| | Poststroke Upper-Limb Rehabilitation Using 5 to 7 Inserted Microstimulators: Implant Procedure, Safety, and Efficacy for Restoration of Function published online 01 September 2008. Abstract Davis R, Sparrow O, Cosendai G, Burridge JH, Wulff C, Turk R, Schulman J. Poststroke upper-limb rehabilitation using 5 to 7 inserted microstimulators: implant procedure, safety, and efficacy for restoration of function. ObjectiveTo investigate the feasibility of implanting microstimulators to deliver programmed nerve stimulation for sequenced muscle activation to recover arm-hand functions. DesignBy using a minimally invasive procedure and local anesthesia, 5 to 7 microstimulators can be safely and comfortably implanted adjacent to targeted radial nerve branches in the arm and forearm of 7 subjects with poststroke paresis. The microstimulators' position should remain stable with no tissue infection and can be programmed to produce effective personalized functional muscle activity with no discomfort for a preliminary 12-week study. Clinical testing, before and after the study, is reported in the accompanying study. SettingMicrostimulator implantations in a sterile operating room. ParticipantsSeven adults, with poststroke hemiparesis of 12 months or more. InterventionUnder local anesthesia, a stimulating probe was inserted to identify radial nerve branches. Microstimulators were inserted by using an introducer and were retrievable for 6 days by attached suture. Each device was powered via a radiofrequency link from 2 external cuff coils connected to a control unit. Main Outcome MeasuresTo achieve low threshold values at the target sites with minimal implant discomfort. Microstimulators and external equipment were monitored over 12 weeks of exercise. ResultsSeven subjects were implanted with 41 microstimulators, 5 to 7 per subject, taking 3.5 to 6 hours. Implantation pain levels were 20% more than anticipated. No infections or microstimulator failures occurred. Mean nerve thresholds ranged between 4.0 to 7.7μcoulomb/cm2/phase over 90 days, indicating that cathodes were within 2 to 4mm of target sites. In 1 subject, 2 additional microstimulators were inserted. ConclusionsMicrostimulators were safely implanted with no infection or failure. The system was reliable and programmed effectively to perform exercises at home for functional restoration. IN UPPER-LIMB POSTSTROKE, surface-applied electric stimulation has been shown to improve function,1, 2, 3 especially with voluntary activation.4 In a review, Chae discussed the successes and limitations of surface-applied stimulation in that “many stroke survivors cannot tolerate the pain”; and “skilled individuals are needed to place … stimulating electrodes on a daily basis to ensure repeatability.”3(p99) Some of these problems have been addressed by the Ness H200a in which the wrist is held in a functional position of slight extension by a rigid splint, and surface electrodes are attached to the splint so that, as long as the splint is worn in the same position relative to the underlying structures, muscle activation should remain consistent.5 However, the Ness H200 does not extend to the upper arm for elbow extension, limiting its use for activities of daily living to those subjects who have functioning elbow extension. A study by Chae and Hart6 showed that muscle activity from attempted movements in the paretic limb could be recorded by percutaneous intramuscular electrodes, which, in turn, triggered selective stimulation to similar electrodes implanted at selected motor point sites for functional movements in hemiparetic patients. Further reported by Chae, “Data demonstrated that percutaneous intramuscular stimulation is significantly better tolerated than surface stimulation.”3(p99) However, the skin entry points required frequent and proper maintenance.6 The cumulative 1-year failure rate varied between 56% to 80%, limiting their use to short-term applications (<3mo). Other complications also reported6 included granulomas from retained electrode fragments and electrode-related infections, which were