Showing papers in "Neuromodulation in 2015"

Treatment-Limiting Complications of Percutaneous Spinal Cord Stimulator Implants: A Review of Eight Years of Experience From an Academic Center Database

Abstract: Objective The study aims to evaluate the long-term implant survival and complications of spinal cord stimulation (SCS) leading to surgical revision or explant in patients treated for chronic noncancer pain. Materials and Methods This is a retrospective study of all patients who underwent a percutaneous spinal cord stimulation trial followed by implant in an academic Pain Medicine division by four practitioners from 2007 to 2013, with follow-up data through April 2014. Results A total of 345 patients were considered candidates for dorsal column stimulation and underwent a trial. Two hundred thirty-four patients were implanted with an implant-to-trial ratio of 67–86% across various chronic pain entities (postlaminectomy syndrome, complex regional pain syndrome, small-fiber peripheral neuropathy, abdominal/pelvic pain, nonsurgical candidates with lumbosacral neuropathy, and neuropathic pain not otherwise specified), with the exception of nonsurgical candidates with lumbosacral neuropathy who had an implant ratio of 43%. The complication rate was 34.6%, with the hardware related being the most common reason, comprising 74.1% of all complications. The revision and explant rates were 23.9% each. The most common reason for explant was loss of therapeutic effect (41.1%). Conclusions SCS is an effective treatment for chronic noncancer pain. It is a minimally invasive procedure, safe, and with good long-term outcomes. However, the surgical revision and explant rates are relatively high. As the use of SCS continues to grow, research into the causes of and risk factors for SCS-related complications is paramount to decrease complication rates in the future.

One-Year Outcomes of Spinal Cord Stimulation of the Dorsal Root Ganglion in the Treatment of Chronic Neuropathic Pain

Abstract: Objectives Spinal cord stimulation of the dorsal root ganglion (DRG-SCS) is a new therapy for treating chronic neuropathic pain. Previous work has demonstrated the effectiveness of DRG-SCS for pain associated with failed back surgery syndrome, complex regional pain syndrome, chronic postsurgical pain, and other etiologies through 6 months of treatment; this report describes the maintenance of pain relief, improvement in mood, and quality of life through 12 months. Materials and Methods Subjects with intractable pain in the back and/or lower limbs were implanted with an active neurostimulator device. Up to four percutaneous leads were placed epidurally near DRGs. Subjects were tracked prospectively for 12 months. Results Overall, pain was reduced by 56% at 12 months post-implantation, and 60% of subjects reported greater than 50% improvement in their pain. Pain localized to the back, legs, and feet was reduced by 42%, 62%, and 80%, respectively. Measures of quality of life and mood were also improved over the course of the study, and subjects reported high levels of satisfaction. Importantly, excellent pain–paresthesia overlap was reported, remaining stable through 12 months. Discussion Despite methodological differences in the literature, DRG-SCS appears to be comparable to traditional SCS in terms of pain relief and associated benefits in mood and quality of life. Its benefits may include the ability to achieve precise pain–paresthesia concordance, including in regions that are typically difficult to target with SCS, and to consistently maintain that coverage over time.

The dorsal root ganglion in chronic pain and as a target for neuromodulation: a review.

Abstract: Background In the not-too-distant past, the dorsal root ganglion (DRG) was portrayed as a passive neural structure without involvement in the development or maintenance of chronic neuropathic pain (NP). The DRG was thought of as a structure that merely “supported” physiologic communication between the peripheral nervous system (PNS) and the central nervous system (CNS). Newer scientific information regarding the anatomic and physiologic changes that occur within the DRG as a result of environmental pressures has dispelled this concept and suggests that the DRG is an active participant in the development of NP. This new information, along with new clinical data showing that stimulation of the DRG reduces intensity of pain, suggests that the DRG can be a robust target for neuromodulation therapies. Methods A review of the anatomical and physiological literature regarding the role of the DRG in the development of NP was performed utilizing SciBase, PubMed, and Google Scholar. The information gathered was used to lay an anatomic and physiologic foundation for establishing the DRG as a relevant target for neuromodulation therapies and to formulate a hypothesis as to how electrical stimulation of the DRG might reverse the process and perception of NP. Conclusions The DRG is an active participant in the development of NP. DRG stimulation has multiple effects on the abnormal changes that occur within the DRG as a result of peripheral afferent fiber injury. The sum total of these stimulation effects is to stabilize and decrease hyperexcitability of DRG neurons and thereby decrease NP.

Dorsal Root Ganglion (DRG) Stimulation in the Treatment of Phantom Limb Pain (PLP).

Abstract: Objectives Phantom limb pain (PLP) is a neuropathic condition in which pain is perceived as arising from an amputated limb. PLP is distinct from, although associated with, pain in the residual limb and nonpainful phantom sensations of the missing limb. Its treatment is extremely challenging; pharmaceutical options, while commonly employed, may be insufficient or intolerable. Neuromodulatory interventions such as spinal cord stimulation have generated mixed results and may be limited by poor somatotopic specificity. It was theorized that dorsal root ganglion (DRG) neuromodulation may be more effective. Materials and Methods Patients trialed a DRG neurostimulation system for their PLP and were subsequently implanted if results were positive. Retrospective chart review was completed, including pain ratings on a 100-mm visual analogue scale (VAS) and patient-reported outcomes. Results Across eight patients, the average baseline pain rating was 85.5 mm. At follow-up (mean of 14.4 months), pain was rated at 43.5 mm. Subjective ratings of quality of life and functional capacity improved. Some patients reduced or eliminated pain medications. Patients reported precise concordance of the paresthesia with painful regions, including in their phantom limbs; in one case, stimulation eliminated PLP as well as nonpainful phantom sensations. Three patients experienced a diminution of pain relief, despite good initial outcomes. Conclusions DRG neuromodulation may be an effective tool in treating this pain etiology. Clinical outcomes in this report support recent converging evidence suggesting that the DRG may be the site of PLP generation and/or maintenance. Further research is warranted to elucidate mechanisms and optimal treatment pathways.

