sciences 1997;835:168–186. 6. Glickstein SB, Golanov EV, Reis DJ. Intrinsic neurons of fastigial nucleus mediate neurogenic neuroprotection against excitotoxic and ischemic neuronal injury in rat. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 1999;19(10):4142–4154. 7. Patel SS, Huang D-LD, Sagher OO. Evidence for a central pathway in the cerebrovascular effects of spinal cord stimulation. Neurosurgery 2004;55(1):201–206. 8. Takanashi Y, Shinonaga M. Spinal cord stimulation for cerebral vasospasm as prophylaxis. Neurologia Medico-Chirurgica 2000;40(7):352–356; discussion 356–357. 9. Slavin KV, Vannemreddy PSSV, Goellner E, Alaraj AM, Aydin S, Eboli P et al. Use of cervical spinal cord stimulation in treatment and prevention of arterial vasospasm after aneurysmal subarachnoid hemorrhage. Technical details. The Neuroradiology Journal 2011;24(1):131–135. 10. Ter Laan M, van Dijk JCM, Stewart R, Staal MJ, Elting JJ. Modulation of cerebral blood flow with transcutaneous electrical neurostimulation (TENS) in patients with cerebral vasospasm after subarachnoid hemorrhage. Neuromodulation: Technology at the Neural Interface 2014;17:431–437.
Comments not included in the Early View version of this paper.
REFERENCES 1. Cook AW, Oygar A, Baggenstos P, Pacheco S, Kleriga E. Vascular disease of extremities. Electric stimulation of spinal cord and posterior roots. New York State Journal of Medicine 1976;76(3):366–368.
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Neuromodulation 2014; 17: 431–437
Revised: February 9, 2014
Accepted: February 13, 2014
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12177
Modulation of Cerebral Blood Flow With Transcutaneous Electrical Neurostimulation (TENS) in Patients With Cerebral Vasospasm After Subarachnoid Hemorrhage Mark ter Laan, MD, PhD*1; J. Marc C. van Dijk, MD, PhD*; Roy Stewart, PhD†; Michiel J. Staal, MD, PhD*; Jan-Willem J. Elting, MD, PhD‡ Objectives: Transcutaneous electrical neurostimulation (TENS) and spinal cord stimulation have been shown to increase peripheral and cerebral blood flow. We postulate that certain pathological conditions attenuate cerebral autoregulation, which may result in a relative increase of the importance of neurogenic regulation of cerebral blood flow, which could be decreased by electrical modulation. We therefore assess the effects of TENS on cerebral blood flow velocities (CBFVs) and cerebral saturation in patients with cerebral vasospasm after subarachnoid hemorrhage (SAH). Materials and Methods: Cervical TENS was applied in 10 SAH patients with transcranial Doppler (TCD)-proven cerebral vasospasm. Measurements included plethysmography, near-infrared spectroscopy, capnography, and CBFVs by TCD. After determining the optimal frequency and current, patients were treated with cervical TENS for two periods of three days, with a pause of one day in between. Results: The TENS electrodes were not always tolerated by the patients. Higher frequencies demonstrated the most prominent combined effects. ETCO2 was 0.19% lower with TENS off than with TENS on (p = 0.05). Mean arterial blood pressure and pulse were not significantly different over time. CBFV in MCA was decreased (p = 0.07) while cerebral oxygen saturation was increased (p = 0.01) after the use of TENS. Conclusions: Our data suggest improved cerebral blood flow when using cervical TENS in patients with cerebral vasospasm. Several factors could have attenuated the effects: the electrodes were poorly tolerated, ETCO2 increased during TENS, few vessels showed prolonged vasospasm, and overall flow velocities were low. Still, an on–off effect of TENS over time was detected. Keywords: Cerebral blood flow, electrical stimulation, subarachnoid hemorrhage, sympathetic nervous system, vasospasm Conflict of Interest: The authors reported no conflict of interest.