treated with oral antibiotics and minor outpatient surgical procedures. In view of the problems experienced with surface and percutaneous intramuscular electrode stimulating systems, especially for neurostimulation projects over 6 weeks, we have developed and are reporting on an implantable, programmable stimulation system anticipated to extend over a 5-year study. The hypotheses of this stimulating system to be tested were (1) using a minimally invasive procedure and local anesthesia, 5 to 7 microstimulators can be safely and comfortably implanted adjacent to targeted radial nerve branches or motor points in the arm and forearm of subjects with poststroke hemiparesis, and (2) once the devices are implanted, their position will remain stable with no tissue infection and can be programmed to produce effective personalized functional muscle activity with no discomfort for a preliminary 12-week study. This feasibility study is designed after implantation, with 2 phases, each with 12 weeks of programmed stimulation for functional exercises; the phase 1 clinical results for each of the 7 subjects is detailed and reported elsewhere.7 Methods  Human Subjects During 2005, 7 adult volunteers were recruited at least 1 year after an ischemic stroke causing hemiparesis (table 1). All had limited control of hand function and weakness of extension of the elbow and wrist (but with perceivable voluntary wrist extension only up to 75% of normal passive range), sufficient volitional finger flexion to grip, elbow flexion to bring the hand to the mouth, and shoulder flexion to lift the arm away from the body against gravity to an angle of approximately 45°. Spasticity was acceptable at 2 or less (Modified Ashworth Scale). The protocol was approved by the Thames Valley Multicenter Research Ethics Committee, UK (no. 04/12/021), and by the Medicines and Healthcare Products Regulatory Agency (no. CI/2004/0027). | | |  | Subjects | Age (y) | Sex | Stroke (y) | Pain Expected VAS (/10) | Pain Experienced VAS (/10) | Implant Time (h) | |
|---|
| 1 | 45 | F | 10.5 | 4.9 | 1.7 | 3.5 | | | 2 | 48 | M | 1.4 | 1.0 | 1.3 | 4.5 | | | 3 | 49 | M | 1.1 | 5.2 | 6.1 | 5.25 | | | 4 | 58 | M | 2.3 | 7.4 | 7.5 | 5.5 | | | 5 | 32 | F | 7.1 | 3.0 | 6.9 | 4.75 | | | 6 | 45 | M | 1.7 | 3.1 | 5.4 | 4.5 | | | 7 | 67 | F | 3.2 | 4.9 | 7.5 | 6.0 | | | | | | | Avg 4.2 | Avg 5.2 | Avg 4.9 | | | | |
Before acceptance, all subjects were tested with surface-applied stimulation to the motor points of the targeted muscles to ensure adequate muscle responses and joint movements to extend the elbow, wrist, and fingers and thumb as follows: (1) the MHT and LHT; (2) the extensor carpi radialis longus, extensor carpi radialis brevis, and extensor carpi ulnaris; (3) the posterior interosseous nerve involving the extensor digitorum; and (4) the extensor pollicis longus and abductor pollicis longus. One week before implantation, a 5-cm electromyography needle electrode monopolar stimulation study was performed (by C.W.) to identify and mark the skin with an indelible pen over each target site. A 30-Hz stimulus was delivered, and an optimal needle position was defined when an intensity of less than 1mA evoked a strong contraction of targeted extensor muscle(s). Measurements were taken for the vertical needle depth and the distance of the target sites in relation to bony anatomic sites (appendix 1). Also, baseline radial and median nerve conduction velocities and amplitudes were performed (table 2) and repeated (by C.W.) 6 to 16 months after radial nerve branches were implanted and stimulated. | | | | | Radial (d1 elbow) | Median (d3 wrist) | Radial Nerve | Median Nerve | |
|---|
| | Velocity (m/s) | Amplitude (μV) | |
|---|
| Subject | Before | After | Before | After | Before | After | Before | After | |
|---|
| 1 | 55 | 58 | 56 | 57 | 3.3 | 3.1 | 17.0 | 17.2 | | | 2 | 54 | 52 | 47 | 45 | 1.9 | 2.8 | 7.8 | 5.8 | | | 3 | 42 | 49 | 38 | 52 | 4.0 | 5.7 | 4.9 | 10.0 | | | 4 | 46 | 56 | 46 | 51 | 4.1 | 2.5 | 3.5 | 7.2 | | | 5 | 52 | 59 | 49 | 59 | 4.1 | 5.9 | 27.4 | 31.2 | | | 6 | 49 | 54 | 55 | 47 | 5.1 | 11.4 | 18.2 | 20.5 | | | 7 | 45 | 55 | 36 | 45 | 5.0 | 6.0 | 18.5 | 7.0 | | | Sum | 343 | 383 | 327 | 356 | 27.5 | 37.4 | 97.3 | 98.9 | | | Mean | 49.0 | 54.7 | 46.7 | 50.9 | 3.9 | 5.3 | 13.9 | 14.1 | | | | |