Deep Brain Stimulation for Essential Tremor: Targeting the Dentato‐Rubro‐Thalamic Tract?

Abstract: Objective The aim of our study was to evaluate the influence of the stimulation site relative to the dentato-rubro-thalamic tract (DRTT) on the alleviation of tremor in deep brain stimulation. Methods Ten DRTTs in five patients were investigated using preoperative diffusion tensor imaging (DTI). Regions of interest for fiber tracking were located in the cerebellar dentate nucleus, the superior cerebellar peduncle and the contralateral red nucleus. The position and distance of all intraoperative stimulation sites to the DRTT were measured and correlated to the amount of tremor reduction. Results Nine of 10 DRTTs could be identified using DTI-based fiber tracking. Better tremor reduction was achieved in locations in or posterior and lateral to the DRTT than in medial and anterior positions (p = 0.001). Stimulation sites inferior to and in the DRTT achieved better results than locations superior to the DRTT (p < 0.05). The vicinity of the stimulation site to the DRTT did not correlate with tremor alleviation. Discussion In deep brain stimulation targeting for thalamic stimulation sites is limited to statistical, atlas-based coordinates. Diffusion tensor imaging and fiber tracking was used to visualize the dentato-rubro-thalamic tract as a potential, individualized target structure. However, we could not demonstrate that contacts closer to the DRTT provided better clinical effects than distant contacts, in any given direction. DTI sequences with a higher number of read-out directions, probabilistic fiber tracking and three Tesla MRI scanners may lead to different results in the depiction of the chosen fiber tract and may provide a better correlation with stimulation effects. Conclusions The results do not provide sufficient evidence to define the DRTT as a new DBS-target for tremor. Further investigations on different fiber tracts, DTI sequences, and fiber tracking algorithms are mandatory.

High-Frequency Electrical Nerve Block for Postamputation Pain: A Pilot Study

Abstract: Objectives This study aimed to assess the analgesic effect of kilohertz alternating current applied to the severed nerves in amputees afflicted by intractable limb pain. Methods Ten lower-limb amputees with chronic and severe residual limb pain or phantom limb pain who attained significant pain reduction after local nerve block injection were enrolled. A cuff electrode was wrapped around the sciatic or tibial nerve. An external waveform generator was used for the main part of the study, while an implantable generator was developed and implanted in the responders after 9 to 12 months. Sinusoidal waveforms of 10 kHz and up to 10 V were applied for 30 min during each subject-initiated treatment session. A diary was used to record pain intensities before and after each session. Results Among the seven subjects who received treatment, the average pain reduction was 75% at the three-month primary end point. These subjects were responders per predefined criterion of achieving ≥50% pain reduction in ≥50% of treatment sessions for the three-month end point. Pain medication use and interference of pain on functions was significantly reduced. The treatment efficacy was sustained through the follow-up period of up to 12 months. Besides dislodgement and loss of function for one electrode in one subject, all other devices functioned as intended. No changes of residual motor and sensory function were observed. Conclusion This pilot study generated preliminary evidence on the efficacy and safety of kilohertz electrical nerve block for postamputation pain, justifying a pivotal study for regulatory approval.

The rationale driving the evolution of deep brain stimulation to constant-current devices.

Abstract: Objective Deep brain stimulation (DBS) is an effective therapy for the treatment of a number of movement and neuropsychiatric disorders. The effectiveness of DBS is dependent on the density and location of stimulation in a given brain area. Adjustments are made to optimize clinical benefits and minimize side effects. Until recently, clinicians would adjust DBS settings using a voltage mode, where the delivered voltage remained constant. More recently, a constant-current mode has become available where the programmer sets the current and the stimulator automatically adjusts the voltage as impedance changes. Methods We held an expert consensus meeting to evaluate the current state of the literature and field on constant-current mode versus voltage mode in clinical brain-related applications. Results/Conclusions There has been little reporting of the use of constant-current DBS devices in movement and neuropsychiatric disorders. However, as impedance varies considerably between patients and over time, it makes sense that all new devices will likely use constant current.

Cost‐Effectiveness and Cost‐Utility Analysis of Spinal Cord Stimulation in Patients With Failed Back Surgery Syndrome: Results From the PRECISE Study

Abstract: Objective To assess the cost-effectiveness and cost-utility of Spinal Cord Stimulation (SCS) in patients with failed back surgery syndrome (FBSS) refractory to conventional medical management (CMM). Materials and Methods We conducted an observational, multicenter, longitudinal ambispective study, where patients with predominant leg pain refractory to CMM expecting to receive SCS+CMM were recruited in 9 Italian centers and followed up to 24 months after SCS. We collected data on clinical status (pain intensity, disability), Health-Related Quality-of-Life (HRQoL) and on direct and indirect costs before (pre-SCS) and after (post-SCS) the SCS intervention. Costs were quantified in € 2009, adopting the National Health Service's (NHS), patient and societal perspectives. Benefits and costs pre-SCS versus post-SCS were compared to estimate the incremental cost-effectiveness and cost utility ratios. Results 80 patients (40% male, mean age 58 years) were recruited. Between baseline and 24 months post-SCS, clinical outcomes and HRQoL significantly improved. The EQ-5D utility index increased from 0.421 to 0.630 (p < 0.0001). Statistically significant improvement was first observed six months post-SCS. Societal costs increased from €6600 (pre-SCS) to €13,200 (post-SCS) per patient per year. Accordingly, the cost-utility acceptability curve suggested that if decision makers' willingness to pay per Quality-Adjusted-Life-Years (QALYs) was €60,000, SCS implantation would be cost-effective in 80% and 85% of cases, according to the NHS's and societal point of views, respectively. Conclusions Our results suggest that in clinical practice, SCS+CMM treatment of FBSS patients refractory to CMM provides good value for money. Further research is encouraged in the form of larger, long-term studies.

