Development and Characterization of Novel Conductive Sensing Fibers for In Vivo Nerve Stimulation.

Advancements in electrode technologies to both stimulate and record the central nervous system's electrical activities are enabling significant improvements in both the understanding and treatment of different neurological diseases. However, the current neural recording and stimulating electrodes are metallic, requiring invasive and damaging methods to interface with neural tissue. These electrodes may also degrade, resulting in additional invasive procedures. Furthermore, metal electrodes may cause nerve damage due to their inherent rigidity. This paper demonstrates that novel electrically conductive organic fibers (ECFs) can be used for direct nerve stimulation. The ECFs were prepared using a standard polyester material as the structural base, with a carbon nanotube ink applied to the surface as the electrical conductor. We report on three experiments: the first one to characterize the conductive properties of the ECFs; the second one to investigate the fiber cytotoxic properties in vitro; and the third one to demonstrate the utility of the ECF for direct nerve stimulation in an in vivo rodent model.

Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease. METHODS: This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396. FINDINGS: Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3-4·7; p<0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation. INTERPRETATION: This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes. FUNDING: Boston Scientific.

Prevention of Implant-Associated Infection in Neuromodulation: Review of the Literature and Prototype of a Novel Protective Implant Coating.

Background: Implanting hardware into surgical sites increases the rate of infection associated with these sites. Without novel efforts to reduce this rate of infection, we can expect to see an increase in the number of hardware-associated infections as more patients are implanted with these devices. These infections often necessitate the removal of these devices resulting in a significant financial and clinical burden to patients. We developed a prototype antibiotic coating using products that are both low cost and that can be sourced easily. Our study aims to test the effectiveness of this coating against bacteria commonly observed in hospital-associated infections. Methods: The antibiotic coating was prepared by combining one gram of vancomycin and 500 mg of ciprofloxacin in 50 mL of glycerol. The coating was examined for inhibition of growth of Pseudomonas aeruginosa PA14 and Staphylococcus aureus AH2486 and compared with the bacterial growth of the above bacteria in glycerol alone. The growth curves were plotted measuring the bacterial growth at 5 h intervals. Results: The results of the growth curves clearly demonstrate a lack of bacterial growth when these bacteria are combined with glycerol combined with our selected antibiotic agents. Conclusion: There appears to be a limited interest from device companies in developing new strategies for infection prevention associated with neurosurgical hardware, and we propose that this prototype will be an effective and low-cost solution to a large problem.

Covalent Poly(lactic acid) Nanoparticles for the Sustained Delivery of Naloxone.

The opioid epidemic currently plaguing the United States has been exacerbated by an alarming rise in fatal overdoses as a result of the proliferated abuse of synthetic mu opioid receptor (MOR) agonists, such as fentanyl and its related analogues. Attempts to manage this crisis have focused primarily on widespread distribution of the clinically approved opioid reversal agent naloxone (Narcan); however, due to the intrinsic metabolic lability of naloxone, these measures have demonstrated limited effectiveness against synthetic opioid toxicity. This work reports a novel polymer-based strategy to create a long-acting formulation of naloxone with the potential to address this critical issue by utilizing covalent nanoparticle (cNP) drug delivery technology. Covalently loaded naloxone nanoparticles (Nal-cNPs) were prepared via the naloxone-initiated, ring-opening polymerization (ROP) of l-lactide in the presence of a bifunctional thiourea organocatalyst with subsequent precipitation of the resulting naloxone-poly(l-lactic acid) polymer. This protocol afforded well-defined nanoparticles possessing a drug loading of approximately 7% w/w. The resulting Nal-cNPs demonstrated excellent biocompatibility, while exhibiting sustained linear release kinetics in vitro and blocking the effects of high dose (10 mg/kg) acute morphine for up to 98 h in an in vivo rodent model of neuropathic pain.

Deep Brain Stimulation of the Hypothalamus Leads to Increased Metabolic Rate in Refractory Obesity.