INTRODUCTION
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Address correspondence to: Mark ter Laan, MD, PhD, Department of Neurosurgery, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen 9700, The Netherlands. Email: [email protected] * Department of Neurosurgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands † Department of Health Sciences, Community & Occupational Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands ‡ Department of Neurophysiology and Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 1 Current Address: Mark ter Laan, MD, PhD, Department of Neurosurgery, Radboud University Medical Center, Nijmgen, The Netherlands. For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1 Clinical Trial Registration: Dutch Trial Registry: http://www.trialregister.nl/trialreg/ index.asp, unique identifier: NTR2358.
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Cervical spinal cord stimulation (SCS) has been reported to increase cerebral blood flow (CBF) (1–3). Studies with thoracic SCS in patients with coronary vasospasm showed increased coronary perfusion, as did studies using transcutaneous electrical nerve stimulation (TENS) (4–6). This effect may be partly mediated by the sympathetic nervous system (7,8). Indeed, inhibitory effects of TENS on sympathetically mediated reflexes have been shown (9). Because of the analogies of TENS with SCS and because of the proven effect on coronary perfusion and sympathetic tone, possibly, cervical TENS also increases CBF. Symptomatic delayed cerebral ischemia (DCI) occurs in up to 30% of patients with subarachnoid hemorrhage (SAH). Fifteen to 20% of them remain disabled or die as a result of progressive ischemia or stroke. Current treatment cannot prevent this morbidity (10). A previous study that showed that cervical TENS could be safely applied in healthy subjects failed to demonstrate an effect on CBF (11). This is thought to be due to the regulatory effects of the intact cerebral autoregulation. We hypothesize that after SAH, cerebral
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Figure 1. Study protocol. TENS, transcutaneous electrical neurostimulation.
autoregulation is disrupted, which might open possibilities for TENS to influence CBF. If TENS increases CBF, it might decrease ischemia and could as such be a useful adjunct in the treatment or prevention of DCI SAH. In this pilot study, cervical TENS was applied in SAH patients with cerebral vasospasm.
METHODS The local research ethical board approved the study protocol. Ten patients with cerebral vasospasm after confirmed aneurysmatic SAH were included. Cerebral vasospasm was defined as a middle cerebral artery (MCA) to internal carotid artery (ICA) flow velocity ratio of more than 3 (Lindegaard index). Inclusion and exclusion criteria were as follows:
In the first part of the study, the optimal frequency for the subject was determined. After a baseline data collection, stimulation took place for 10 min for each frequency. In the second part of the study, changes in study parameters were monitored during a seven-day period of stimulation, using the frequency determined in the first part of the study. Patients received continuous TENS treatment for three days (additional to regular SAH treatment), then it was stopped for one day, and again continued for three days. In this way, effects of TENS can be discerned from the physiological decrease of flow velocities over time in patients with vasospasm; for example, an increase of flow velocities after stopping TENS makes it more plausible that an observed decrease during TENS was indeed caused by TENS. Data were collected on day 0, day 3, day 4, and day 7 (Fig. 1).
• History of cervical spine or skull-base surgery • Known adverse reaction to TENS pads • The presence of any implanted electronic device (including pacemakers) • Preexisting disease that can obscure follow-up • Unacceptable interference with electrocardiography registration (in case intensive care is necessary) • Insufficient temporal bony windows • The use of sympathomimetic or sympatholytic agents
Data Collection and Integration An experimental setup was designed to indirectly determine CBF (represented by CBF velocity and cerebral oxygenation), as well as to continuously monitor as many factors that influence CBF as possible. Data were collected using a continuous TCD monitor (Nicolet Pioneer TC8080, Carefusion Corporation, San Diego, CA USA) to measure cerebral blood flow velocities (CBFVs) in the MCA on both sides. Each time the highest flow velocities were used in the first session (mostly found around 50 mm depth), and the subsequent measurements were taken at the same depth. A plethysmograph was used for assessing blood pressure and heart rate (HR) (Finometer-Pro, Finapress Medical Systems, Amsterdam, the Netherlands), a capnograph (CapnomacUltima, GE Healthcare, Chalfont St Giles, UK) to measure end tidal CO2, and a near-infrared spectroscope (Invos 5100C, Somanetics, Troy, MI, USA) to measure cerebral oxygenation (ScO2). The near-infrared spectroscopy (NIRS) electrodes were placed bilaterally on the forehead, covering mostly MCA territory, but also anterior cerebral artery (ACA) territory. The data were continuously registered using Labview 9.0 software (Labview, National Instruments, Austin, TX , USA). Raw data were sampled at 250 Hz. Beat-to-beat averages were calculated by using the arterial blood pressure curve for triggering (12).
