Success Using Neuromodulation With BURST (SUNBURST) Study: Results From a Prospective, Randomized Controlled Trial Using a Novel Burst Waveform.

OBJECTIVE: The purpose of the multicenter, randomized, unblinded, crossover Success Using Neuromodulation with BURST (SUNBURST) study was to determine the safety and efficacy of a device delivering both traditional tonic stimulation and burst stimulation to patients with chronic pain of the trunk and/or limbs. METHODS: Following a successful tonic trial, 100 subjects were randomized to receive one stimulation mode for the first 12 weeks, and then the other stimulation mode for the next 12 weeks. The primary endpoint assessed the noninferiority of the within-subject difference between tonic and burst for the mean daily overall VAS score. An intention-to-treat analysis was conducted using data at the 12- and 24-week visits. Subjects then used the stimulation mode of their choice and were followed for one year. Descriptive statistics were used analyze additional endpoints and to characterize the safety profile of the device. RESULTS: The SUNBURST study demonstrated that burst stimulation is noninferior to tonic stimulation (p < 0.001). Superiority of burst was also achieved (p < 0.017). Significantly more subjects (70.8%) preferred burst stimulation over tonic stimulation (p < 0.001). Preference was sustained through one year: 68.2% of subjects preferred burst stimulation, 23.9% of subjects preferred tonic, and 8.0% of subjects had no preference. No unanticipated adverse events were reported and the safety profile was similar to other spinal cord stimulation studies. CONCLUSIONS: The SUNBURST study demonstrated that burst spinal cord stimulation is safe and effective. Burst stimulation was not only noninferior but also superior to tonic stimulation for the treatment of chronic pain. A multimodal stimulation device has advantages.

Clinical Paresthesia Atlas Illustrates Likelihood of Coverage Based on Spinal Cord Stimulator Electrode Location.

OBJECTIVE: Concordant paresthesia coverage is an independent predictor of pain relief following spinal cord stimulation (SCS). Using aggregate data, our objective is to produce a map of paresthesia coverage as a function of electrode location in SCS. METHODS: This retrospective analysis used x-rays, SCS programming data, and paresthesia coverage maps from the EMPOWER registry of SCS implants for chronic neuropathic pain. Spinal level of dorsal column stimulation was determined by x-ray adjudication and active cathodes in patient programs. Likelihood of paresthesia coverage was determined as a function of stimulating electrode location. Segments of paresthesia coverage were grouped anatomically. Fisher's exact test was used to identify significant differences in likelihood of paresthesia coverage as a function of spinal stimulation level. RESULTS: In the 178 patients analyzed, the most prevalent areas of paresthesia coverage were buttocks, anterior and posterior thigh (each 98%), and low back (94%). Unwanted paresthesia at the ribs occurred in 8% of patients. There were significant differences in the likelihood of achieving paresthesia, with higher thoracic levels (T5, T6, and T7) more likely to achieve low back coverage but also more likely to introduce paresthesia felt at the ribs. Higher levels in the thoracic spine were associated with greater coverage of the buttocks, back, and thigh, and with lesser coverage of the leg and foot. CONCLUSION: This paresthesia atlas uses real-world, aggregate data to determine likelihood of paresthesia coverage as a function of stimulating electrode location. It represents an application of "big data" techniques, and a step toward achieving personalized SCS therapy tailored to the individual's chronic pain.

Intraoperative electromyography as an adjunct to sacral neuromodulation for chronic pelvic pain.

OBJECTIVE: Sacral neuromodulation is an established technique for the treatment of chronic intractable pelvic and anorectal pain. Stimulation of sacral roots S2-4 is typically associated with therapeutic paresthesia, while stimulation of the S1 nerve root causes unwanted leg paresthesia. Here we describe and evaluate the use of intraoperative electromyography (EMG) of the gastrocnemius, foot intrinsic muscles, and anal sphincter as an adjunct to epidural stimulator placement. MATERIALS AND METHODS: Two female patients with intractable pelvic pain underwent implantation of sacral epidural paddles with intraoperative EMG. These cases were retrospectively reviewed to evaluate intraoperative EMG activation and therapeutic paresthesia. RESULTS: We found cephalad-to-caudal transitions in EMG activation with stimulation: medial gastrocnemius to foot intrinsics to anal sphincter. Coactivation of foot intrinsic muscles with anal sphincter and absence of medial gastrocnemius stimulation correlated with therapeutic perineal paresthesia. CONCLUSIONS: Intraoperative EMG of the gastrocnemius, foot intrinsics, and anal sphincter may be a useful adjunct to sacral stimulation for pelvic pain.