OBJECTIVE: Obesity has become a worldwide epidemic, with very few long-term successful treatment options for refractory disease. Deep brain stimulation (DBS) of the bilateral lateral hypothalamus (LH) in refractory obesity has been performed safely. However, questions remain regarding the optimal settings and its effects on metabolic rate. The goals of our experiment were to determine the optimal DBS settings and the actual effect of optimal stimulation on energy expenditure. METHODS: After bilateral LH DBS implantation, 2 subjects with treatment refractory obesity underwent 4 days of metabolic testing. The subjects slept overnight in a respiratory chamber to measure their baseline sleep energy expenditure, followed by 4 consecutive days of resting metabolic rate (RMR) testing at different stimulation settings. On day 4, the optimized DBS settings were used, and sleep energy expenditure was measured again overnight in the room calorimeter. RESULTS: During daily testing, the RMR fluctuated acutely with changes in stimulation settings and returned to baseline immediately after turning off the stimulation. Optimal stimulation settings selected for participants showed a 20% and 16% increase in RMR for the 2 participants. Overnight sleep energy expenditure measurements at these optimized settings on day 4 yielded a 10.4% and 4.8% increase over the baseline measurements for the 2 participants. CONCLUSIONS: These findings have demonstrated the efficacy of optimized DBS of the LH on increasing the RMR acutely and maintaining this increase during overnight sleep. These promising preliminary findings have laid the groundwork for the possible treatment of refractory obesity with DBS.

Deep brain stimulation for appetite disorders: a review.

The mechanisms of appetite disorders, such as refractory obesity and anorexia nervosa, have been vigorously studied over the last century, and these studies have shown that the central nervous system has significant involvement with, and responsibility for, the pathology associated with these diseases. Because deep brain stimulation has been shown to be a safe, efficacious, and adjustable treatment modality for a variety of other neurological disorders, it has also been studied as a possible treatment for appetite disorders. In studies of refractory obesity in animal models, the ventromedial hypothalamus, the lateral hypothalamus, and the nucleus accumbens have all demonstrated elements of success as deep brain stimulation targets. Multiple targets for deep brain stimulation have been proposed for anorexia nervosa, with research predominantly focusing on the subcallosal cingulate, the nucleus accumbens, and the stria terminalis and medial forebrain bundle. Human deep brain stimulation studies that focus specifically on refractory obesity and anorexia nervosa have been performed but with limited numbers of patients. In these studies, the target for refractory obesity has been the lateral hypothalamus, ventromedial hypothalamus, and nucleus accumbens, and the target for anorexia nervosa has been the subcallosal cingulate. These studies have shown promising findings, but further research is needed to elucidate the long-term efficacy of deep brain stimulation for the treatment of appetite disorders.

Thalamic Deep Brain Stimulation.

The use of deep brain stimulation (DBS) of the thalamus has been proven to be a safe and efficacious treatment for the management of many diseases. The most common indication for thalamic DBS remains essential tremor (ET), one of the most common movement disorders in the world. ET patients should be considered for surgical intervention when their tremor has demonstrated to be refractory to medication, a characteristic estimated to be present in roughly 50% of ET cases. Advantages of DBS over thalamotomy include its reversibility, the ability to adjust stimulation settings to optimize efficacy and minimize side effects, the ability to perform bilateral procedures safely, and an association with a lower risk of postoperative cognitive problems. The most common target of DBS for ET is the ventralis intermedius (VIM) of the thalamus, and the optimal electrode location corresponds to the anterior margin of the VIM. Other indications for thalamic DBS include non-ET tremor, obsessive-compulsive disorder, neuropathic pain, traumatic brain injury, Tourette's syndrome, and drug-resistant epilepsy among others.

Scoliosis Secondary to Dystonia: A Case Report and Review of the Literature.

CASE: An adolescent girl presented with an atypical scoliotic curve, pelvic obliquity, back pain, and lower-extremity paresthesias. A workup revealed generalized primary torsion dystonia. The condition was refractory to medical treatment and necessitated implantation of a deep brain stimulator. The scoliosis required operative correction, and the patient underwent posterior spinal arthrodesis with hook-rod instrumentation, which resulted in successful correction through 7 years of follow-up. CONCLUSION: The differential diagnosis for adolescent scoliosis should include dystonia as a potential cause, especially when a patient presents with muscular contractures, an atypical scoliotic curve, pelvic obliquity, or changing curve characteristics.

Deep Brain Stimulation for Obesity: From a Theoretical Framework to Practical Application.