The subjects were treated with conventional TENS, providing a continuous flow of symmetrical rectangular biphasic pulses (Schwa Medico, Pierenkemper GMBH, Ehringhausen, Germany). Stimulation was performed at 90% of the highest tolerated current (painful or motor response evoking), with a pulse width of 200 msec. Stimulation frequencies were 20, 50, 100, and 120 Hz. Subjects were positioned supine during the entire experiment. The TENS electrodes were applied cervically on both sides of the dorsal midline at the level of the mandibular angle.
Statistical Analysis In order to determine the optimal frequency of stimulation, an ad hoc analysis was performed (12). Stable sections of data of the same length with least artifacts were selected for analysis after visual inspection. In order to clean the data from artifacts, 5% of top and bottom of data were deleted, replacing those by linear interpolation using in-house written routines in the Matlab environment (Matlab 6.5, The Math Works, Inc., Natick, MA, USA). Recordings of data were
Inclusion Criteria • Confirmed aneurysmatic SAH • Cerebral vasospasm demonstrated by transcranial Doppler (TCD), defined as an MCA/ICA ratio >3 • Aneurysm secured with a surgical or endovascular procedure • Age >18 years • Treatment can be started promptly • Informed consent signed by patient or family Exclusion Criteria
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Table 1. Patient Characteristics.
1 2 3 4 5 6 7 8 9 10
Age
WFNS
Fisher
HC
Aneurysm
Aneurysm treatment
Day first spasm
Day inclusion
55 51 51 53 40 65 55 69 23 55
5 1 1 1 1 2 1 2 1 2
4 3 2 2 1 4 1 2 1 2
Y Y N Y N Y N N N Y
Acom MCA-L Pcom-R Acom MCA-L Acom Pcom-L Pcom-R ICA-R MCA-L
Coil Coil Coil Coil Clip Coil Coil Coil Coil Clip
5 5 5 3 7 7 3 7 7 7
6 7 8 4 8 8 4 10 8 9
Acom, anterior communicating artery; Fisher, Fisher grade; HC, hydrocephalus; ICA, internal carotid artery; L, left; MCA, middle cerebral artery; Pcom, posterior communicating artery; R, right; WFNS, World Federation of Neurological Surgeons grading.
compared with baseline using the Student’s t-test. An effect size was calculated for the significant differences over time (with baseline as anchor point) in order to determine the frequency with the greatest amount of change from the baseline. If none of the frequencies showed an effect of more than 20% of the pooled standard deviation, no superiority was assumed (13). A multilevel model was used for the analysis of the frequency data of all patients for left and right side using SAS 9.2 software (SAS 9.2, SAS Institute Inc, Raleigh, NC, USA). Measurements were nested in patient, and data were adjusted for variance of the confounders mean arterial blood pressure (MAP), HR, and ETCO2. For analyzing the CBFV in the MCA and the ScO2, data were extracted at the left and right side, at four different days (0, 3, 4, and 7). A multilevel model was designed where side was nested within patient, day was nested within side, and measurement was nested within day. The computer software MLwin 2.28 (Centre of Multilevel Modelling, University of Bristol, UK) was used for calculating these models.
RESULTS Between July 2010 and November 2011, 10 patients could be included. One patient refused to continue TENS a few hours after the first data collection (subject nr. 5, Table 1). All other included subjects (N = 9) completed TENS treatment for seven days, or until vasospasm disappeared. Characteristics of patients are shown in Table 1. In five patients, dislodged electrodes had to be replaced at least once. Main causes of dislodged electrodes were disease-related restlessness and the fact that poorly cooperating patients could not tolerate the paresthesias. All patients developed a slight burning of the skin around the sites of TENS application, although this never led to stopping the TENS application.