Anterograde and retrograde epidural paddle placement through a single laminotomy for the treatment of back and lower extremity pain using spinal cord stimulation: case reports and technical note.

OBJECTIVE: Spinal cord stimulation can be effectively used in the treatment of low back pain and extremity pain in failed back surgery syndrome. Ideal targets for stimulation corresponding to paresthesia overlap in the low back versus the extremities may differ in cranial-caudal location. MATERIALS AND METHODS: We present here a technical report of three cases demonstrating a technique to place anterograde and retrograde epidural paddles through a single laminotomy. RESULTS: Using this technique we were able to cover five spinal levels in each patient, and different stimulation programs at different levels created paresthesia overlap in back versus lower extremity in those patients. CONCLUSION: Dual paddle placement through a single laminotomy may be a reasonable option for select patients where coverage of anatomically-separated pain regions is necessary. This technique can be performed in most patients without significantly increased morbidity.

Posttraumatic stress disorder: neurocircuitry and implications for potential deep brain stimulation.

Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling psychiatric disorder that is notoriously difficult to treat. At some point in their lifetimes, 5-8% of men, 10-14% of women, and up to a quarter of combat veterans carry this diagnosis. Despite pharmacological and behavioral therapies, up to 30% of patients are still symptomatic 10 years after initial diagnosis. Recent advances in imaging have implicated changes in the limbic and autonomic corticostriatopallidothalamocortical (CSPTC) circuitry in the pathogenesis of this disease. Deep brain stimulation modulates CSPTC circuits in movement and other neuropsychiatric disorders. In this review, we discuss the salient clinical features and neurocircuitry of PTSD and propose a neuromodulation strategy for the disorder.

Murine de novo methyltransferase Dnmt3a demonstrates strand asymmetry and site preference in the methylation of DNA in vitro.

CpG methylation is involved in a wide range of biological processes in vertebrates as well as in plants and fungi. To date, three enzymes, Dnmt1, Dnmt3a, and Dnmt3b, are known to have DNA methyltransferase activity in mouse and human. It has been proposed that de novo methylation observed in early embryos is predominantly carried out by the Dnmt3a and Dnmt3b methyltransferases, while Dntm1 is believed to be responsible for maintaining the established methylation patterns upon replication. Analysis of the sites methylated in vivo using the bisulfite genomic sequencing method confirms the previous finding that some regions of the plasmid are much more methylated by Dnmt3a than other regions on the same plasmid. However, the preferred targets of the enzyme cannot be determined due to the presence of other methylases, DNA binding proteins, and chromatin structure. To discern the DNA targets of Dnmt3a without these compounding factors, sites methylated by Dnmt3a in vitro were analyzed. These analyses revealed that the two cDNA strands have distinctly different methylation patterns. Dnmt3a prefers CpG sites on a strand in which it is flanked by pyrimidines over CpG sites flanked by purines in vitro. These findings indicate that, unlike Dnmt1, Dnmt3a most likely methylates one strand of DNA without concurrent methylation of the CpG site on the complementary strand. These findings also indicate that Dnmt3a may methylate some CpG sites more frequently than others, depending on the sequence context. Methylation of each DNA strand independently and with possible sequence preference is a novel feature among the known DNA methyltransferases.

