Target selection for deep brain stimulation in treatment resistant schizophrenia.

The use of deep brain stimulation (DBS) in treatment resistant patients with schizophrenia is of considerable current interest, but where to site the electrodes is challenging. This article reviews rationales for electrode placement in schizophrenia based on evidence for localized brain abnormality in the disorder and the targets that have been proposed and employed to date. The nucleus accumbens and the subgenual anterior cingulate cortex are of interest on the grounds that they are sites of potential pathologically increased brain activity in schizophrenia and so susceptible to the local inhibitory effects of DBS; both sites have been employed in trials of DBS in schizophrenia. Based on other lines of reasoning, the ventral tegmental area, the substantia nigra pars reticulata and the habenula have also been proposed and in some cases employed. The dorsolateral prefrontal cortex has not been suggested, probably reflecting evidence that it is underactive rather than overactive in schizophrenia. The hippocampus is also of theoretical interest but there is no clear functional imaging evidence that it shows overactivity in schizophrenia. On current evidence, the nucleus accumbens may represent the strongest candidate for DBS electrode placement in schizophrenia, with the substantia nigra pars reticulata also showing promise in a single case report; the ventral tegmental area is also of potential interest, though it remains untried.

Selección de objetivos para la estimulación cerebral profunda en la esquizofrenia resistente al tratamiento / Target Selection For Deep Brain Stimulation In Treatment Resistant Schizophrenia

Tras co-liderar el primer ensayo clínico sobre la estimulación cerebralprofunda en esquizofrenia resistente al tratamiento, investigadoresde FIDMAG, junto con investigadores del Hospital de la SantaCreu i Sant Pau revisan la literatura hasta la fecha sobre las basesneurobiológicas de la esquizofrenia y las localizaciones previamentepropuestas y empleadas en estimulación cerebral profunda (ECP).Esta revisión aporta información clave para la colocación de loselectrodos en futuros ensayos clínicos, destacando estructuras comoel núcleo accumbens o el córtex cingulado anterior, como potencialmenteprometedoras para su empleo en la ECP. Y destacando lanecesidad de continuar con la investigación para dilucidar las basesneurobiológicas de la esquizofrenia que permitirán avanzar en lostratamientos de la esquizofrenia. (AU)

After co-leading the first clinical trial on deep brain stimulationin treatment-resistant schizophrenia, FIDMAG researchers, togetherwith researchers from the Hospital de la Santa Creu i Sant Pau reviewthe literature to date on the neurobiological basis of schizophreniaand the locations previously proposed and used in deep brain stimulation(DBS). This review provides key information for the placementof electrodes in future clinical trials, highlighting structuressuch as the nucleus accumbens or the anterior cingulate cortex aspotentially promising for use in DBS. And highlighting the need forcontinued research to elucidate the neurobiological basis of schizophreniathat will advance treatments for schizophrenia. (AU)

Eficacia y seguridad del tratamiento quirúrgico en la cefalea en racimos / Efficacy and safety of surgical treatment of cluster headache

ANTECEDENTES Y OBJETIVO: La cefalea en racimos (CR) es la cefalea humana más grave y se cronifica en un 10-20% de los pacientes, pudiendo llegar a ser refractaria a todos los fármacos eficaces en un 10% de ellos. En este escenario se indican procedimientos quirúrgicos: radiofrecuencias del ganglio esfenopalatino ipsilateral al dolor (RF-GEFP), estimulación bilateral de los nervios occipitales (E-NOM) y estimulación cerebral profunda (ECP) del hipotálamo posteroinferior ipsilateral. Se ha analizado específicamente la eficacia y seguridad de cada una de ellas, pero no se ha descrito la evolución de una serie de pacientes siguiendo este itinerario quirúrgico por orden de agresividad. PACIENTES: Pacientes con CR crónica y refractaria según los criterios de la European Headache Federation. Fueron sometidos secuencialmente a RF-GEFP, E-NOM si ineficacia del anterior y ECP si ineficacia del anterior. RESULTADOS: Incluimos prospectivamente a 44 pacientes entre noviembre de 2003 y junio de 2018 con una edad media de 38,3 años siendo el 70% hombres. El seguimiento medio fue de 87,4 meses. Respondieron a 74 procedimientos de RF-GEFP 19 pacientes (33,3%). De los 25 restantes, se implantó un dispositivo de E-NOM en 22 de ellos, mostrando una eficacia del 50%. Finalmente, se sometieron a ECP del hipotálamo posteroinferior ipsilateral 9 pacientes con una eficacia del 88,8%. No se constataron complicaciones graves en ninguno de los 3 procedimientos. CONCLUSIONES: La aplicación secuencial de los 3 procedimientos quirúrgicos logró revertir la grave situación de CR crónica y refractaria a una CR episódica en el 93% de los pacientes con una morbilidad quirúrgica aceptable