TENS FREQUENCIES
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Differences in MAP, HR, and ETCO2 over time were not significant (Fig. 2a). ETCO2 was 0.19% lower with TENS off than with TENS on (p = 0.05). MCA blood flow velocities and cerebral oxygenation (ScO2 by NIRS) are shown in Figure 2b, corrected for variability in MAP, HR, and ETCO2 (in a multilevel analysis). When comparing CBFV and ScO2 at days 0 and 4 (TENS off) with days 3 and 7 (TENS on), CBFV was 8.72 m/sec slower when TENS was on (p = 0.07) and saturation improved by 2.66% (p = 0.01). We analyzed spastic and non-spastic vessels separately in a fourlevel model. Spasm was determined as an ICA/MCA ratio >3 on two or more occasions (because not all included patients showed spasm after inclusion). Differences in MCA flow velocities were not statistically significant, but a trend toward an on–off effect was found. Significant differences were found in ScO2 between days 0 and 3 in the non-spastic vessels and between days 3 and 4 and 4 and 7 in the spastic vessels (Fig. 3). When comparing CBFV and ScO2 at days 0 and 4 (TENS off) with days 3 and 7 (TENS on), CBFV did not significantly change for neither non-spastic nor spastic vessels. ScO2 increased 3.35% when TENS was on in non-spastic vessels (p = 0.07) and ScO2 increased 2.40% in spastic vessels (p = 0.06).
DISCUSSION Interpretation of TCD and NIRS Data During the measurements at day 0, the higher frequencies showed more convincing effects than the lower frequencies. Therefore, stimulation frequencies of 100 and 120 Hz were used. Our data showed a trend toward decreased MCA flow velocities, while oxygenation of the frontal lobe significantly increased during TENS treatment. This is suggestive of decreased vasospasm and increased CBF. Because ETCO2 increased during TENS, the measured effects on CBFV may have been attenuated, while effects on ScO2 could be overestimated. Even though few effects reached statistical significance in the small study population, there is an on–off effect over time. These results comply with previous findings of increased CBF in patients treated with cervical SCS (1–3). Especially, the non-spastic vessels seem to contribute to the significant increase of cerebral saturation during TENS treatment, while the changes in flow velocities are more prominent in spastic vessels.
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In four subjects, 100 Hz demonstrated the most prominent combined effects (t-test, data not shown), while in other four, 120 Hz was superior. In two patients, no differences could be demonstrated and 100 Hz was used on pragmatic grounds. When comparing the frequencies used in all patients, no significant differences were found in flow velocities. There was a small but significantly higher cerebral oxygenation (5%) though when using TENS in the highest frequencies.
ANALYSIS OF TENS TREATMENT
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Figure 2. a. Cerebral blood flow velocity (CBFV in centimeter per second) in middle cerebral arteries of all patients (18 arteries) and cerebral oxygen saturation (ScO2 in %). p values are indicated. b. Mean arterial blood pressure (MAP) and heart rate (HR) during the seven-day period of treatment showed no significant changes. c. End tidal CO2 showed a slight increase when TENS was on. Subjects 3, 7, and 8 had no vasospasm anymore on day 4. In these patients, only the measurements of days 1, 3, and 4 are included. All means on day 7 were calculated from the remaining six subjects.
TCD alone is not reliable for estimating CBF, especially when vessel diameters change. It is impossible to determine with sufficient certainty if proximal or distal diameter changes have occurred. We have used NIRS to measure distal cerebral oxygenation to facilitate this. Provided that brain metabolism, oxygen extraction, blood pressure, and PaCO2 remain unaltered during the measurement, an increase in oxygenation indicates vasodilatation and an increase in CBF, while a decrease indicates vasoconstriction and a decrease in CBF. Still, even though a raised ETCO2 or MAP can also explain an increase in CBFV, a decrease in CBFV under these circumstances cannot be disregarded and could be caused by an increased vessel diameter.