Magnetic Resonance Therapy Improves Clinical Phenotype and EEG Alpha Power in Posttraumatic Stress Disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a disabling and prevalent psychiatric disorder with limited effective treatment options. In addition to the clinical features of the disease, pathologic changes in the electroencephalogram (EEG), including decreased alpha power, have been reported. OBJECTIVES: To determine if magnetic brain stimulation can induce normalization of EEG abnormalities and improve clinical symptoms in PTSD in a preliminary, open-label evaluation. MATERIALS AND METHODS: We reviewed prospectively-collected data on 21 veterans that were consecutively-treated for PTSD. Magnetic resonance therapy (MRT) was administered for two weeks at treatment frequencies based on frequency-domain analysis of each patient's dominant alpha-band EEG frequencies and resting heart rate. Patients were evaluated on the PTSD checklist (PCL-M) and pre- and post-treatment EEGs before and after MRT. RESULTS: Of the 21 patients who initiated therapy, 16 completed treatment. Clinical improvements on the PCL-M were seen in these 16 patients, with an average pre-treatment score of 54.9 and post-treatment score of 31.8 (P < 0.001). In addition, relative global EEG alpha-band (8 - 13 Hz) power increased from 32.0 to 38.5 percent (P = 0.013), and EEG delta-band (1 - 4 Hz) power decreased from 32.3 percent to 26.8 percent (P = 0.028). CONCLUSIONS: These open-label data show trends toward normalization of EEG and concomitant clinical improvement using magnetic stimulation for PTSD.

Deep brain stimulation for treatment-resistant depression.

BACKGROUND: Major depressive disorder is a common and disabling illness and is the leading cause of disability worldwide. Despite aggressive medical, behavioral, and electroconvulsive therapies, a significant number of patients remain refractory to treatment. Deep brain stimulation (DBS) has proven efficacy in neurobehavioral disorders and, in a general sense, works by modulation of corticostriatopallidothalamocortical circuits implicated in these disorders. METHODS: Current data, treatment rationales, and future directions are presented. RESULTS: The two targets most commonly used for DBS in treatment-resistant depression are the subgenual cingulate gyrus and the ventral capsule/ventral striatum. Data on DBS of these regions are preliminary, with promise shown in early studies. CONCLUSIONS: Early work suggests DBS may become a therapeutic option in treatment-resistant depression. Further study is justified given the immense burden of disease.

Minimally invasive posterior atlantoaxial fusion: a cadaveric and clinical feasibility study.

OBJECTIVE: Minimally invasive surgical (MIS) techniques have several potential advantages for the patient over open techniques, including decreased loss of blood, postoperative pain, and recovery time. We aimed to demonstrate atlantoaxial fusion by using the MIS techniques, shown previously in only two reports. A smaller operating corridor with MIS may increase difficulty of instrumentation placement and risk of instrumentation-related complications. METHODS: Five cadaveric specimens were studied presurgically with computed tomography (CT) to determine bony anatomy, vertebral artery course, and the trajectory for C1/C2 screw placement. Four specimens had adequate C2 pedicle sizes to accommodate screw placement. Specimens were used to perform C1-2 instrumentation through minimal access tubular retractors. After procedures, specimens were re-examined with CT to assess accuracy of MIS C1-2 screw placement. RESULTS: Through minimal access expandable tubular retractors, C1-lateral mass and C2 pedicle screws were placed in all four specimens. Postinstrumentation CT analysis demonstrated no violation of the foramen transversarium in all cases. There was one grade 1 medial breach from C1 lateral mass screw placement. Two patients with type-2 odontoid fractures were treated with MIS C1-2 fusion with follow-up 4-24 months. Average operating time was 3.5 hours, and average surgical blood loss was 125 mL. Both cases were examined with CT scan postsurgically, and there were no bony breaches with screw placement. Both patients remained neurologically intact postoperatively, with significant improvement revealed in pain scores. Follow-up imaging at two years demonstrated union of odontoid fracture. CONCLUSIONS: Minimally invasive atlantoaxial fixation is feasible and safe. Preoperative CT is paramount for preoperative evaluation of the vertebral artery anatomy in relation to C1/2 vertebra.

Surgery of the mind, mood, and conscious state: an idea in evolution.