Obesity remains a pervasive global health problem. While there are a number of nonsurgical and surgical options for treatment, the incidence of obesity continues to increase at an alarming rate. The inability to curtail the growing rise of the obesity epidemic may be related to a combination of increased food availability and palatability. Research into feeding behavior has yielded a number of insights into the homeostatic and reward mechanisms that govern feeding. However, there remains a gap between laboratory investigations of feeding physiology in animals and translation into meaningful treatment options for humans. In addition, laboratory investigation may not be able to recapitulate all aspects of human food consumption. In a landmark pilot study of deep brain stimulation (DBS) of the lateral hypothalamic area for obesity, we found that there was an increase in resting metabolic rate as well as a decreased urge to eat. In this review, the authors will review some of the work relating to feeding physiology and research surrounding two nodes involved in feeding homeostasis, nucleus accumbens (NAc) and hypothalamus, and use this to provide a framework for future investigations of DBS as a viable therapeutic modality for obesity.

Biomechanics of Posterior Dynamic Fusion Systems in the Lumbar Spine: Implications for Stabilization With Improved Arthrodesis.

STUDY DESIGN: A comparative biomechanical human cadaveric spine study of a dynamic fusion rod and a traditional titanium rod. OBJECTIVE: The purpose of this study was to measure and compare the biomechanical metrics associated with a dynamic fusion device, Isobar TTL Evolution, and a rigid rod. SUMMARY OF BACKGROUND DATA: Dynamic fusion rods may enhance arthrodesis compared with a rigid rod. Wolff's law implies that bone remodeling and growth may be enhanced through anterior column loading (AL). This is important for dynamic fusion rods because their purpose is to increase AL. METHODS: Six fresh-frozen lumbar cadaveric specimens were used. Each untreated specimen (Intact) underwent biomechanical testing. Next, each specimen had a unilateral transforaminal lumbar interbody fusion performed at L3-L4 using a cage with an integrated load cell. Pedicle screws were also placed at this time. Subsequently, the Isobar was implanted and tested, and finally, a rigid rod replaced the Isobar in the same pedicle screw arrangement. RESULTS: In terms of range of motion, the Isobar performed comparably to the rigid rod and there was no statistical difference found between Isobar and rigid rod. There was a significant difference between the intact and rigid rod and also between intact and Isobar conditions in flexion extension. For interpedicular displacement, there was a significant increase in flexion extension (P=0.017) for the Isobar compared with the rigid rod. Isobar showed increased AL under axial compression compared with the rigid rod (P=0.024). CONCLUSIONS: Isobar provided comparable stabilization to a rigid rod when using range of motion as the metric, however, AL was increased because of the greater interpedicular displacement of dynamic rod compared with a rigid rod. By increasing interpedicular displacement and AL, it potentially brings clinical benefit to procedures relying on arthrodesis.

Effect of TLIF Cage Placement on In Vivo Kinematics.

BACKGROUND: The influence of interbody cage positioning on clinical outcomes following lumbar interbody fusion is not well understood, though it has been hypothesized to play a significant role in stability of the treated level. The purpose of this study was to evaluate any correlations between cage placement in TLIF procedures and post-operative kinematics. METHODS: Thirteen patients who had previously undergone a TLIF procedure were evaluated using the Vertebral Motion Analysis (VMA) system, an automated fluoroscopic method of tracking kinematics in vivo. Upright and recumbent bending platforms were used to guide patients through a set range of motion (ROM) standing up and lying down, respectively, in both flexion-extension (FE) and lateral bending (LB). Intervertebral ROM was measured via fluoroscopic images captured sequentially throughout the movement. DICOM images acquired by the VMA system were used to calculate cage positioning. Intra-rater and inter-rater reliability of TLIF cage position were also assessed. RESULTS: Statistically significant correlations were noted between sagittal cage position and lying LB (r = -0.583, p = 0.047), and coronal cage positioning with both standing (r = 0.672, p = 0.012) and lying LB (r = 0.632, p = 0.027). Additionally, the correlation between sagittal cage position and standing FE was trending towards significance (r = -0.542, p = 0.055). CONCLUSIONS: The intuitive correlation between coronal cage position and both standing and lying lateral bending ROM is supported by the data from this study, suggesting placement closer to midline is optimal for stability. Additionally, the VMA system appears to be a sensitive and repeatable means to obtain information on postoperative kinematic outcomes. Further work to establish the relationship between cage placement, these kinematic outcomes and, potentially, functional pain outcomes seems to be warranted based on the results obtained here.

Stability and Load Sharing Characteristics of a Posterior Dynamic Stabilization Device.