Improved Pain Relief With Burst Spinal Cord Stimulation for Two Weeks in Patients Using Tonic Stimulation: Results From a Small Clinical Study.

Abstract: Objectives Conventional spinal cord stimulation (SCS) delivers a tonic waveform with consistent stream of pulses; burst delivers groups of pulses separated by short pulse-free periods. The current study compared the short-term safety and efficacy of burst with tonic stimulation in subjects already receiving SCS. Materials and Methods At 4 IRB-approved sites, 22 subjects previously implanted with an SCS device for intractable, chronic pain gave informed consent and received burst stimulation for 14 days. Subjects reported average daily Visual Analog Scale (VAS) for overall, trunk, and limb pain using tonic stimulation and after 7 and 14 days of burst stimulation. Thoughts about pain were assessed using the Pain Catastrophizing Scale. Areas of paresthesia were assessed during tonic and burst stimulation using body maps. Assessment of patient satisfaction and preferred stimulation occurred after 14 days of burst. Results Average daily overall VAS reduced 46% from a mean of 53.5 (±20.2) mm during tonic SCS to 28.5 (±18.1) mm during burst (p < 0.001); trunk and limb VAS scores were also reduced by 33% and 51%, respectively. During burst, 16 subjects (73%) reported no paresthesia, 5 (23%) reported a reduction, and 1 (4%) reported increased paresthesia. After 14 days, 21 subjects (95%) reported being very satisfied or satisfied with burst. Burst was preferred by 20 subjects (91%), tonic by 1 (5%), and 1 (5%) reported no preference. Better pain relief was the most common reason cited for preference. Conclusions A majority of subjects reported improved pain relief using burst compared with tonic stimulation. Most subjects experienced less paresthesia during burst and preferred burst citing better pain relief.

The Use of 10-Kilohertz Spinal Cord Stimulation in a Cohort of Patients With Chronic Neuropathic Limb Pain Refractory to Medical Management

Abstract: Objective It is the purpose of this study to document our experience with the use of a 10-kHz high-frequency spinal cord stimulation (SCS) device for the relief of neuropathic pain of the upper and lower limbs. Materials and Methods A retrospective chart review was performed of all patients treated with the 10-kHz high-frequency SCS system for neuropathic pain (upper or lower limb) refractory to conventional treatment. All patients underwent a trial with one or two eight-contact percutaneous leads using 50-Hz traditional stimulation. If ≥80% paresthesia coverage of the painful area with traditional SCS was obtained, high-frequency 10-kHz SCS was used. Patients who had a significant reduction in pain score (≥50%) at the end of the trial received a permanent implant and were then followed for up to six months. Outcome measures included a numeric rating scale for pain, the Brief Pain Inventory, health-related quality of life (EQ-5D), the Pain Catastrophizing Scale, and patient satisfaction. Results Fifteen patients completed a trial of high-frequency 10-kHz SCS. Eleven patients proceeded to permanent implantation. Ten of the 11 patients who proceeded to full implantation had significant reductions in all of the collected outcome variables at one, three, and six months. Conclusions In this small cohort of patients, high-frequency 10-kHz SCS reduced pain and improved quality of life. However, before we can conclude that high-frequency 10-kHz SCS for neuropathic pain of the upper and lower extremities is efficacious, a large-scale multicenter observational study should be performed to corroborate our small retrospective study.

Tremor Reduction by Deep Brain Stimulation Is Associated With Gamma Power Suppression in Parkinson's Disease

Abstract: OBJECTIVES: Rest tremor is a cardinal symptom of Parkinson's disease (PD), and is readily suppressed by deep brain stimulation (DBS) of the subthalamic nucleus (STN). The therapeutic effect of the latter on bradykinesia and rigidity has been associated with the suppression of exaggerated beta (13–30 Hz) band synchronization in the vicinity of the stimulating electrode, but there is no correlation between beta suppression and tremor amplitude. In the present study, we investigate whether tremor suppression is related to suppression of activities at other frequencies. MATERIALS AND METHODS: We recorded hand tremor and contralateral local field potential (LFP) activity from DBS electrodes during stimulation of the STN in 15 hemispheres in 11 patients with PD. DBS was applied with increasing voltages starting at 0.5 V until tremor suppression was achieved or until 4.5 V was reached. RESULTS: Tremor was reduced to 48.9% ± 10.9% of that without DBS once stimulation reached 2.5–3 V (t14 = −4.667, p < 0.001). There was a parallel suppression of low gamma (31–45 Hz) power to 92.5% ± 3% (t14 = −2.348, p = 0.034). This was not seen over a band containing tremor frequencies and their harmonic (4–12 Hz), or over the beta band. Moreover, low gamma power correlated with tremor severity (mean r = 0.43 ± 0.14, p = 0.008) within subjects. This was not the case for LFP power in the other two bands. CONCLUSIONS: Our findings support a relationship between low gamma oscillations and PD tremor, and reinforce the principle that the subthalamic LFP is a rich signal that may contain information about the severity of multiple different Parkinsonian features.