Since the beginning of recorded history, humans have sought a physical means of altering disordered behavior and consciousness. This quest has spawned numerous innovations in neurosurgery and the neurosciences, from the earliest prehistoric attempts at trepanation to the electrocortical and anatomic localization of cerebral function that emerged in the 19th century. At the start of the 20th century, the overwhelming social impact of psychiatric illness intersected with the novel but imperfect understanding of frontal lobe function, establishing a decades-long venture into the modern origin of psychosurgery, the prefrontal lobotomy. The subsequent social and ethical ramifications of the widespread overuse of transorbital lobotomies drove psychosurgery to near extinction. However, as the pharmacologic treatment of psychiatric illness was established, numerous concomitant technical and neuroscientific innovations permitted the incremental development of a new paradigm of treating the disordered mind. In this article, we retrospectively examine these early origins of psychosurgery and then look to the recent past, present, and future for emerging trends in surgery of the psyche. Recent decades have seen a revolution in minimalism, noninvasive imaging, and functional manipulation of the human cerebrum that have created new opportunities and treatment modalities for disorders of the human mind and mood. Early contemporary efforts were directed at focal lesioning of abnormal pathways, but deep-brain stimulation now aims to reversibly alter and modulate those neurologic activities responsible for not only psychiatric disorders, but also to modulate and even to augment consciousness, memory, and other elements of cerebral function. As new tools become available, the social and medical impact of psychosurgery promises to revolutionize not only neurosurgery, but also humans' capability for positively impacting life and society.

Advances in the management of spinal cord and spinal column injuries.

Spinal cord injury (SCI) is a significant public problem, with recent data suggesting that over 1 million people in the U.S.A. alone are affected by paralysis resulting from SCI. Recent advances in prehospital care have improved survival as well as reduced incidence and severity of SCI following spine trauma. Furthermore, increased understanding of the secondary mechanisms of injury following SCI has provided improvements in critical care and acute management in patients suffering from SCI, thus limiting morbidity following injury. In addition, improved technology and biomechanical understanding of the mechanisms of spine trauma have allowed further advances in available techniques for spinal decompression and stabilization. In this chapter we review the most recent data and salient literature regarding SCI and address current controversies, including the use of pharmacological adjuncts in the setting of acute SCI. We will also attempt to provide a reader with basic understanding of the classifications of SCI and spinal column injury. Finally, we review advances in spinal column stabilization including improvements in instrumented fusion and minimally invasive surgery.

Obesity and brain addiction circuitry: implications for deep brain stimulation.

Obesity is a growing health problem worldwide and is responsible for a significant proportion of health expenditures in developed nations. It is also notoriously difficult to treat. Prior attempts at pharmacological or neurological modulation, including deep brain stimulation, have primarily targeted homeostatic mechanisms of weight control centered in the hypothalamus. To date, these attempts have had limited success. Multiple lines of independent data suggest that dysregulated reward circuitry in the brain underlies behaviors leading to obesity. Here, we review the existing data and related neurocircuitry, as well as the scope of obesity and currently available treatments. Finally, we suggest a neuromodulation strategy geared toward regulating these dysfunctional circuits, primarily by alteration of frontolimbic circuits.

Surgery of the mind, mood, and conscious state: an idea in evolution.

Since the beginning of recorded history, humans have sought a physical means of altering disordered behavior and consciousness. This quest has spawned numerous innovations in neurosurgery and the neurosciences, from the earliest prehistoric attempts at trepanation to the electrocortical and anatomic localization of cerebral function that emerged in the 19th century. At the start of the 20th century, the overwhelming social impact of psychiatric illness intersected with the novel but imperfect understanding of frontal lobe function, establishing a decades-long venture into the modern origin of psychosurgery, the prefrontal lobotomy. The subsequent social and ethical ramifications of the widespread overuse of transorbital lobotomies drove psychosurgery to near extinction. However, as the pharmacologic treatment of psychiatric illness was established, numerous concomitant technical and neuroscientific innovations permitted the incremental development of a new paradigm of treating the disordered mind. In this article, we retrospectively examine these early origins of psychosurgery and then look to the recent past, present, and future for emerging trends in surgery of the psyche. Recent decades have seen a revolution in minimalism, noninvasive imaging, and functional manipulation of the human cerebrum that have created new opportunities and treatment modalities for disorders of the human mind and mood. Early contemporary efforts were directed at focal lesioning of abnormal pathways, but deep-brain stimulation now aims to reversibly alter and modulate those neurologic activities responsible for not only psychiatric disorders, but also to modulate and even to augment consciousness, memory, and other elements of cerebral function. As new tools become available, the social and medical impact of psychosurgery promises to revolutionize not only neurosurgery, but also humans' capability for positively impacting life and society.