BACKGROUND: Lumbar interbody fusion is a common treatment for a variety of spinal pathologies. It has been hypothesized that insufficient mechanical loading of the interbody graft can prevent proper fusion of the joint. The purpose of this study was to evaluate the mechanical stability and anterior column loading sharing characteristics of a posterior dynamic system compared to titanium rods in an anterior lumbar interbody fusion (ALIF) model. METHODS: Range of motion, interpedicular kinematics and interbody graft loading were measured in human cadaveric lumbar segments tested under a pure moment flexibility testing protocol. RESULTS: Both systems provided significant fixation compared to the intact condition and to an interbody spacer alone in flexion extension and lateral bending. No significant differences in fixation were detected between the devices. A significant decrease in graft loading was detected in flexion for the titanium rod treatment compared to spacer alone. No significant differences in graft loading were detected between the spacer alone and posterior dynamic system or between the posterior dynamic system and the titanium rod. CONCLUSIONS: The results of this study indicate that the posterior dynamic system provides similar fixation compared to that of a titanium rod, however, studies designed to evaluate the efficacy of fixation in a cadaver model may not be sufficiently powered to establish differences in load sharing using the techniques described here.

The history of external ventricular drainage.

External ventricular drainage (EVD) is one of the most commonly performed neurosurgical procedures. It was first performed as early as 1744 by Claude-Nicholas Le Cat. Since then, there have been numerous changes in technique, materials used, indications for the procedure, and safety. The history of EVD is best appreciated in 4 eras of progress: development of the technique (1850-1908), technological advancements (1927-1950), expansion of indications (1960-1995), and accuracy, training, and infection control (1995-present). While EVD was first attempted in the 18th century, it was not until 1890 that the first thorough report of EVD technique and outcomes was published by William Williams Keen. He was followed by H. Tillmanns, who described the technique that would be used for many years. Following this, many improvements were made to the EVD apparatus itself, including the addition of manometry by Adson and Lillie in 1927, and continued experimentation in cannulation/drainage materials. Technological advancements allowed a great expansion of indications for EVD, sparked by Nils Lundberg, who published a thorough analysis of the use of intracranial pressure (ICP) monitoring in patients with brain tumors in 1960. This led to the application of EVD and ICP monitoring in subarachnoid hemorrhage, Reye syndrome, and traumatic brain injury. Recent research in EVD has focused on improving the overall safety of the procedure, which has included the development of guidance-based systems, virtual reality simulators for trainees, and antibiotic-impregnated catheters.

Deep brain stimulation for psychiatric diseases: a pooled analysis of published studies employing disease-specific standardized outcome scales.

BACKGROUND: Deep brain stimulation (DBS) has emerged in recent years as a novel therapy in the treatment of refractory psychiatric disease, including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). Standardized outcome scales were crucial in establishing that DBS was an effective therapy for movement disorders. OBJECTIVE: In order to better characterize the evidence supporting DBS for various psychiatric diseases, we performed a pooled analysis of those studies which incorporated specific standardized rating scales. METHODS: A Medline search was conducted to identify all studies reporting DBS for MDD, OCD, and TS. The search yielded a total of 49 articles, of which 24 were included: 4 related to MDD (n = 48), 10 to OCD (n = 64), and 10 to TS (n = 46). RESULTS: A meta-analysis of DBS for MDD, OCD, and TS in studies employing disease-specific standardized outcome scales showed that the outcome scales all improved in a statistically significant fashion for these psychiatric diseases. Our pooled analysis suggests that DBS for TS has the highest efficacy amongst the psychiatric diseases currently being treated with DBS, followed by OCD and MDD. CONCLUSION: DBS for psychiatric diseases remains investigational; however, even when studies failing to incorporate standardized outcome scales are excluded, there is statistically significant evidence that DBS can improve symptoms in MDD, OCD, and TS. Standardized disease-specific outcome scales facilitate pooled analysis and should be a required metric in future studies of DBS for psychiatric disease.

Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot study with preliminary data on safety, body weight, and energy metabolism.