Reducing transcranial direct current stimulation-induced erythema with skin pretreatment: considerations for sham-controlled clinical trials.

Abstract: Objectives Transcranial direct current stimulation (tDCS)-induced erythema (skin reddening) has been described as an adverse effect that can harm blinding integrity in sham-controlled designs. To tackle this issue, we investigated whether the use of topical pretreatments could decrease erythema and other adverse effects associated with tDCS. Materials and Methods Thirty healthy volunteers were recruited, and four interventions were applied 30 min prior to tDCS in a Latin square design: placebo, ketoprofen 2%, hydroxyzine 1%, and lidocaine 5%. TDCS was applied for 30 min (2 mA, anode and cathode over F3 and F4, respectively) in two active sessions with a minimum 1-week interval. The Draize erythema scoring system scale was used to assess erythema intensity; a tDCS questionnaire was used to assess other adverse effects (e.g., tingling, itching, burning sensation, and pain). Results We found that ketoprofen (but not hydroxyzine or lidocaine) significantly attenuated tDCS-induced erythema regarding intensity and duration, with a medium effect compared with placebo. Erythema was overall mild, short-lived (lasting 18–24 min after tDCS ending), and more intense under the anode. Subjects with darker skin color also tended to present less intense tDCS-induced erythema. The prevalence of other adverse effects was low and did not differ between dermatological groups. Conclusions Ketoprofen 2% topical pretreatment might be an interesting strategy to reduce tDCS-induced erythema and might be useful for blinding improvement in further sham-controlled tDCS trials.

Stimulation parameters define the effectiveness of burst spinal cord stimulation in a rat model of neuropathic pain.

Abstract: Introduction Although burst spinal cord stimulation (SCS) has been reported to reduce neuropathic pain, no study has explicitly investigated how the different parameters that define burst SCS may modulate its efficacy. The effectiveness of burst SCS to reduce neuronal responses to noxious stimuli by altering stimulation parameters was evaluated in a rat model of cervical radiculopathy. Methods Neuronal firing was recorded in the spinal dorsal horn before and after burst SCS on day 7 following painful cervical nerve root compression (N = 8 rats). The parameters defining the stimulation (number of pulses per burst, pulse frequency, pulse width, burst frequency, amplitude) were individually varied in separate stimulation trials while holding the remaining parameters constant. The percent reduction of firing of wide-dynamic-range (WDR) and high-threshold neurons after SCS and the percentage of neurons responding to SCS were quantified for each parameter and correlated to the charge per burst delivered during stimulation. Results Pulse number, pulse width, and amplitude each were significantly correlated (p <0.009) to suppression of neuronal firing after SCS. Pulse frequency and amplitude significantly affected (p <0.05) the percentage of responsive neurons. Charge per burst was correlated to a reduction of WDR neuronal firing (p <0.03) and had a nonlinear effect on the percentage of neurons responding to burst SCS. Conclusions Burst SCS can be optimized by adjusting relevant stimulation parameters to modulate the charge delivered to the spinal cord during stimulation. The efficacy of burst SCS is dependent on the charge per burst.

Incidence of Clinically Significant Percutaneous Spinal Cord Stimulator Lead Migration

Abstract: Objective To examine the incidence of percutaneous spinal cord stimulator lead migration, given current hardware and surgical technique. Materials and Methods We retrospectively reviewed records of patients who underwent spinal cord stimulator implantation with percutaneous leads at our institution from 2008 through 2011. We determined the number of patients who required surgical revision for clinically significant lead migration. Results Clinically significant lead migration requiring surgical revision occurred in three of 143 patients (2.1%) with primary SCS system implants utilizing percutaneous-type leads. Conclusions The rate of lead migration observed in our practice was considerably lower than previously published estimates of clinically significant lead migration or revision for lead migration (13%–22%). However, our study did not determine the reason for the decreased rate, which may be influenced by current hardware and implant techniques.

Long-Term Evaluation of Changes in Operative Technique and Hardware-Related Complications With Deep Brain Stimulation.

Abstract: Background Deep brain stimulation is the most frequent neurosurgical procedure for movement disorders. Objective While this elective procedure carries a low-risk profile, it is not free of complications. As a new procedure, the pattern of complications changed with experience and modification of surgical technique and equipment. Methods This review analyzes the most common hardware-related complications that may occur and techniques to avoid them. It is a retrospective review of 432 patients undergoing 1077 procedures over a 14-year period by one surgeon with emphasis on the analysis of surgical technique and the changes over time. Comparisons were made pre and postimplementation of different surgical techniques over different time periods. The epochs relate to the learning curve, new equipment, and new techniques. Results Overall lead revision was observed at 5.7%, extension revision at 3.2%, infection rate at 1.2%, infarct without intracerebral hemorrhage at 0.8%, and intracerebral hemorrhage at 2.5% with a permanent deficit of 0.2%. An analysis and change in surgical technique which involved isolating the lead from the skin surface at both the cranial and retro-auricular incision also demonstrated a substantial decrease in lead fracture rate and infection rate. There was no mortality. Conclusion This large series of patients and long-term follow-up demonstrates that risks are very low in comparison with other neurosurgical procedures, but DBS is still an elective procedure that necessitates extensive care and precision. In a rapidly evolving field, attention to surgical technique is imperative and will keep rates of complications at a minimum.

Lack of body positional effects on paresthesias when stimulating the dorsal root ganglion (DRG) in the treatment of chronic pain.