Microstimulator and Control System This system was developed, tested in animals, and manufactured at the Alfred Mann Foundation.b Once implanted, the 5 to 7 microstimulators (figs 1A, B) received power and stimulation commands via an external 2-MHz radiofrequency inductive coil and cuff, one for the forearm and one over the upper arm. These coils were connected to a control unit (fig 1 D). The stimulation parameters and timing for each radiofrequency microstimulator were programmed into the control unit by a computer-based clinician fitting unit (see fig 1D). The subject used the normal hand to trigger the control unit by a push button. The radiofrequency microstimulator (see figs 1A, B) is cylindrical (length, 16.7mm; diameter, 2.4mm). The ceramic external case has a titanium cap at each end and with an iridium cathode (area, .0248cm2). The ceramic cases were steam tested, which indicated a 70-year implant survival. The anodal end has an eyelet for an absorbable 4 or 5-O suture to be tied so the radiofrequency microstimulator could be retrieved during insertion and for up to 6 days postoperatively, before tissue encapsulation. The radiofrequency microstimulator is a single-channel stimulator that produces capacitively coupled, charge-balanced, asymmetric, biphasic, and constant-current pulses (see fig 1C). Each device is individually addressed, allowing coordinated and sequential control over the stimulus waveform and pulse train (see fig 1C). Insertion Tools Insertion tools (see fig 1B) were developed at the Alfred Mann Foundation and consist of a stimulation probe and introducer. Stimulation probe The stimulation probe (diameter, 0.7mm; length, 20.5cm) (see fig 1B) was insulated along the shaft except for 5mm at each end; at the distal end, there are 1-cm markings through 10cm. The proximal end was connected by a cable to the cathodal output of an external pulse generator. Introducer The introducer (Enpath dilator plus sheath, 7 French)c (fig 1B) has a Luer-lok fitting to hold the Alfred Mann Foundation modified stainless steel dilator (shaft, 8.5cm) inside the plastic sheath together during the tissue insertion. Five 0.7-mm side holes on the distal part of the sheath allowed current to flow from the radiofrequency microstimulator's cathode to the anode, when inside the lowest part of the sheath, before ejection from the sheath. The Enpath plastic dilator was cut to a length of 9.5cm, marked at 8.0cm from the tip, which was used as the ejector tool. Before ejection, the sheath was filled with an antibiotic-saline solution (figs 2D−F). Implantation Technique The procedures were performed in an operating room at Southampton General Hospital, UK. An intravenous line was inserted for an initial antibiotic (cephalosporin) dose before implantation and before leaving the hospital (usually 6−8h later); also, the intravenous line was available for sedation and pain medication (benzodiazepine). The radiofrequency microstimulators were removed from their sterile packages and tested with a sterile circuit board. Each radiofrequency microstimulator had an absorbable suture tied to its eyelet (see fig 2B) and was placed into a bowl of antibiotic-saline solution. The insertion and ejection tools were opened, and the implanter tested each part in combination with the radiofrequency microstimulator (see fig 2). Each subject lay on their unaffected side with the paretic arm stretched out and supported. The implant area was scrubbed, draped, and covered with an iodinated plastic sheet. Each insertion site was marked 4 to 7cm distal to each marked target site and was injected with local anesthetic. A skin incision of 5mm allowed the insertion tools to be introduced. The probe, connected by a cable to the external pulse generator (stimulation set at 3mA for 0.2ms at 50Hz), was aimed at the marked skin site. The tip was angled to be inserted