Physiological Basis of Neurogenic Control The anatomical and physiological bases of neurogenic control of CBF have been extensively studied and reviewed (14–18). While overruled by stronger mechanisms in normal resting state, we postulate that in pathological conditions such as SAH, sympathetic regulation becomes more important because cerebral autoregulation is (focally) decreased (12). Electrical modulation of the sympathetic nerve activity could then be of therapeutic importance. Our data suggest that if TENS increases CBF, it does so by means of a peripheral vasodilation, because the increase in ScO2 was more convincing than the decrease in CBFV. Possibly locally increased sympathetic tone causes decreased peripheral CBF (leading to DCI), which can be reversed by TENS.
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Limitations of This Study Because this was not a blinded study, bias cannot be ruled out. Our population is small because it concerns a pilot study. We did measure confounding factors like MAP, HR, and ETCO2, but we were not technically able to correct them during the measurements. The average changes in these confounders were very small though www.neuromodulationjournal.com
(Fig. 2). Another problem is that we have chosen to include patients when an ICA/MCA ratio of 3 or higher was detected; some patients only reached this once and therefore fewer spastic vessels were studied than was aimed for. Overall, the flow velocities in our population were not very high. Another factor that could lead to an underestimation of the effects of TENS on CBFV is the fact that ETCO2 was slightly higher when TENS was on than when it was off, which would increase MCA flow velocities. On the other hand, this can cause an overestimation of the effects on ScO2. A technical limitation is the fact that NIRS in our study detects the combined cerebral saturation of (part of ) both ACA and MCA territories. Theoretically, an increased saturation in ACA territory could mask a decreased saturation in MCA territory. Finally, TENS was tolerated far less than expected in this patient group. Several patients did not tolerate the TENS treatment very well, complaining of local paresthesias. Of course, headache after SAH could have sensitized patients. Some patients were too restless to keep the electrodes in place, even though the cutaneous injuries were mild.
Implications for Clinical Practice Our data show that high-frequency cervical TENS has the potential to increase CBF in SAH patients with cerebral vasospasm. The largest effects (in the on–off analysis) on MCA flow velocity and cerebral oxygenation were around 15% and 10%, respectively, which is hardly clinically relevant. The clinical feasibility is low because patients poorly tolerated the electrodes. All in all, we postulate that based on our results, further research toward more invasive kinds of electrical neurostimulation at the cervical level in SAH patients is warranted. Possibly, subcutaneous or epidural electrical stimulation will achieve higher electrical currents, resulting in better effects on CBF. Also, SAH patients might better tolerate these methods.
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Figure 3. Cerebral blood flow velocities and cerebral saturation in spastic and non-spastic vessels (territories). Middle cerebral artery flow velocity (MCAv) in centimeter per second; cerebral oxygen saturation in %. Results of day 7 were calculated based on the data of the six remaining patients. Only eight vessels were considered spastic (see text). No statistically significant differences were found in MCA. p values for ScO2 are shown.
CONCLUSIONS
How to Cite this Article:
Despite its limitations, cervical TENS increases cerebral oxygenation and shows a trend toward decreased MCA flow velocities in the presence of cerebral vasospasm after SAH. The beneficial changes found in our study are clinically not relevant though. More invasive methods of electrical stimulation are probably better tolerated and can as such be expected to achieve better and more relevant clinical results.
ter Laan M., van Dijk J.M.C., Stewart R., Staal M.J., Elting J.-W.J. 2014. Modulation of Cerebral Blood Flow With Transcutaneous Electrical Neurostimulation (TENS) in Patients With Cerebral Vasospasm After Subarachnoid Hemorrhage. Neuromodulation 2014; 17: 431–437
Authorship Statements
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1. Clavo B, Robaina F, Catala L et al. Increased locoregional blood flow in brain tumors after cervical spinal cord stimulation. J Neurosurg 2003;98:1263–1270. 2. Takanashi Y, Shinonaga M. Spinal cord stimulation for cerebral vasospasm as prophylaxis. Neurol Med Chir (Tokyo) 2000;40:352–356. 3. Clavo B, Robaina F, Catala L et al. Effect of cervical spinal cord stimulation on regional blood flow and oxygenation in advanced head and neck tumours. Ann Oncol 2004;15:802–807.
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Drs. ter Laan, van Dijk, Staal, and Elting contributed to the conception and design of the study. Drs. Elting and ter Laan performed experiments and data collection. Analysis of data was performed by Drs. Stewart and ter Laan. Dr. ter Laan drafted the manuscript, with important intellectual input from all other authors. All authors have read and approved the submitted manuscript.