Abstract: textObjectives: One prominent side effect from neurostimulation techniques, and in particular spinal cord stimulation (SCS), is the change in intensity of stimulation when moving from an upright (vertical) to a recumbent or supine (horizontal) position and vice versa. It is well understood that the effects of gravity combined with highly conductive cerebrospinal fluid provide the mechanism by which changes in body position can alter the intensity of stimulation-induced paresthesias. While these effects are well established for leads that are placed within the more medial aspects of the spinal canal, little is known about these potential effects in leads placed in the lateral epidural space and in particular within the neural foramina near the dorsal root ganglion (DRG). Materials and Methods: We prospectively validated a newly developed paresthesia intensity rating scale and compared perceived paresthesia intensities when subjects assumed upright vs. supine bodily positions during neuromodulation of the DRG. Results: On average, the correlation coefficient between stimulation intensity (pulse amplitude) and perceived paresthesia intensity was 0.83, demonstrating a strong linear relationship. No significant differences in paresthesia intensities were reported within subjects when moving from an upright (4.5 ± 0.14) to supine position 4.5 (±0.12) (p > 0.05). This effect persisted through 12 months following implant. Conclusions: Neuromodulation of the DRG produces paresthesias that remain consistent across body positions, suggesting that this paradigm may be less susceptible to positional effects than dorsal column stimulation.

Spinal cord stimulation for the treatment of chronic back pain patients: 500-Hz vs. 1000-Hz burst stimulation.

Abstract: Objective Spinal cord stimulation is a commonly used, safe, and effective procedure applied for medically intractable failed back surgery syndrome, as well as other neuropathic pain syndromes. Recently, a novel stimulation paradigm called burst stimulation has been developed that is paresthesia-free and has a more pronounced suppressive effect on neuropathic pain. Materials and Methods Fifteen patients who were being treated with burst spinal cord stimulation for failed back surgery syndrome participated in an open-label trial to verify whether their pain suppression could be further ameliorated by changing the burst pattern. Burst stimulation with packets of five electrical pulses delivered at 500 Hz with 1000-μsec pulse width 40 times per second was changed to burst mode delivering five spikes at 1000 Hz with 500-μsec pulse width 40 times a second. As the amplitudes did not differ between the two groups, the total delivery of current to the spinal cord was not different between the two modes of burst stimulation. Scores on visual analog scales for pain and paresthesia, the Pain Catastrophizing Scale, the Pain Vigilance and Awareness Questionnaire, and the Short Form 36 quality of life measurement were compared between the two modes of burst stimulation. [Correction added on 06 Feb 2015, after first online publication: this paragraph has been revised to signify the comparison of amplitudes between two groups] Results No statistically significant differences were found between the two modes of stimulation. Conclusion The results suggest that increasing the frequency from 500 to 1000 Hz while keeping the pulse width constant does not add any extra benefit in suppressing pain. Further studies should verify whether increasing the frequency above 1000 Hz has a similar lack of effect.

Intrathecal Pharmacology Update: Novel Dosing Strategy for Intrathecal Monotherapy Ziconotide on Efficacy and Sustainability.

Abstract: Introduction Intrathecal drug delivery is a well-defined strategy to treat malignant and nonmalignant pain. Ziconotide is a well-studied intrathecal medicine option that has many attractive qualities, as it is non-granulomagenic, overdose or underdose is not associated with cardiopulmonary compromise or death, and is a non-opoid analgesic. However, it has had slow adoption into pain care algorithms because it has been historically plagued with the connotation of having a narrow therapeutic window and a low sustainability rate. We introduce a novel dosing strategy to improve patient outcomes and sustainability. Methods Patients were identified as being an intrathecal candidate and trialed with ziconotide based on the current standard of care. Patient demographics, diagnosis, previous treatment failures, and pre-implant visual analog scale (VAS) scores were recorded. Once the trial was deemed successful, based on the dual bolusing strategy, the patient underwent device implantation. Consecutive patients were prospectively followed. Ziconotide was then initiated with a flex dosing strategy, weighted during nocturnal dosing. Outcome endpoints included: reduction in VAS, side effects, durability of therapy, and systemic opioid use prior to implant and at last visit were noted (calculated to daily morphine equivalents). Primary endpoint was tolerability of ziconotide at three months following new dosing strategy. No industry support or funding was obtained for this project. Results All enrolled patients met the endpoint of the study of tolerability of ziconotide at three months. Numbers declined to 75% of patients at four months, and 70% of patients at six months. The discontinuing side-effects were most commonly urinary retention and visual hallucinations. There were no serious adverse events and no unresolved complications reported. Numerical rating scale (NRS) decreased on average from 9.06 to 1.8. Opioid reduction in morphine equivalents averaged 91.5% Discussion The efficacy and tolerability of monotherapy ziconotide may be improved by using a weighted bolus flex dosing strategy as compared with slow continuous infusions. Conclusion We present a novel strategy to deliver ziconotide using a unique continuous infusion flex dosing strategy. Further randomized, prospective, higher-powered studies are needed to critically evaluate the conclusions suggested by this limited prospective case series.

Repetitive transcranial magnetic stimulation once a week induces sustainable long-term relief of central poststroke pain.

