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Background: Transcutaneous afferent patterned stimulation (TAPS) is a noninvasive neuromodulation therapy that improves hand tremor in essential tremor (ET) patients. The benefits of TAPS in ET patients with high unmet need (severe tremor, non-responsive to medication, age ≥65 years) and early responders (substantial TAPS tremor improvement in the first month) remains unknown., Research Design and Methods: Literature was surveyed for TAPS studies to assess the response in the high unmet need subgroup and early responders. Analyses were performed using previously collected Tremor Research Group Essential Tremor Rating Scale (TETRAS) scores, Bain & Findley activities of daily living (BF-ADL) scores, and tremor power., Results: Significant differences in BF-ADL and TETRAS improvement were observed with TAPS over sham for the high unmet need subgroup in a randomized controlled study ( P <0.03). During a 3-month open-label study, the high unmet need subgroup and early responders showed significant improvements in BF-ADL, TETRAS, and tremor power ( P <0.001). Analysis of previous real-world evidence demonstrated that early responders maintained effectiveness and usage at 3 and 12 months ( P <0.001)., Conclusions: TAPS showed comparable improvements in ET with high unmet need as reported in the original studies, and greater efficacy in early responders. These findings inform patient selection and the trial process for identifying TAPS responders.

This study hypothesized that dorsal root ganglion (DRG) stimulation would reduce sympathetic nerve activity and would alter hemodynamic variables. This study directly recorded muscle sympathetic nerve activity during ON and OFF stimulation of the DRG while measuring hemodynamic parameters. DRG stimulation significantly reduced the firing frequency of sympathetic nerves, as well as significantly reducing blood pressure, with greater reductions evident when stimulation was left-sided. Left-sided DRG stimulation lowers sympathetic nerve activity, leading to long-term phenotypic changes. This raises the potential of DRG stimulation being used to treat de novo autonomic disorders such as hypertension or heart failure., Competing Interests: This study was supported by an unrestricted research grant from Spinal Modulation Inc. and the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Kent was employed by Abbott at the time of the study and provided technical support for the study. Drs. FitzGerald and Green have received occasional honoraria from Abbott (primarily for teaching courses about dorsal root ganglion stimulation). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2020 The Authors.)

Introduction: Although nonlinear burst and tonic SCS are believed to treat neuropathic pain via distinct pain pathways, the effectiveness of these modalities on brain activity in vivo has not been investigated. This study compared neuronal firing patterns in the brain after nonlinear burst and tonic SCS in a rat model of painful radiculopathy., Methods: Neuronal activity was recorded in the ACC or S1 before and after nonlinear burst or tonic SCS on day 7 following painful cervical nerve root compression (NRC) or sham surgery. The amplitude of nonlinear burst SCS was set at 60% and 90% motor threshold to investigate the effect of lower amplitude SCS on brain activity. Neuronal activity was recorded during and immediately following light brush and noxious pinch of the paw. Change in neuron firing was measured as the percent change in spikes post-SCS relative to pre-SCS baseline., Results: ACC activity decreases during brush after 60% nonlinear burst compared to tonic (p < 0.05) after NRC and compared to 90% nonlinear burst (p < 0.04) and pre-SCS baseline (p < 0.03) after sham. ACC neuron activity decreases (p < 0.01) during pinch after 60% and 90% nonlinear burst compared to tonic for NRC. The 60% of nonlinear burst decreases (p < 0.02) ACC firing during pinch in both groups compared to baseline. In NRC S1 neurons, tonic SCS decreases (p < 0.01) firing from baseline during light brush; 60% nonlinear burst decreases (p < 0.01) firing from baseline during brush and pinch., Conclusions: Nonlinear burst SCS reduces firing in the ACC from a painful stimulus; a lower amplitude nonlinear burst appears to have the greatest effect. Tonic and nonlinear burst SCS may have comparable effects in S1., (© 2020 International Neuromodulation Society.)