REFERENCES
TER LAAN ET AL. 4. Sanderson JE, Woo KS, Chung HK, Chan WW, Tse LK, White HD. The effect of transcutaneous electrical nerve stimulation on coronary and systemic haemodynamics in syndrome X. Coron Artery Dis 1996;7:547–552. 5. Hautvast RW, Ter Horst GJ, DeJong BM et al. Relative changes in regional cerebral blood flow during spinal cord stimulation in patients with refractory angina pectoris. Eur J Neurosci 1997;9:1178–1183. 6. Jessurun GA, Hautvast RW, Tio RA, DeJongste MJ. Electrical neuromodulation improves myocardial perfusion and ameliorates refractory angina pectoris in patients with syndrome X: fad or future? Eur J Pain 2003;7:507–512. 7. Goellner E, Slavin KV. Cervical spinal cord stimulation may prevent cerebral vasospasm by modulating sympathetic activity of the superior cervical ganglion at lower cervical spinal level. Med Hypotheses 2009;73:410–413. 8. Linderoth B, Herregodts P, Meyerson BA. Sympathetic mediation of peripheral vasodilation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes. Neurosurgery 1994;35:711–719. 9. Sanderson JE, Tomlinson B, Lau MS et al. The effect of transcutaneous electrical nerve stimulation (TENS) on autonomic cardiovascular reflexes. Clin Auton Res 1995;5:81–84. 10. Weyer GW, Nolan CP, Macdonald RL. Evidence-based cerebral vasospasm management. Neurosurg Focus 2006;21:E8. 11. Ter Laan M, van Dijk JMC, Elting JWJ, Fidler V, Staal MJ. The influence of transcutaneous electrical neurostimulation (TENS) on human cerebral blood flow velocities. Acta Neurochir (Wien) 2010;152:1367–1373. 12. Ter Laan M, van Dijk JMC, Staal MJ, Elting JWJ. Electrical modulation of the sympathetic nervous system in order to augment cerebral blood flow: a protocol for an experimental study. BMJ Open 2011;1:e000120. 13. Middel B, Stewart R, Bouma J, Van Sonderen E, Van den Heuvel WJ. How to validate clinically important change in health-related functional status. Is the magnitude of the effect size consistently related to magnitude of change as indicated by a global question rating? J Eval Clin Pract 2001;7:399–410. 14. Edvinsson L, Hamel E.Perivascular nerves in brain vessels.In: Edvinsson L, Krause DN, eds. Cerebral blood flow and metabolism, Vol. 2nd. Philadelphia, PA: Lippincott, Williams and Wilkins, 2002:43–67. 15. Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol 2006;100:1059–1064. 16. Goadsby PJ, Edvinsson L. Neurovascular control of the cerebral circulation. In: Edvinsson L, Krause DN, eds. Cerebral blood flow and metabolism, Vol. 2nd. Philadelphia, PA: Lippincott, Williams & Wilkins, 2002:172–188. 17. Sandor P. Nervous control of the cerebrovascular system: doubts and facts. Neurochem Int 1999;35:237–259. 18. Ter Laan M, van Dijk JM, Elting JW, Staal MJ, Absalom AR. Sympathetic regulation of cerebral blood flow in humans: a review. Br J Anaesth 2013;111:361–367.