Determination of relevant neuron-neuron connections for neural prosthetics using time-delayed mutual information: tutorial and preliminary results.

BACKGROUND: Identification of functional dependence among neurons is a necessary component in both the rational design of neural prostheses as well as in the characterization of network physiology. The objective of this article is to provide a tutorial for neurosurgeons regarding information theory, specifically time-delayed mutual information, and to compare time-delayed mutual information, an information theoretic quantity based on statistical dependence, with cross-correlation, a commonly used metric for this task in a preliminary analysis of rat hippocampal neurons. METHODS: Spike trains were recorded from rats performing delayed nonmatch-to-sample task using an array of electrodes surgically implanted into the hippocampus of each hemisphere of the brain. In addition, spike train simulations of positively correlated neurons, negatively correlated neurons, and neurons correlated by nonlinear functions were generated. These were evaluated by time-delayed mutual information (MI) and cross-correlation. RESULTS: Application of time-delayed MI to experimental data indicated the optimal bin size for information capture in the CA3-CA1 system was 40 ms, which may provide some insight into the spatiotemporal nature of encoding in the rat hippocampus. On simulated data, time-delayed MI showed peak values at appropriate time lags in positively correlated, negatively correlated, and complexly correlated data. Cross-correlation showed peak and troughs with positively correlated and negatively correlated data, but failed to capture some higher order correlations. CONCLUSIONS: Comparison of time-delayed MI to cross-correlation in identification of functionally dependent neurons indicates that the methods are not equivalent. Time-delayed MI appeared to capture some interactions between CA3-CA1 neurons at physiologically plausible time delays missed by cross-correlation. It should be considered as a method for identification of functional dependence between neurons and may be useful in the development of neural prosthetics.

Heterogeneity and randomness of DNA methylation patterns in human embryonic stem cells.

DNA methylation has been proposed to be important in many biological processes and is the subject of intense study. Traditional bisulfite genomic sequencing allows detailed high-resolution methylation pattern analysis of each molecule with haplotype information across a few hundred bases at each locus, but lacks the capacity to gather voluminous data. Although recent technological developments are aimed at assessing DNA methylation patterns in a high-throughput manner across the genome, the haplotype information cannot be accurately assembled when the sequencing reads are short or when each hybridization target only includes one or two cytosine-phosphate-guanine (CpG) sites. Whether a distinct and nonrandom DNA methylation pattern is present at a given locus is difficult to discern without the haplotype information, and the DNA methylation patterns are much less apparent because the data are often obtained only as methylation frequencies at each CpG site with some of these methods. It would facilitate the interpretation of data obtained from high-throughput bisulfite sequencing if the loci with nonrandom DNA methylation patterns could be distinguished from those that are randomly methylated. In this study, we carried out traditional genomic bisulfite sequencing using the normal diploid human embryonic stem (hES) cell lines, and utilized Hamming distance analysis to evaluate the existence of a distinct and nonrandom DNA methylation pattern at each locus studied. Our findings suggest that Hamming distance is a simple, quick, and useful tool to identify loci with nonrandom DNA methylation patterns and may be utilized to discern links between biological changes and DNA methylation patterns in the high-throughput bisulfite sequencing data sets.

Hidden semi-Markov models in the computerized decoding of microelectrode recording data for deep brain stimulator placement.

OBJECTIVE: To describe an approach to the analysis of deep brain stimulation (DBS) of the subthalamic nucleus (STN) using a hidden semi-Markov model (HsMM) and early results of the analysis of microelectrode recordings for STN DBS. METHODS: The author simulated the anatomy and electrophysiology of STN DBS and built a seven-state model to compare Hidden Markov model (HMM) and HsMM approaches. RESULTS: Accuracy of these competing models was similar for correctly identifying brain nuclei; however, HsMMs showed superior specificity in detecting microelectrode passes traversing the STN. CONCLUSIONS: Further clinical work must be done; however, based on these data, HsMMs may be best suited to computer-assisted anatomic delineation for DBS.