Abstract: Objective Central poststroke pain is a serious problem for some patients after stroke. Repetitive transcranial magnetic stimulation (rTMS) has been reported to relieve poststroke pain but its efficacy is still controversial. We tested the possibility that rTMS, when applied once a week, would induce sustainable relief of poststroke pain. Materials and Methods Eighteen patients with central poststroke pain were included in this study. rTMS (10 trains of 10-sec 5 Hz-rTMS) was delivered over the primary motor cortex on the affected side. The rTMS session was repeated once a week for 12 weeks, and for six patients the intervention was continued for one year. The degree of the pain was assessed before each weekly rTMS session to evaluate sustainable effects. Results The effects of the rTMS reached a plateau at the eighth week. At the 12th week, the rTMS was effective in 61.1% of the patients; 5 of the 18 patients showed more than 70% reduction based on a visual analog scale, 6 patients showed 40–69% reduction, and 7 remained at a pain reduction level of less than 40%. When patients were divided into two groups with or without severe dysesthesia, it was found that eight patients with severe dysesthesia showed less pain relief than those without. In the six patients who continued rTMS for one year, the pain relief effects also were sustained. Conclusion Although this was an open-label study without a control group, our findings suggest that rTMS of the primary motor cortex, when maintained once a week, could help to relieve poststroke pain.

Predictors of Spinal Cord Stimulation Success.

Abstract: Introduction As many as 30% of spinal cord stimulation (SCS) patients fail to obtain long-term pain coverage, even with the strictest parameters of a successful trial, unremarkable psychological assessment, and ideal placement of the permanent device. Why these patients either never receive adequate benefit or lose benefit remains elusive. Methods We perform a retrospective review of our prospective database of SCS patients undergoing surgery for routine indications. Six-month postoperative follow-up data were available for 57 patients. Two providers who routinely saw the patients were asked to independently grade the patient's outcome in a blinded fashion on a Global Outcome Ratings scale of 1 to 10, with 5 being 50% improvement at 6 months postoperation. A score of less than 5 was deemed a failure. The impact of body mass index (BMI), random drug screen results, workers' compensation status, depression, and smoking were assessed. Results We report a phi correlation of 0.350 between smoking and failure (p = 0.017). Smoking status is correlated with both lead migration revisions (phi = 0.269) (p = 0.044) and with revision due to new pain symptoms (phi = 0.241) (p = 0.072). Further, there is a trend of correlation (phi = 0.289) between drug use and patients (N = 3) who underwent device removal (p = 0.045). In this cohort, worker's compensation status, BMI, and depression did not impact outcome. Conclusions Tobacco use correlates with less success with SCS at 6-month follow-up. Whether that is because of issues with healing and our transmission of signals to the periphery warrants further exploration. These data provide further evidence that tobacco cessation is important to surgical results.

Short-Term Neuroplastic Effects of Brain-Controlled and Muscle-Controlled Electrical Stimulation

Abstract: Objectives Functional electrical stimulation (FES) has been shown to facilitate the recovery of grasping function in individuals with incomplete spinal cord injury. Neurophysiological theory suggests that this benefit may be further enhanced by a more consistent pairing of the voluntary commands sent from the user's brain down their spinal cord with the electrical stimuli applied to the user's periphery. The objective of the study was to compare brain-machine interfaces (BMIs)-controlled and electromyogram (EMG)-controlled FES therapy to three more well-researched therapies, namely, push button-controlled FES therapy, voluntary grasping (VOL), and BMI-guided voluntary grasping. Materials and Methods Ten able-bodied participants underwent one hour of each of five grasping training modalities, including BMI-controlled FES (BMI-FES), EMG-controlled FES (EMG-FES), conventional push button-controlled FES, VOL, and BMI-guided voluntary grasping. Assessments, including motor-evoked potential, grip force, and maximum voluntary contraction, were conducted immediately before and after each training period. Results Motor-evoked potential-based outcome measures were more upregulated following BMI-FES and especially EMG-FES than they were following VOL or FES. No significant changes were found in the more functional outcome measures. Conclusions These results provide preliminary evidence suggesting the potential of BMI-FES and EMG-FES to induce greater neuroplastic changes than conventional therapies, although the precise mechanism behind these changes remains speculative. Further investigation will be required to elucidate the underlying mechanisms and to conclusively determine whether these effects can translate into better long-term functional outcomes and quality of life for individuals with spinal cord injury.

Review: Bioelectrical Mechanisms in Spinal Cord Stimulation

Abstract: Objectives The aim of this review is to make specialists in a variety of disciplines familiar with basic aspects of spinal cord stimulation and the role of mathematical modeling in understanding its mechanisms of action and the solution of basic problems. Methods The paper is divided into five sections. The content of each section also covers aspects of various disciplines. Most aspects are presented in an unusual way, likely resulting in new viewpoints and further developments in the growing field of neuromodulation. Results A special, integrating role is the mathematical modeling of spinal cord stimulation and the simulation studies of various aspects, such as the stimulation in axial low-back pain. Conclusions In particular the conclusions from several computer simulation studies are relevant and of interest to specialists in many disciplines. © 2015 International Neuromodulation Society.

Transcranial Direct Current Stimulation Ameliorates Behavioral Deficits and Reduces Oxidative Stress in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Mouse Model of Parkinson's Disease.

Abstract: Purpose Oxidative stress is involved in the pathological process of Parkinson's disease (PD). The present study was designed to investigate the effects of transcranial direct current stimulation (tDCS) on the oxidative stress in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Methods The animals were modulated by tDCS. Behavioral alterations were observed after three weeks of tDCS treatment using rotary performance tests. The mice were sacrificed for the measurement of the level of dopamine (DA), enzymatic tyrosine hydroxylase (TH), nonenzymatic malonaldehyde (MDA), an enzymatic superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the mouse brain and serum. Results The mice treated with MPTP had an increased MDA level but a decreased SOD and GSH-Px activity, as well as a behavior impairment. These abnormalities were significantly attenuated by tDCS treatment and by levodopa and benserazide. Discussion The study demonstrated that the tDCS could have a potential for the therapeutic usage in the PD.