about 2cm deep for the forearm sites and to about 4 to 5cm for upper arm sites (see appendix 1) to produce a muscle response and an appropriate limb movement. An optimal response was an adequate muscle contraction with joint movement, and the threshold level was below 1.0mA. The stimulator lead from the external pulse generator was removed from the probe, and the tip of the introducer (sheath plus dilator) was slipped over and down to its tip, as indicated by a middle mark on the probe. After placing the introducer, the external pulse generator lead was reconnected to the probe, and stimulation was reapplied to confirm that the optimal response had not changed. If there was a change, then the probe and introducer together were gently moved in and out again to relocate the optimal response. The probe and dilator were then removed, leaving the sheath. A radiofrequency microstimulator was inserted into the sheath with the cathode end first (see fig 2C), and then, using the ejector tool to add the antibiotic-saline solution inside the sheath, the tool was pushed gently up to the mark on the ejector's shaft (see figs 2D, E), where the microstimulator's cathode now reached the sheath's tip (see fig 2F). Further saline mixture was instilled. A sterile antenna coil, connected to the control unit, was laid on the skin over the radiofrequency microstimulator. Connection between the control unit and the clinician fitting unit enabled the coil output to be adjusted so that motor response could again be observed; the microstimulator stimulation threshold and stimulation parameters were recorded. If the optimal response had changed, then the sheath with radiofrequency microstimulator plus ejector tool was moved gently in and out of the tissues by ±3mm. When found, the device was ejected from the sheath by withdrawing the sheath up over the mark on the ejector shaft. The ejector tool was then withdrawn from the sheath. Next, the sheath was carefully removed from the tissues avoiding a pull on the suture connected to the radiofrequency microstimulator's anodal eyelet. The implanter gained the impression that placing a finger on the skin overlying the microstimulator reduced microstimulator movement while the insertion tools were being removed. The device was activated again to confirm that the response had remained acceptable; the incision site was pushed inward, allowing maximum suture protrusion before it was cut off flush. When the skin was released, the suture ends receded into the underlying tissue, which was closed with 1 suture. After all sites were implanted, antibiotic ointment and adhesive sterile dressings were applied. Retrieval Technique Alternatively, if the response was unacceptable, the radiofrequency microstimulator was retrieved slowly by gently pulling on the attached suture while stimulation was applied. If the muscle response returned to being adequate, then the device was left at that site. If not, the microstimulator was removed by suture traction and then reinserted; about 2 of every 3 microstimulators inserted were retrieved during implanting and reinserted (table 3). | | | | Subject | Upper Arm | Forearm | RFMs | Retrieval | |
|---|
| 1 | LHT, MHT | ECU, ECR, PIN | 5 | 0 | | | 2 | LHT, MHT | ECU, ECR, PIN, ED | 6 | 2 | | | 3 | LHT, MHT | ECU, ECR, PIN, ED | 6 | 0 | | | 4 | LHT, MHT, LHT, MHT, (R) | ECU, ECRL+ECRB, PIN, ED | 7 (+2) | 9 | | | 5 | LHT, MHT | ECU, ECR, PIN | 5 | 10 | | | 6 | LHT, MHT | ECU, ECR, PIN, ED | 6 | 4 | | | 7 | LHT, MHT | ECU, ECR, PIN, ED | 6 | 4 | | | 41 original RFMs (+2): 29 Retrievals | | | | |