BACKGROUND AND OBJECTIVES: Cluster headache (CR) is the most severe human headache and is chronic in 10%-20% of patients, and 10% can become refractory to all effective drugs. In this scenario, surgical procedures are indicated: radiofrequencies of the sphenopalatine ganglion ipsilateral to pain (RF-SPG), bilateral stimulation of the occipital nerves (NOM-S) and deep brain stimulation (DBS) of the ipsilateral posterior hypothalamus. The efficacy and safety of each of these procedures has been specifically analyzed, but the progress of a series of patients following this surgical route in order of aggressiveness has not been described. PATIENTS: Patients with chronic and refractory CR according to the criteria of the European Headache Federation. The patients underwent RF-SPG, NOM-S sequentially if the previous procedure had been ineffective, and DBS if the previous procedure had been ineffective. RESULTS: We prospectively included 44 patients between November 2003 and June 2018 with an average age of 38.3 years; 70% were men. The mean follow-up was 87.4 months. Nineteen patients responded to 74 procedures of RF-SPG (33.3%). Of the remaining 25 patients, a NOM-S device was implanted in 22, showing an efficacy of 50%. Finally, 9 patients underwent ECP of the ipsilateral lower-posterior hypothalamus with an efficacy of 88.8%. No serious complications were found following any of these 3 procedures. CONCLUSIONS: The sequential application of these three surgical procedures succeeded in reversing the serious situation of chronic CR refractory to an episodic CR in 93% of patients with acceptable surgical morbidity

Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial.

BACKGROUND: Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly. METHODS: Eight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed). FINDINGS: One implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators' knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively). INTERPRETATION: These preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects.

Efficacy and safety of surgical treatment of cluster headache. / Eficacia y seguridad del tratamiento quirúrgico en la cefalea en racimos.

BACKGROUND AND OBJECTIVES: Cluster headache (CR) is the most severe human headache and is chronic in 10%-20% of patients, and 10% can become refractory to all effective drugs. In this scenario, surgical procedures are indicated: radiofrequencies of the sphenopalatine ganglion ipsilateral to pain (RF-SPG), bilateral stimulation of the occipital nerves (NOM-S) and deep brain stimulation (DBS) of the ipsilateral posterior hypothalamus. The efficacy and safety of each of these procedures has been specifically analyzed, but the progress of a series of patients following this surgical route in order of aggressiveness has not been described. PATIENTS: Patients with chronic and refractory CR according to the criteria of the European Headache Federation. The patients underwent RF-SPG, NOM-S sequentially if the previous procedure had been ineffective, and DBS if the previous procedure had been ineffective. RESULTS: We prospectively included 44 patients between November 2003 and June 2018 with an average age of 38.3 years; 70% were men. The mean follow-up was 87.4 months. Nineteen patients responded to 74 procedures of RF-SPG (33.3%). Of the remaining 25 patients, a NOM-S device was implanted in 22, showing an efficacy of 50%. Finally, 9 patients underwent ECP of the ipsilateral lower-posterior hypothalamus with an efficacy of 88.8%. No serious complications were found following any of these 3 procedures. CONCLUSIONS: The sequential application of these three surgical procedures succeeded in reversing the serious situation of chronic CR refractory to an episodic CR in 93% of patients with acceptable surgical morbidity.

A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention.