COMMENTS
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The authors of this study are to be congratulated with an attempt to eliminate a dangerous and potentially deadly complication of aneurysmal subarachnoid hemorrhage (aSAH) with a non-invasive neuromodulation approach. The practical implications of this concept have a huge clinical potential, mainly because there is still no reliable way to prevent, or treat, for that matter, the cerebral arterial vasospasm that develops in up to a half of aSAH patients. The choice of neuromodulation approach is remarkable. The first clinical observations of spinal cord stimulation (SCS) effects on cerebral flow took place almost 30 years ago (1). Following this, SCS was shown to be effective in relief of arterial vasospasm in various animal models (2–4). This was then tested in humans—initially in Japan by Takanashi and Shinonaga (5), and then in the US by our group (6). A hypothesis was proposed to explain the SCS action (7), but it appears that clinical effects we discovered were, at least in part, opposite to the hypothesized mechanism of vasospasm-relieving effect. The limited clinical experience is insufficient to draw any meaningful conclusions or come up with any practical recommendations. It is clear, however, that a larger prospective study may be able to define optimal stimulation parameters, best electrode location, most effective timing of stimulation, the rest of the so far unanswered questions, and perhaps make this modality an acceptable treatment of vasospasm after aSAH. In the meantime, transcutaneous electrical nerve stimulation (TENS) remains a much more attractive way to modulate neural activity, mainly because it is cheaper, safer and easier than SCS—and these advantages make the efforts of the authors of this study worthwhile. www.neuromodulationjournal.com
Even though the results presented here are not clinically impressive, the research should continue. As the authors mention in their article, the ultimate goal is to use this in “treatment and prevention of delayed cerebral ischemia.” If TENS, with proper optimization, turns out to be an effective approach to reach this goal, millions of patients and families will appreciate the investigators’ efforts. With this, I feel that research should gradually shift from attempts to treat ischemia to a reliable way to prevent it. Konstantin Slavin, MD Chicago, IL, USA REFERENCES 1. Hosobuchi Y. Electrical stimulation of the cervical spinal cord increases cerebral blood flow in humans. Stereotact Funct Neurosurg 1985;48:372–376. 2. Vicocchi M, Argiolas L, Meglio M, Cioni B, Dal Basso P, Rollo M, Cabezas D. Spinal cord stimulation and early experimental cerebral spasm: the “functional monitoring” and the “preventing effect”. Acta Neurochir (Wien) 2001;143:177–185. 3. Karadağ Ö, Erdoğlu E, Gürelik M, Göksel HM, Kiliç E, Gültürk S. Cervical spinal cord stimulation increases cerebral cortical blood flow in an experimental cerebral vasospasm model. Acta Neurochir (Wien) 2005;147:79–84. 4. Lee JY, Huang DL, Keep R, Sagher O. Effect of electrical stimulation of the cervical spinal cord on blood flow following subarachnoid hemorrhage. J Neurosurg 2008;109:1148– 1154. 5. Takanashi Y, Shinonaga M. Spinal cord stimulation for cerebral vasospasm as prophylaxis. Neurol Med Chir (Tokyo) 2000;40:352–357. 6. Slavin KV, Vannemreddy PSSV, Goellner E, Alaraj AM, Aydin S, Eboli P, Mlinarevich N, Watson KS, Walters LE, Amin-Hanjani S, Deveshwar R, Aletich V, Charbel FT. Use of cervical spinal cord stimulation in treatment and prevention of arterial vasospasm after aneurysmal subarachnoid hemorrhage: Technical details. Neuroradiology J 2011;24:131– 135. 7. Goellner E, Slavin KV. Cervical spinal cord stimulation may prevent cerebral vasospasm by modulating sympathetic activity of the superior cervical ganglion at lower cervical spinal level. Med Hypothes 2009;73:410–413.