The ACCURATE randomized, controlled trial compared outcomes of dorsal root ganglion (DRG) stimulation versus tonic spinal cord stimulation (SCS) in 152 subjects with chronic lower extremity pain due to complex regional pain syndrome (CRPS) type I or II. This ACCURATE substudy was designed to evaluate whether therapy habituation occurs with DRG stimulation as compared to SCS through 12-months. A modified intention-to-treat analysis was performed to assess percentage pain relief (PPR) and responder rates at follow-up visits (end-of-trial, 1, 3, 6, 9, 12-months postpermanent implant) for all subjects that completed trial stimulation (DRG:N = 73, SCS:N = 72). For both groups, mean PPR was significantly greater at end-of-trial (DRG = 82.2%, SCS =0 77.0%) than all other follow-ups. Following permanent DRG system implantation, none of the time points were significantly different from one another in PPR (range = 69.3-73.9%). For the SCS group, PPR at 9-months (58.3%) and 12-months (57.9%) was significantly less than at 1-month (66.9%). The responder rate also decreased for the SCS group from 1-month (68.1%) to 12-months (61.1%). After stratifying by diagnosis, it was found that only the CRPS-I population had diminishing pain relief with SCS. DRG stimulation resulted in more stable pain relief through 12-months, while tonic SCS demonstrated therapy habituation at 9- and 12-months. Trial Registration: The ACCURATE study was registered at ClinicalTrials.gov with Identifier NCT01923285. PERSPECTIVE: This article reports on an ACCURATE substudy, which found that long-term therapy habituation occurred at 12-months with SCS, but not DRG stimulation, in patients with CRPS. The underlying mechanisms of action for these results remain unclear, although several lines of inquiry are proposed., (Copyright © 2019 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: ACCURATE, a randomized controlled trial comparing dorsal root ganglion (DRG) stimulation to spinal cord stimulation, showed that DRG stimulation is a safe and effective therapy in individuals with lower extremity chronic pain due to complex regional pain syndrome (CRPS) type I or II. Investigators noted that DRG stimulation programming could be adjusted to minimize, or eliminate, the feeling of paresthesia while maintaining adequate pain relief. The present study explores treatment outcomes for DRG subjects who were paresthesia-free vs. those who experienced the sensation of paresthesia, as well as the factors that predicted paresthesia-free analgesia., Methods: A retrospective analysis of therapy outcomes was conducted for 61 subjects in the ACCURATE study who received a permanent DRG neurostimulator. Outcomes of subjects who were paresthesia-free were compared to those who experienced paresthesia-present therapy at 1, 3, 6, 9, and 12-month follow-ups. Predictor variables for the presence or absence of paresthesias with DRG stimulation were also explored., Results: The percentage of subjects with paresthesia-free pain relief increased from 16.4% at 1-month to 38.3% at 12-months. Paresthesia-free subjects generally had similar or better outcomes for pain severity, pain interference, quality of life, and mood state as subjects with paresthesia-present stimulation. Factors that increased the odds of a subject feeling paresthesia were higher stimulation amplitudes and frequencies, number of implanted leads, and younger age., Conclusions: Some DRG subjects achieved effective paresthesia-free analgesia in the ACCURATE trial. This supports the observation that paresthesia is not synonymous with pain relief or required for optimal analgesia with DRG stimulation., (© 2019 International Neuromodulation Society.)

Although burst and high-frequency (HF) spinal cord stimulation (SCS) relieve neuropathic pain, their effects on neuronal hyperexcitability have not been compared. Specifically, it is unknown how the recharge components of burst SCS-either actively balanced or allowed to passively return-and/or different frequencies of HF SCS compare in altering neuronal activity. Neuronal firing rates were measured in the spinal dorsal horn on day 7 after painful cervical nerve root compression in the rat. Motor thresholds (MTs) and evoked neuronal recordings were collected during noxious stimuli before (baseline) and after delivery of SCS using different SCS modes: 10 kHz HF, 1.2 kHz HF, burst with active recharge, or burst with passive recharge. Spontaneous firing rates were also evaluated at baseline and after SCS. The average MT for 10 kHz SCS was significantly higher (p < 0.033) than any other mode. Burst with passive recharge was the only SCS mode to significantly reduce evoked (p = 0.019) and spontaneous (p = 0.0076) firing rates after noxious pinch. This study demonstrates that HF and burst SCS have different MTs and effects on both evoked and spontaneous firing rates, indicating they have different mechanisms of providing pain relief. Since burst with passive recharge was the only waveform to reduce firing, that waveform may be important in the neurophysiological response to stimulation.