BACKGROUND: To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation. METHODS: We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON-OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF-ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation. RESULTS: We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ(2)1 = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria. LIMITATIONS: The small sample size limited the statistical power and external validity. CONCLUSION: These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects. TRIAL REGISTRATION: NCT01268137 (ClinicalTrials.gov).

Cognitive functioning after deep brain stimulation in subcallosal cingulate gyrus for treatment-resistant depression: an exploratory study.

Deep brain stimulation (DBS) is being investigated as a therapeutic alternative for patients with treatment-resistant depression (TRD), but its cognitive safety has been scarcely explored. The aim of this exploratory study is to evaluate cognitive function of patients before and after deep brain stimulation of the subgenual cingulate gyrus (SCG). Eight treatment-resistant depressed patients were implanted in subgenual cingulate gyrus. A neuropsychological battery was used to evaluate patients before surgery and 1-year after. A matched group of eight first-episode patients was also assessed. A MANOVA was performed for each cognitive domain and those tests showing main time effects were then correlated with depressive symptoms and with medication load. There were significant group and time effects for memory and a group effect for language. No significant interactions between groups or cognitive domains were observed. Medication load was negatively correlated with memory at time 1, and clinical change negatively correlated with memory improvement. These findings support the cognitive safety of DBS of subgenual cingulate gyrus, as cognitive function did not worsen after chronic stimulation and memory performance even improved. The results, though, should be interpreted cautiously given the small sample size and the fact that some treatment-resistant patients received electroconvulsive therapy (ECT) before implantation.

Immediate cerebral metabolic changes induced by discontinuation of deep brain stimulation of subcallosal cingulate gyrus in treatment-resistant depression.

BACKGROUND: Positron emission tomography (PET) studies have shown that the antidepressant effect of chronic deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) may be consequence of modifications of brain metabolism at key structures involved in depression. Like clinical benefits, these metabolic changes may reverse when the stimulation is discontinued, even preceding clinical worsening. However no data on immediate effects of DBS discontinuation are available. The aim of this study was to determine immediate cerebral metabolism changes during a short switch-off of electrical stimulation in implanted patients with treatment-resistant depression (TRD) who had achieved clinical improvement after a period of chronic DBS. METHODS: Seven patients with TRD who had been previously implanted for DBS in SCG were included. After a period of clinical stabilization two consecutive FDG-PET were acquired, the first with active stimulation and the second after 48 h of inactive stimulation. A HAMD-17 to assess depressive symptoms was performed before both scans. Analyses were performed with SnPM8. RESULTS: Inactive stimulation was characterized by metabolism decreases in dorsal anterior cingulate (Broadmann Area, BA24), premotor region (BA6) and putamen with respect to active stimulation. No clinical changes according to HAMD-17 were detected. LIMITATIONS: The main limitation of this study is the small sample size. CONCLUSION: Our results point to immediate effects of DBS discontinuation on metabolism of brain depressive network which precede clinical changes, helping to disentangle the rationale behind DBS efficacy in TRD.

Human herpesvirus 1 meningoencephalitis after trigeminal neuralgia surgery.

We report a case of human herpesvirus 1 (HHV-1) meningoencephalitis in a patient who underwent trigeminal neuralgia surgery. Although this surgery has been reported to increase the risk of mucocutaneous HHV-1 recurrence, to our knowledge, an association between trigeminal surgery and HHV-1 encephalitis has not been previously described.

Glioblastoma therapy with cytotoxic mesenchymal stromal cells optimized by bioluminescence imaging of tumor and therapeutic cell response.

Genetically modified adipose tissue derived mesenchymal stromal cells (hAMSCs) with tumor homing capacity have been proposed for localized therapy of chemo- and radiotherapy resistant glioblastomas. We demonstrate an effective procedure to optimize glioblastoma therapy based on the use of genetically modified hAMSCs and in vivo non invasive monitoring of tumor and therapeutic cells. Glioblastoma U87 cells expressing Photinus pyralis luciferase (Pluc) were implanted in combination with hAMSCs expressing a trifunctional Renilla reniformis luciferase-red fluorescent protein-thymidine kinase reporter in the brains of SCID mice that were subsequently treated with ganciclovir (GCV). The resulting optimized therapy was effective and monitoring of tumor cells by bioluminescence imaging (BLI) showed that after 49 days GCV treatment reduced significantly the hAMSC treated tumors; by a factor of 10(4) relative to controls. Using a Pluc reporter regulated by an endothelial specific promoter and in vivo BLI to image hAMSC differentiation we gained insight on the therapeutic mechanism. Implanted hAMSCs homed to tumor vessels, where they differentiated to endothelial cells. We propose that the tumor killing efficiency of genetically modified hAMSCs results from their association with the tumor vascular system and should be useful vehicles to deliver localized therapy to glioblastoma surgical borders following tumor resection.

Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression.

Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-µs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.

Laparoscopic approach to retrorectal tumors: review of the literature and report of 4 cases.

BACKGROUND: Retrorectal or presacral tumors are extremely rare and their histologic origin varies greatly. Surgical excision is indicated to prevent complications or to rule out malignancy. A laparoscopic approach has been infrequently reported to date. The aim of this article is to report our experience in 4 cases, and to review the current world experience on laparoscopic approach to retrorectal tumors. METHODS: Between 1998 and 2009, we operated 4 cases in which a presacral tumor was diagnosed. A pure laparoscopic procedure was performed in 3 cases and a combined laparoscopic/transacral approach in a fourth. In addition, a systematic literature review and relevant reports on laparoscopic approach of these tumors were analyzed. RESULTS: All patients underwent laparoscopic dissection of the tumor with extraction through a Phannestiel incision except in 1 case that was performed transsacrally. Simultaneously, the literature review showed 11 articles with a total number of 18 patients approached by laparoscopy. CONCLUSIONS: The laparoscopic approach of retrorectal tumors is feasible. The advantages are an enhanced access and visualization of the pelvic structures and a more controlled preservation of nerve and vascular integrity. It seems to be a safe procedure and can be combined with a posterior approach if needed.

The effects of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation.

OBJECTIVE: After randomizing 100 failed back surgery syndrome patients to receive spinal cord stimulation (SCS) plus conventional medical management (CMM) or CMM alone, the results of the 6-month Prospective Randomized Controlled Multicenter Trial of the Effectiveness of Spinal Cord Stimulation (i.e., PROCESS) showed that SCS offered superior pain relief, health-related quality of life, and functional capacity. Because the rate of crossover favoring SCS beyond 6 months would bias a long-term randomized group comparison, we present all outcomes in patients who continued SCS from randomization to 24 months and, for illustrative purposes, the primary outcome (>50% leg pain relief) per randomization and final treatment. METHODS: Patients provided data on pain, quality of life, function, pain medication use, treatment satisfaction, and employment status. Investigators documented adverse events. Data analysis included inferential comparisons and multivariate regression analyses. RESULTS: The 42 patients continuing SCS (of 52 randomized to SCS) reported significantly improved leg pain relief (P < 0.0001), quality of life (P

Quality of life, resource consumption and costs of spinal cord stimulation versus conventional medical management in neuropathic pain patients with failed back surgery syndrome (PROCESS trial).

BACKGROUND: Chronic back and leg pain conditions result in patients' loss of function, reduced quality of life and increased costs to the society. AIMS: To assess health-related quality of life (HRQoL) and cost implications of spinal cord stimulation plus non-surgical conventional medical management (SCS group) versus non-surgical conventional medical management alone (CMM group) in the management of neuropathic pain in patients with failed back surgery syndrome. METHODS: A total of 100 patients were randomised to either the SCS or CMM group. Healthcare resource consumption data relating to screening, the use of the implantable generator in SCS patients, hospital stay, and drug and non-drug pain-related treatment were collected prospectively. Resource consumption was costed using UK and Canadian 2005-2006 national figures. HRQoL was assessed using the EuroQol-5D (EQ-5D) questionnaire. Costs and outcomes were assessed for each patient over their first 6-months of the trial. RESULTS: The 6-month mean total healthcare cost in the SCS group (CAN$19,486; 12,653 euros) was significantly higher than in the CMM group (CAN$3994; 2594 euros), with a mean adjusted difference of CAN$15,395 (9997 euros) (p<0.001). However, the gain in HRQoL with SCS over the same period of time was markedly greater in the SCS group, with a mean EQ-5D score difference of 0.25 [p<0.001] and 0.21 [p<0.001], respectively at 3- and 6-months after adjusting for baseline variables. CONCLUSIONS: The addition of SCS to CMM in patients with neuropathic leg and back pain results in higher costs to health systems but also generates important improvements in patients' EQ-5D over the same period.

Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome.

Patients with neuropathic pain secondary to failed back surgery syndrome (FBSS) typically experience persistent pain, disability, and reduced quality of life. We hypothesised that spinal cord stimulation (SCS) is an effective therapy in addition to conventional medical management (CMM) in this patient population. We randomised 100 FBSS patients with predominant leg pain of neuropathic radicular origin to receive spinal cord stimulation plus conventional medical management (SCS group) or conventional medical management alone (CMM group) for at least 6 months. The primary outcome was the proportion of patients achieving 50% or more pain relief in the legs. Secondary outcomes were improvement in back and leg pain, health-related quality of life, functional capacity, use of pain medication and non-drug pain treatment, level of patient satisfaction, and incidence of complications and adverse effects. Crossover after the 6-months visit was permitted, and all patients were followed up to 1 year. In the intention-to-treat analysis at 6 months, 24 SCS patients (48%) and 4 CMM patients (9%) (p<0.001) achieved the primary outcome. Compared with the CMM group, the SCS group experienced improved leg and back pain relief, quality of life, and functional capacity, as well as greater treatment satisfaction (p

Usefulness of an intraoperative electrophysiological navigator system for subthalamic nucleus surgery in Parkinson's disease.

OBJECTS: The characteristics and benefits are presented of an intraoperative neurophysiological navigator computerized system developed in our center (Columbus-Track 1.0) that helps the surgical team in neuronal identification and in strategy processes in subthalamic nucleus surgery for Parkinson's disease (PD). METHODS: The navigator consists of three assembled parts: (1) neuronal identification, based on wavelet processing, filtering and gaussian characteristics of the signal; (2) track identification, based on anatomical coincidence, somatomotor response and microstimulation quotient, and (3) strategy, coordinating correction for the next track. A retrospective comparative study was performed with 15 consecutive PD patients (30 targets) operated without the system and the next 15 consecutive patients operated with the aid of the system. With the aid of the computerized navigation system, a significant reduction in the number of tracks was observed (t = -2.503, p = 0.0015), with a mean difference of 1.2 tracks per hemisphere. A non-significant reduction in the total intervention time was also observed, with a mean difference of 20 min per hemisphere (t = -1.418, p = 0.161). CONCLUSIONS: The intraoperative computerized navigation system can aid the surgical team in better identifying the neuronal signal and in defining the optimal track to achieve the target.

Spinal Cord Stimulation vs. Conventional Medical Management: A Prospective, Randomized, Controlled, Multicenter Study of Patients with Failed Back Surgery Syndrome (PROCESS Study).

Introduction. Since its first application in 1967, numerous case series indicate that spinal cord stimulation (SCS) is an effective treatment for the management of failed back surgery syndrome (FBSS). However, only one randomized controlled trial has demonstrated that SCS provides more effective pain relief than re-operation and conventional medical management. The PROCESS randomized, controlled, multicenter trial aims to assess the clinical effectiveness and cost-effectiveness of SCS when added to conventional medical management compared to conventional medical management alone in patients with FBSS. Methods/Design. A total of 100 FBSS patients with predominantly neuropathic leg pain will be recruited from 12 centers and randomized to receive either conventional medical management alone or in combination with SCS for a period of 24 months. Patients will be evaluated at 1, 3, 6, 9, 12, 18, and 24 months. At the 6-month visit, patients will be classified as successful (≥  50% pain relief in the legs) or unsuccessful (< 50% pain relief in the legs). If the results of the randomized treatment are unsuccessful, patients can cross over to the alternative treatment arm. Discussion. This paper highlights the rationale, design, methods, and challenges of an ongoing prospective, randomized, controlled, multicenter clinical trial that has been undertaken to obtain conclusive evidence of the clinical efficacy and cost-effectiveness of an SCS system in patients with FBSS.