Early Use of 60 Hz Frequency Subthalamic Stimulation in Parkinson's Disease: A Case Series and Review.

Abstract: Background Deep brain stimulation (DBS) is effective in treating the segmental symptoms of Parkinson's disease (PD) as well as axial symptoms that are levodopa responsive. PD patients on chronic DBS who develop axial symptoms and gait disturbances several years later oftentimes are refractory to high frequency stimulation (HFS). Several studies report benefit produced by low frequency subthalamic nucleus (STN) stimulation in such patients, though the sustainability of the effects has been mixed. Objective To report the clinical outcomes of a series of patients with Parkinson's disease and levodopa responsive axial and gait disturbances who were switched to 60 Hz stimulation within one year of their DBS surgery. Methods A retrospective review of 5 patients, whose severe pre-DBS, levodopa responsive gait disorders worsened on HFS STN-DBS and were subsequently switched to 60 Hz stimulation within 1 year of their surgery. Results The median age of this cohort was 66 years with median disease duration of 14 years. Four of 5 patients' experienced acute worsening of their axial and gait UPDRS III scores on HFS. All patients' gait disorder improved with 60 Hz along with amelioration of their segmental symptoms and reduction of their levodopa induced dyskinesia. The median time on HFS prior to switching to 60 Hz was two months. Stimulation through the ventral contacts was utilized in all patients with relatively modest changes achieved in levodopa equivalent daily dose. Conclusion This case series demonstrates the clinical efficacy of utilizing low frequency (60 Hz) STN stimulation early in the DBS programming course in more advanced PD patients with levodopa responsive gait disturbance and freezing of gait. Activation of a broader stimulation field likely contributed to both axial and segmental symptom improvement while possibly aiding in the reduction of dyskinesia.

Analysis of Adverse Events in the Management of Chronic Migraine by Peripheral Nerve Stimulation

Abstract: Objective In this study, we analyze device- and procedure-related adverse events (AEs) from a recent prospective, multicenter, double-blinded controlled study that utilized peripheral nerve stimulation (PNS) of occipital nerves for management of chronic migraine. Methods PNS device characteristics (lead length and spacing), surgical techniques including lead orientation (parallel or perpendicular to the nerve), and implantable pulse generator (IPG) placement (upper buttock, abdomen, infraclavicular, or lower axilla) in 157 patients were analyzed to identify any relationship with the AE incidence rate. Number of prior PNS implants performed (NPPIP) by the implanter and its relationship with different AE categories (hardware-related, biological, and stimulation-related events) and frequently observed device/procedure-related AEs (lead migration/fracture/breakage, persistent pain at the lead/IPG location, unintended/undesirable changes in stimulation, infection) were also evaluated. Three-way ANOVA tests were utilized to evaluate the dependence of AE occurrence on the variables described above. Results IPG pocket locations closer to the lead (e.g. infraclavicular region) were associated with a lower AE incidence rate (p < 0.05). Higher NPPIP was related to lower stimulation- and hardware-related AEs (p < 0.05), frequently observed AEs like lead migration, pain, and infection (p < 0.05), and procedure-related additional surgeries (p < 0.05). Conclusion Implantation of the IPG closer to the lead location was associated with reduced AEs. PNS is a relatively new procedure, and the skill and precision in performing these procedures improves with experience. Our results demonstrate that as the implanter gains more experience with these procedures, a significant reduction in device- and procedure-related AEs may be expected.

Subject-Specific Multiscale Modeling to Investigate Effects of Transcranial Magnetic Stimulation

Abstract: Objective Transcranial magnetic stimulation (TMS) is an effective intervention in noninvasive neuromodulation used to treat a number of neurophysiological disorders. Predicting the spatial extent to which neural tissue is affected by TMS remains a challenge. The goal of this study was to develop a computational model to predict specific locations of neural tissue that are activated during TMS. Using this approach, we assessed the effects of changing TMS coil orientation and waveform. Materials and Methods We integrated novel techniques to develop a subject-specific computational model, which contains three main components: 1) a figure-8 coil (Magstim, Magstim Company Limited, Carmarthenshire, UK); 2) an electromagnetic, time-dependent, nonhomogeneous, finite element model of the whole head; and 3) an adaptation of a previously published pyramidal cell neuron model. We then used our modeling approach to quantify the spatial extent of affected neural tissue for changes in TMS coil rotation and waveform. Results We found that our model shows more detailed predictions than previously published models, which underestimate the spatial extent of neural activation. Our results suggest that fortuitous sites of neural activation occur for all tested coil orientations. Additionally, our model predictions show that excitability of individual neural elements changes with a coil rotation of ±15°. Conclusions Our results indicate that the extent of neuromodulation is more widespread than previous published models suggest. Additionally, both specific locations in cortex and the extent of stimulation in cortex depend on coil orientation to within ±15° at a minimum. Lastly, through computational means, we are able to provide insight into the effects of TMS at a cellular level, which is currently unachievable by imaging modalities.