Symptomatic vertebral artery compression by the rod of a C1-C2 posterior fusion construct: case report and review of the literature.

STUDY DESIGN: Case report. OBJECTIVE: To report a rare complication of atlantoaxial fusion. SUMMARY OF BACKGROUND DATA: Vertebral artery injury is a serious complication of screw-based atlantoaxial fusion. To our knowledge, injury to the vertebral artery has only been described as a result of screw placement. We describe the first case of atlantoaxial fixation complicated by symptomatic and reversible external compression of the vertebral artery by the rod in a Harms construct. METHODS: Medical records and imaging reports were reviewed. RESULTS: A neurologically intact 84-year-old woman presented after a ground-level fall. Imaging revealed a nondisplaced type II odontoid fracture associated with a C1 ring fracture. She underwent a minimally invasive Harms atlantoaxial fusion. After surgery, she developed fluctuating level of consciousness in the setting of an otherwise normal neurologic and metabolic workup. A computed tomographic angiogram was obtained and showed good screw placement except for compression of the right vertebral artery from the right transfixing rod causing 75% luminal narrowing. She underwent a revision with rod shortening, and after surgery, improved neurologically, without any further episodes of altered mental status. CONCLUSION: In atlantoaxial fusion, the incidence of vertebral artery compression by the rod component of fusion construct may be underreported because it is difficult to detect with noncontrast computed tomography without computed tomographic angiography, which is not routinely obtained unless there is a high suspicion for vascular injury. We recommend inserting the rods with the cut (sharp) end pointing inferiorly, to avoid lacerating the vertebral artery. A vertebral artery compression from the rod in the absence of screw violation of the foramen transversarium should be considered in a patient with altered mental status after atlantoaxial fusion.

Intramedullary abscess of the spinal cord in the setting of patent foramen ovale.

BACKGROUND: Intramedullary abscess of the spinal cord is a rare entity, especially in the setting of an intracardiac shunt, which, to our knowledge, has not been described in the literature. Here we present a case of an intramedullary spinal cord abscess in a patient with a patent foramen ovale. METHODS: The article includes a chart review and description of a clinical case presentation. RESULTS: A 59-year-old man was admitted with rapidly progressive quadriparesis. Magnetic resonance imaging of the cervical spine demonstrated a large intramedullary mass extending from the level of C3 to C7. The patient was taken to the operating room for biopsy and surgical evacuation of the mass. Intraoperative pathology was consistent with abscess, and subsequent cultures grew Streptococcus viridans. On further workup, the patient was found to have a patent foramen ovale with right-to-left flow. Postoperatively, the strength improved significantly in all extremities with residual weakness. CONCLUSION: This is the first published case of an intramedullary spinal cord abscess in the setting of an intracardiac right-to-left shunt. Although intramedullary spinal cord abscess is rare, there are certain predisposing conditions that increase the risk of its occurrence.

An automated navigation system for deep brain stimulator placement using hidden Markov models.

OBJECTIVE: Placement of deep brain stimulators (DBSs) currently involves the use of both image-based stereotaxy and intraoperative microelectrode recording (MER). Interpretations of MER data and integration with anatomical data are currently manual processes. Hidden Markov models (HMMs) are commonly used in signal processing, speech recognition, and a wide array of biologic applications. METHODS: A 6-state HMM was designed and trained for evaluation in simulated surgery for subthalamic nucleus (STN) DBS. RESULTS: The accuracy of identifying the correct brain location was 98.5%. Sensitivity of detecting passes intersecting the STN was 100%, and specificity was 84.9%. Anatomical location of the MER passes was calculated with a mean error of 0.06 mm (95% confidence interval, -0.54 to 0.42 mm) in the medial-lateral axis. CONCLUSION: Automated DBS intraoperative navigation using HMMs may be feasible based on promising results of this prototype system.