Postimplant and Phase 1 Procedures Immediately after the implantation session, radiographs of the upper limb were taken to record radiofrequency microstimulator sites (eg, see fig 3A). Each microstimulator's stimulation levels were adjusted by varying the current level (in milliamps) only and keeping the other parameters of pulse width and frequency fixed at 0.2ms at 30Hz. Each microstimulator's current level was adjusted to stimulate its target nerve or motor point to produce a minimal muscle response (threshold) and a maximum response, which were recorded (day 0). At day 4, the subject returned to have an evaluation of implant sites and remeasuring each microstimulator's threshold current level; any marked change would indicate a microstimulator migration, which may require possible retrieval and repositioning before encapsulation at day 6+. At day 15, the sutures were removed; each radiofrequency microstimulator's threshold current was recorded, and then the current level was adjusted to produce a useful joint movement. With the clinician fitting unit (see fig 1D), programmed joint movements were coordinated to produce effective personalized functional exercises to start the 12-week phase 1 project.7 The stimulation thresholds were measured at days 30 and 60 and again at the completion of phase 1 (day 90). For each of these 6 days (days 0−90), the mean value with SD of the 41 microstimulator stimulation thresholds was calculated and are displayed in figure 4A. Results Seven subjects were implanted with 41 microstimulators, using 5 to 7 per subject; each implantation session took 3.5 to 6 hours (mean, 4.9h) (see table 1). Implantation pain levels were 20% more than anticipated (see table 1). No failures or infections of microstimulator occurred during phase 1 in which stimulation of the system was for 1 hour daily. The mean threshold range of the 41 implanted microstimulators measured 6 times over the 90 days was 4.0 to 7.7μcoulomb/cm2/phase (see fig 4A). In subject 4, the microstimulator activating the MHT motor point migrated during the first week but was still able to evoke a weak elbow extension response, which was supplemented 5 months later by 2 implanted microstimulators, one to the motor point of MHT and one to the LHT. From our data on 5 sheep implanted with 13 identical radiofrequency microstimulators near their targeted hypoglossal nerves from 4 months to 6 years, each microstimulator's final threshold value for tongue movement was recorded before each animal was euthanized. Figure 4B shows the distance of each microstimulator's cathode to their dissected nerve plotted against their individual thresholds expressed in charge density: (mA × ms)/cathodal area: cm2 = μcoulombs/cm2/phase. From the 7 subjects, 41 radiofrequency microstimulators' mean threshold range for the 6 time intervals over the 90 days was 4.0 to 7.7μcoulomb/cm2/phase (see fig 4A). From the sheep data in figure 4B, one can deduce that their mean cathodal distances are probably between 2 and 4mm from their targeted nerve or motor point. Discussion In response to our hypotheses, the findings indicate that by using this minimally invasive procedure and local anesthesia, 5 to 7 microstimulators could be carefully and safely implanted in proximity to the targeted radial nerve branches or motor points in the paretic upper limb in a defined group of 7 subjects with poststroke paresis. For implantation discomfort, oral paracetamol or intravenous medication can be administered during the procedure. Once the devices were implanted, no failure or infections occurred, and their position remained stable, except in subject 4, in whom 1 radiofrequency microstimulator migrated from the MHT but was supplemented 5 months later by a microstimulator to the motor points of MHT and of LHT to allow functional elbow extension. This study of subjects with the devices will continue for 5 years. Sensory-conduction velocities and amplitudes of both the radial and median nerves were measured before radial nerve implantation and 6 to 16 months later (see table 2). Velocities along both nerves were slightly faster after the implantation compared with preimplant conduction studies. We do not consider this difference to be of any significance. These findings imply that the radiofrequency microstimulator implantations and stimulations have been noninjurious to the radial nerve branches. As an alternative to preimplant electromyography needle insertion and stimulation to find nerves and motor points, we plan to evaluate the use of ultrasound devices with high-resolution transducers (10−15MHz) that provide high axial resolution in which beam penetration is limited to 3 to 4cm8. This technique could allow target plotting during preimplant evaluation and/or during implantation. Conclusions There were no failures in the implanted radiofrequency microstimulator electronics and no infections in the adjacent tissues, and targeted and stimulated nerves appeared to be unharmed. The stimulator system was programmed to produce effective personalized functional muscle activity with little to no discomfort. The results with 7 subjects using the 41 implanted microstimulators for 12 weeks of programmed nerve stimulation (phase 1) allowing sequenced muscle activation to recover arm-hand functions have been fully reported elsewhere.7 Suppliers Acknowledgments The U.S. Food and Drug Administration has granted the Alfred Mann Foundation an investigational device exemption to study the radiofrequency microstimulator used in lower-extremity poststroke research (IDE G070151). We thank and appreciate the engineering and animal care teams at the Alfred Mann Foundation. References 1. 1Mann GE, Burridge JH, Malone LJ, Strike PW. A pilot study to investigate the effects of electrical stimulation on hand function and sensation in stroke. Neuromodulation. 2005;8:193–202. 2. 2Popovic DB, Popovic MB, Sinkjaer T, Stefanovic A, Schwirtlich L. Therapy of paretic arm in hemiplegic subjects augmented with a neural prosthesis: a cross-over study. Can J Physiol Pharmacol. 2004;82:749–756. MEDLINE |
CrossRef
3. 3Chae J. Neuromuscular electrical stimulation for motor relearning in hemiparesis. Phys Med Rehabil Clin N Am. 2003;14:93–109. 4. 4De Kroon JR, IJzerman MJ, Chae J, Lankhorst GJ, Zilvold G. Relation between stimulation characteristics and clinical outcome in studies using electrical stimulation to improve motor control of the upper extremity in stroke. J Rehabil Med. 2005;37:65–74. MEDLINE |
CrossRef
5. 5Alon G, McBride K, Ring H. Improving selected hand functions using a noninvasive neuroprosthesis in persons with chronic stroke. J Stroke Cerebrovasc Dis. 2002;11:99–106. 6. 6Chae J, Hart R. Intramuscular hand neuroprosthesis for chronic stroke survivors. Neurorehabil Neural Repair. 2003;17:109–117. MEDLINE 7. 7Turk R, Burridge JH, Davis R, et al. Therapeutic effectiveness of electric stimulation of the upper-limb poststroke using implanted microstimulators. Arch Phys Med Rehabil. 2008;89:1913–1922. Abstract | Full Text |
Full-Text PDF (543 KB)
|
CrossRef
8. 8Brull R, Perlas A, Chan V. Ultrasound-guided peripheral nerve blockade. Curr Pain Headache Rep. 2007;11:25–32. MEDLINE |
CrossRef
a Alfred Mann Foundation, Santa Clarita, CA b Southampton University Hospitals NHS Trust, Southampton, UK c University of Southampton, Southampton, UK  Reprint requests to Ross Davis, MD, Alfred Mann Foundation, 25134 Rye Canyon Loop, Santa Clarita, CA 91355
Supported by the Alfred Mann Foundation. A commercial party having a direct financial interest in the results of the research supporting this article may confer a financial benefit on the author or one or more of the authors. The Alfred Mann Foundation is developing the radiofrequency microstimulator used in this study. Davis and Cosendai are consultants to the Alfred Mann Foundation; Schulman was an employee of the Alfred Mann Foundation while the study was conducted. PII: S0003-9993(08)00432-2 doi:10.1016/j.apmr.2008.05.010 © 2008 American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved. | |
|
FULL TEXT00432-2/journalimage?img=PIIS0003999308004322.gr1.lrg.gif&fig=fig1&kwhquery=&issn=0003-9993&ishighres=false&allhighres=false&free=yes','journalimage');)
00432-2/journalimage?img=PIIS0003999308004322.gr2.lrg.gif&fig=fig2&kwhquery=&issn=0003-9993&ishighres=false&allhighres=false&free=yes','journalimage');)
00432-2/journalimage?img=PIIS0003999308004322.gr3.lrg.gif&fig=fig3&kwhquery=&issn=0003-9993&ishighres=false&allhighres=false&free=yes','journalimage');)
00432-2/journalimage?img=PIIS0003999308004322.gr4.lrg.gif&fig=fig4&kwhquery=&issn=0003-9993&ishighres=false&allhighres=false&free=yes','journalimage');)