Purpose: High-dose-rate (HDR) brachytherapy boost is a treatment of intermediate- to high-risk prostate cancer, but long-term clinical outcome data are sparse. We report long-term survival and toxicity data in a cohort of patients treated in a single institution., Methods: Between 1998 and 2004, 654 patients with localized prostate cancer received either 3-dimensional conformal radiotherapy (median 46 Gy) with an HDR (median 18 Gy in three fractions) boost ("3-D conformal radiotherapy [3DCRT] + HDR"; 215 patients) or 3DCRT alone ("3DCRT"; median 70 Gy; 439 patients) with curative intent. Men with National Comprehensive Cancer Network intermediate risk were offered neoadjuvant androgen deprivation and with high risk were also offered adjuvant androgen deprivation. Data collection included patient-reported outcome measures., Results: The 3DCRT + HDR group was older (72.3 vs. 68.9 yrs), had higher presenting PSAs (iPSA) (15.66 and 12.57 ng/mL, respectively), higher proportion of Gleason scores >7 (15.3% vs. 12.4%), and higher proportions of extracapsular disease (29.3% vs. 25.5%). 3DCRT + HDR men had lower proportions of low-risk patients (3.3% vs. 19.4%) and higher proportions of high-risk patients (50.7% vs. 37.4%) than the 3DCRT group. The 5-, 10-, and 15-year overall survival was superior at 92%, 81%, and 67%, respectively, for the 3DCRT + HDR group, compared with 88%, 71%, and 53%, respectively, in the 3DCRT group (p < 0.001). The 5-, 10-, and 15-year cause specific survival also favored the HDR boost group with survival of 96%, 93%, and 87% (3DCRT + HDR) and 95% 88% and 79% (3DCRT), respectively (p < 0.037)., Conclusions: HDR brachytherapy boost in conjunction with 3DCRT offered superior overall survival and cause-specific survival in our patient population., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: There is increasing literature evidence both clinically and experimentally on the existence of potent, adaptive interactions between the central and peripheral aspects of the neuroimmune system in the genesis and maintenance of chronic neuropathic extremity pain and nociceptive back pain. The neuroinflammatory pathways are modulated by the interaction of pro- and anti-inflammatory cytokines and chemokines, which are released by peripheral immune system-derived cell species (macrophages and leukocytes). This review examines the possible impact of spinal and peripheral neurostimulation on the inflammatory response in the context of acute and chronic pain pathologies of different origin., Study Design: A narrative review of preclinical and clinical studies addressed to the spinal cord and peripheral nerve stimulation and neuroinflammation., Methods: Available literature was reviewed on neurostimulation technologies and both acute and chronic low-grade inflammation to identify primary outcome measures and to provide an overview of postulated mechanisms of action of neurostimulation on host inflammatory responses. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles., Results: A comprehensive review of the literature indicates an alternate or synergistic mechanism of action of neurostimulation, beyond modulating somatosensory pain pathways, in modifying inflammatory response associated with chronic pain, by promoting a systemic anti-inflammatory state with upregulation of anti-inflammatory mediators., Conclusions: These preliminary findings may have important implications on the potential applications of neurostimulation as an anti-inflammatory therapy and the role of molecular profiling as a preimplant screening modality and post-implant outcome validation. Thus, future targeted clinical and experimental research is highly warranted in this particular novel field of neuromodulation., (© 2018 International Neuromodulation Society.)