*** The quest to enhance blood flow with SCS is almost as old as the therapy itself. Even as far back as 1976, investigators noted that SCS resulted in potentially important improvements in tissue perfusion (1). While the question of whether the same effect could be seen for cerebral blood flow wasn’t raised until 1985, it has been investigated in a number of animal models and occasional clinical reports since then (2–4). Experimental work has shown fairly convincingly that SCS could result in increases in CBF, when applied to the high cervical spine. In addition, there is evidence that the mechanism for this effect involves modulation of vasomotor centers in the rostral ventral lateral medulla and cerebellum (5–7). Clinical reports of the potentially salubrious effect of SCS have lagged behind, however (8,9). Despite a few promising small studies in humans, electrical stimulation for the treatment or prevention of stroke still remains on the “to-do list” of neuromodulation. One of principal hurdles to clinical investigation of electrical stimulation therapy for the treatment of cerebral ischemia is the invasiveness of this modality. Spinal cord stimulation requires the placement of an electrode into the spinal canal—a non-trivial consideration in a patient who may be a candidate for thrombolytic therapy in a time-critical window. In the case of subarachnoid hemorrhagerelated vasospasm, the implantation of a SCS lead in a patient who is critically ill, and who may be undergoing systemic anticoagulation, also presents a significant logistical challenge. The study of these modalities is therefore curtailed by the apparent conflict with established acute therapies. In light of the challenges presented by invasive electrical stimulation therapies, ter Laan et al. take a step back and examine the effect of noninvasive stimulation on cerebral perfusion in the setting of cerebral vasospasm (10). The clear advantage of this approach is the ability to study its efficacy with little to no risk. The potential disadvantage of using TENS to study therapeutic benefit to cerebral blood flow is the
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TENS FOR VASOSPASM AFTER SAH increased likelihood that this treatment would be ineffective. Since the presumed goal is the modulation of vasomotor centers within the brainstem, it is entirely possible that TENS would lack sufficient power to modulate a target so far centrally. The modest central vasomotor effects seen in this study are therefore not surprising. It is also not surprising that the authors found that the most consistent effect of TENS was patient discomfort. It is likely that the amplitude of stimulation required for any vasoactive changes to be appreciated would be high enough to be intolerable. It is important that we continue our efforts to harness the nervous system’s natural protective mechanisms. Doing so is the core of neuromodulation. Inasmuch as delivering these therapies in the least invasive way possible is our goal, approaches like the one undertaken by ter Laan are to be encouraged. Perhaps we will eventually have the technology to deliver such modulation more centrally without being invasive. For now, however, we are still fighting the limits of peripheral stimulation when attempting to do so without any invasion whatsoever. Oren Sagher, MD Ann Arbor, MI, USA
2. Hosobuchi Y. Electrical stimulation of the cervical spinal cord increases cerebral blood flow in humans. Applied Neurophysiology 1985;48(1–6):372–376. 3. Meglio M, Cioni B, Visocchi M, Nobili F, Rodriguez G, Rosadini G, et al. Spinal cord stimulation and cerebral haemodynamics. Acta Neurochirurgica 1991;111(1–2):43–48. 4. Visocchi M, Cioni B, Vergari S, Marano G, Pentimalli L, Meglio M. Spinal cord stimulation and cerebral blood flow: an experimental study. Stereotactic and Functional Neurosurgery 1994;62(1–4):186–190. 5. Reis DJ, Golanov EV, Galea E, Feinstein DL. Central neurogenic neuroprotection: central neural systems that protect the brain from hypoxia and ischemia. Annals of the New York Academy of Sciences 1997;835:168–186. 6. Glickstein SB, Golanov EV, Reis DJ. Intrinsic neurons of fastigial nucleus mediate neurogenic neuroprotection against excitotoxic and ischemic neuronal injury in rat. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 1999;19(10):4142–4154. 7. Patel SS, Huang D-LD, Sagher OO. Evidence for a central pathway in the cerebrovascular effects of spinal cord stimulation. Neurosurgery 2004;55(1):201–206. 8. Takanashi Y, Shinonaga M. Spinal cord stimulation for cerebral vasospasm as prophylaxis. Neurologia Medico-Chirurgica 2000;40(7):352–356; discussion 356–357. 9. Slavin KV, Vannemreddy PSSV, Goellner E, Alaraj AM, Aydin S, Eboli P et al. Use of cervical spinal cord stimulation in treatment and prevention of arterial vasospasm after aneurysmal subarachnoid hemorrhage. Technical details. The Neuroradiology Journal 2011;24(1):131–135. 10. Ter Laan M, van Dijk JCM, Stewart R, Staal MJ, Elting JJ. Modulation of cerebral blood flow with transcutaneous electrical neurostimulation (TENS) in patients with cerebral vasospasm after subarachnoid hemorrhage. Neuromodulation: Technology at the Neural Interface 2014;17:431–437.
Comments not included in the Early View version of this paper.
REFERENCES 1. Cook AW, Oygar A, Baggenstos P, Pacheco S, Kleriga E. Vascular disease of extremities. Electric stimulation of spinal cord and posterior roots. New York State Journal of Medicine 1976;76(3):366–368.
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