Noninvasive Spinal Cord Stimulation: Technical Aspects and Therapeutic Applications

Abstract: Background Electrical and magnetic trans-spinal stimulation can be used to increase the motor output of multiple spinal segments and modulate cortico-spinal excitability. The application of direct current through the scalp as well as repetitive transcranial magnetic stimulation are known to influence brain excitability, and hence can also modulate other central nervous system structures, including spinal cord. Objective This study aimed to evaluate the effects and the therapeutic usefulness of these noninvasive neuromodulatory techniques in healthy subjects and in the neurorehabilitation of patients with spinal cord disorders, as well as to discuss the possible mechanisms of action. A comprehensive review that summarizes previous studies using noninvasive spinal cord stimulation is lacking. Methods PubMed (MEDLINE) and EMBASE were systematically searched to identify the most relevant published studies. We performed here an extensive review in this field. Results By decreasing the spinal reflex excitability, electrical and magnetic trans-spinal stimulation could be helpful in normalizing reflex hyperexcitability and treating hypertonia in subjects with lesions to upper motor neurons. Transcutaneous spinal direct current stimulation, based on applying direct current through the skin, influences the ascending and descending spinal pathways as well as spinal reflex excitability, and there is increasing evidence that it also can induce prolonged functional neuroplastic changes. When delivered repetitively, magnetic stimulation could also modulate spinal cord functions; however, at present only a few studies have documented spastic-reducing effects induced by repetitive spinal magnetic stimulation. Moreover, paired peripheral and transcranial stimulation can be used to target the spinal cord and may have potential for neuromodulation in spinal cord-injured subjects. Conclusions Noninvasive electrical and magnetic spinal stimulation may provide reliable means to characterize important neurophysiologic and pathophysiologic aspects of spinal cord function. Moreover, transcutaneous direct current stimulation and repetitive magnetic stimulation may hold therapeutic promise in patients with spinal cord disorders, although future well-controlled studies are needed to corroborate and extend the preliminary findings.

Follow‐Up Study of Children Whose Mothers Were Treated With Transcranial Magnetic Stimulation During Pregnancy: Preliminary Results

Abstract: Objectives The purpose of this study is to determine the impact of repetitive transcranial stimulation (rTMS) treatment during pregnancy on neurodevelopment of children. Materials and Methods Women who were treated with rTMS during pregnancy and delivered liveborn children between 2008 and 2013 were selected. A control group consisted of children whose mothers had a history of untreated depression during their pregnancy (N = 26). Early developmental characteristics of all the children in the study were evaluated, and their developmental levels were determined using the Ankara Developmental Screening Inventory. Results The mean age of the children in the rTMS treatment group was 32.4 months (range 16–64 months), and that of the untreated group was 29.04 (range 14–63 months). Jaundice (N = 2) and febrile convulsion (N = 1) were the reported medical conditions in the children of the rTMS-treated group; jaundice (N = 3) and low birth weight (N = 1) were reported in the untreated group. In the rTMS group, mothers' perception of delay in language development was observed, but there were not any statistically significant differences in the prevalence rate compared with the untreated group (OR = 0.38; 95% CI 0.0860–1.6580). Conclusions Our results suggest that rTMS exposure during pregnancy is not associated with poorer cognitive or motor development outcomes in children aged 18–62 months. Although language development as reported by the mothers was found to be poorer than expected in the rTMS-treated group, the delay was found to be similar to the language delay observed in offspring of untreated mothers, as reported in previous studies of prenatal depression treated with selective serotonin reuptake inhibitors.

Improved Poly(3,4-Ethylenedioxythiophene) (PEDOT) for Neural Stimulation.

Abstract: Objective This study compares the stability of three variations of the conductive polymer poly(3,4-ethylenedioxythiophene) or PEDOT for neural micro-stimulation under both in vitro and in vivo conditions. We examined PEDOT films deposited with counter-ions tetrafluoroborate (TFB) and poly(styrenesulfonate) (PSS), and PEDOT:PSS combined with carbon nanotubes (CNTs). Methods For the in vitro stability evaluation, implantable micro-wires were coated with the polymers, placed in a vial containing phosphate buffered saline (PBS) under accelerated aging conditions (60°C), and current pulses were applied. The resulting voltage profile was monitored over time. Following the same polymer deposition protocol, chronic neural micro-probes were modified and implanted in the motor cortex of two rats for the in vivo stability comparison. Similar stimulating current pulses were applied and the output voltage was examined. The electrochemical impedance spectroscopic (EIS) data were also recorded and fit to an equivalent circuit model that incorporates and quantifies the time-dependent polymer degradation and impedance associated with tissue surrounding each micro-electrode site. Results Both in vitro and in vivo voltage output profiles show relatively stable behavior for the PEDOT:TFB modified micro-electrodes compared to the PEDOT:PSS and CNT:PEDOT:PSS modified ones. EIS modeling demonstrates that the time-dependent increase in the polymeric resistance is roughly similar to the rise in the respective voltage output in vivo and indicates that the polymeric stability and conductivity, rather than the impedance due to the tissue response, is the primary factor determining the output voltage profile. It was also noted that the number of electrodes showing unit activity post-surgery did not decay for PEDOT:TFB as was the case for PEDOT:PSS and CNT:PEDOT:PSS. Conclusions PEDOT:TFB may be an enabling material for achieving long lasting micro-stimulation and recording.

Longevity and cost of implantable intrathecal drug delivery systems for chronic pain management: A retrospective analysis of 365 patients

Abstract: Objectives Intrathecal drug delivery systems represent an important component of interventional strategies for refractory chronic pain syndromes. Continuous intrathecal administration of opioids results in higher subarachnoid drug concentrations, improved pain scores, and less frequent side effects when compared with systemic opioid administration. Substantial costs arise at the time of surgical implantation and at revision for battery depletion or treatment of a complication. Despite current widespread use, the real-world longevity and cost of implanted intrathecal pumps (ITP) has not been fully quantified.