OBJECT: Deep brain stimulation (DBS) of the lateral hypothalamic area (LHA) has been suggested as a potential treatment for intractable obesity. The authors present the 2-year safety results as well as early efficacy and metabolic effects in 3 patients undergoing bilateral LHA DBS in the first study of this approach in humans. METHODS: Three patients meeting strict criteria for intractable obesity, including failed bariatric surgery, underwent bilateral implantation of LHA DBS electrodes as part of an institutional review board- and FDA-approved pilot study. The primary focus of the study was safety; however, the authors also received approval to collect data on early efficacy including weight change and energy metabolism. RESULTS: No serious adverse effects, including detrimental psychological consequences, were observed with continuous LHA DBS after a mean follow-up of 35 months (range 30-39 months). Three-dimensional nonlinear transformation of postoperative imaging superimposed onto brain atlas anatomy was used to confirm and study DBS contact proximity to the LHA. No significant weight loss trends were seen when DBS was programmed using standard settings derived from movement disorder DBS surgery. However, promising weight loss trends have been observed when monopolar DBS stimulation has been applied via specific contacts found to increase the resting metabolic rate measured in a respiratory chamber. CONCLUSIONS: Deep brain stimulation of the LHA may be applied safely to humans with intractable obesity. Early evidence for some weight loss under metabolically optimized settings provides the first "proof of principle" for this novel antiobesity strategy. A larger follow-up study focused on efficacy along with a more rigorous metabolic analysis is planned to further explore the benefits and therapeutic mechanism behind this investigational therapy.

Ethical Considerations in Deep Brain Stimulation for the Treatment of Addiction and Overeating Associated With Obesity.

The success of deep brain stimulation (DBS) for movement disorders and the improved understanding of the neurobiologic and neuroanatomic bases of psychiatric diseases have led to proposals to expand current DBS applications. Recent preclinical and clinical work with Alzheimer's disease and obsessive-compulsive disorder, for example, supports the safety of stimulating regions in the hypothalamus and nucleus accumbens in humans. These regions are known to be involved in addiction and overeating associated with obesity. However, the use of DBS targeting these areas as a treatment modality raises common ethical considerations, which include informed consent, coercion, enhancement, threat to personhood, and manipulation of the reward center. Pilot studies for both of these conditions are currently investigational. If these studies show promise, then there is a need to address the ethical concerns related to the initiation of clinical trials including the reliability of preclinical evidence, patient selection, study design, compensation for participation and injury, cost-effectiveness, and the need for long-term follow-up. Multidisciplinary teams are necessary for the ethical execution of such studies. In addition to establishing safety and efficacy, the consideration of these ethical issues is vital to the adoption of DBS as a treatment for these conditions. We offer suggestions about the pursuit of future clinical trials of DBS for the treatment of addiction and overeating associated with obesity and provide a framework for addressing ethical concerns related to treatment.

Cranial plate anchoring of spinal cord stimulation paddle leads: technical note.

BACKGROUND: Lead migration is a frequent complication of spinal cord stimulation (SCS) and requires revision surgery. The evolution of wider paddle leads has necessitated more extensive laminotomy and epidural adhesiolysis, which may increase the risk of lead migration. OBJECTIVE: We describe a novel anchoring technique for SCS paddle leads with use of a cranial "dogbone" plate. METHODS: We retrospectively reviewed a consecutive series of 11 patients who underwent placement of paddle lead spinal cord stimulators with titanium plate anchoring. Patients were followed for a mean of 29.5 months from SCS implantation (range, 5-65 months). A 4-hole linear titanium cranial plate and two 4-mm screws were used to tightly affix the proximal paddle lead wiring to the lamina below the laminotomy defect. RESULTS: All patients continue to have satisfactory spinal cord stimulation with no loss of efficacy or need for revision. No complications have been attributed to titanium plate anchoring, and there have been no cases of lead migration with this technique. Titanium plate anchoring added minimal time (approximately 3-5 minutes) to the operative case. CONCLUSION: We report a safe and effective anchoring technique for paddle lead SCS with the use of a cranial plate. Our experience has been that this technique, which anchors the proximal lead wiring to the remaining lamina at the inferior laminotomy defect, is superior to anchoring methods that rely on suturing of lead wiring.

Deep brain stimulation for obesity--from theoretical foundations to designing the first human pilot study.

Obesity is perhaps an evolutionary consequence of a species reared with intermittent caloric reward. Humans are hardwired to enjoy food, and our bodies voraciously extract and store energy from food as if each meal was the last. As an amalgam of behavioral and metabolic disturbance, obesity is an attractive target for deep brain stimulation (DBS) since neuromodulation may be able to influence both eating behavior and metabolism. The current pandemic proportions of obesity combined with the failures and morbidity of modern treatments remain the impetus behind the application of DBS to this complex disease. We review the rationale and scientific foundations for obesity DBS and explain how this preclinical evidence has helped sculpt the design of the first human pilot study.