Background: Burst spinal cord stimulation (SCS) technology uses a novel waveform that consists of closely packed high-frequency electrical impulses followed by a quiescent period. Within the growing field of neuromodulation, burst stimulation is unique in that it mimics the natural burst firing of the nervous system, in particular the thalamo-cingulate rhythmicity, resulting in modulation of the affective and attentional components of pain processing (e.g., medial thalamic pathways)., Study Design: A review of preclinical and clinical studies regarding burst SCS for various chronic pain states., Methods: Available literature was reviewed on burst stimulation technology. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles., Outcome Measures: The primary outcome measure was to understand the mechanisms of action with regards to burst stimulation and to review clinical data on the indications of burst SCS for various chronic pain states., Results: We present both mechanisms of action and review uses of burst stimulation for various pain states., Conclusions: Burst stimulation offers a novel pain reduction tool with the absence of uncomfortable paresthesia for failed back surgery syndrome, diabetic neuropathic pain, and anesthesia dolorosa. Preclinical models have emphasized that the potential mechanisms for burst therapy could be related to neural coding algorithms that mimic the natural nervous system firing patterns, resulting in effects on both the medial and lateral pain pathways. Other mechanisms include frequency dependent opioid release, modulation of the pain gate, and activation of electrical and chemical synapses., (© 2018 International Neuromodulation Society.)

Objective: The mechanisms of dorsal root ganglion (DRG) stimulation for chronic pain remain unclear. The objective of this work was to explore the neurophysiological effects of DRG stimulation using computational modeling., Methods: Electrical fields produced during DRG stimulation were calculated with finite element models, and were coupled to a validated biophysical model of a C-type primary sensory neuron. Intrinsic neuronal activity was introduced as a 4 Hz afferent signal or somatic ectopic firing. The transmembrane potential was measured along the neuron to determine the effect of stimulation on intrinsic activity across stimulation parameters, cell location/orientation, and membrane properties., Results: The model was validated by showing close correspondence in action potential (AP) characteristics and firing patterns when compared to experimental measurements. Subsequently, the model output demonstrated that T-junction filtering was amplified with DRG stimulation, thereby blocking afferent signaling, with cathodic stimulation at amplitudes of 2.8-5.5 × stimulation threshold and frequencies above 2 Hz. This amplified filtering was dependent on the presence of calcium and calcium-dependent small-conductance potassium channels, which produced a hyperpolarization offset in the soma, stem, and T-junction with repeated somatic APs during stimulation. Additionally, DRG stimulation suppressed somatic ectopic activity by hyperpolarizing the soma with cathodic or anodic stimulation at amplitudes of 3-11 × threshold and frequencies above 2 Hz. These effects were dependent on the stem axon being relatively close to and oriented toward a stimulating contact., Conclusions: These results align with the working hypotheses on the mechanisms of DRG stimulation, and indicate the importance of stimulation amplitude, polarity, and cell location/orientation on neuronal responses., (© 2018 International Neuromodulation Society.)

Background: Catheter ablation of ventricular tachycardia (VT) has been shown to reduce the number of recurrent shocks in patients with an implantable cardioverter-defibrillator (ICD). However, how VT ablation affects postprocedural medical and pharmaceutical usage remains unclear., Objective: The purpose of this study was to investigate changes in health care resource utilization (HCRU) after VT ablation., Methods: This large-scale, real-world, retrospective study used the MarketScan databases to identify patients in the United States with an ICD or cardiac resynchronization therapy-defibrillator (CRT-D) undergoing VT ablation. We calculated cumulative medical and pharmaceutical expenditures, office visits, hospitalizations, and emergency room (ER) visits in the 1-year periods before and after ablation., Results: A total of 523 patients met the study inclusion criteria. After VT ablation, median annual cardiac rhythm-related medical expenditures decreased by $5,408. Moreover, the percentage of patients with at least 1 cardiac rhythm-related hospitalization and ER visit decreased from 53% and 41% before ablation to 28% and 26% after ablation, respectively. Similar changes were observed in the number of all-cause hospitalizations and ER visits, but there were no significant changes in all-cause medical expenditures. During the year before VT ablation, there was an increasing rate of health care resource utilization, followed by drastic slowing after ablation., Conclusion: This retrospective study demonstrated that catheter ablation seems to reduce hospitalization and overall health care utilization in VT patients with an ICD or CRT-D in place., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: A shorter delay time from chronic pain diagnosis to spinal cord stimulation (SCS) implantation may make it more likely to achieve lasting therapeutic efficacy with SCS. The objective of this analysis was to determine the impact of pain-to-SCS time on patients' post-implant healthcare resource utilization (HCRU)., Methods: A retrospective observational study was performed using a real-world patient cohort derived from MarketScan(®) Commercial and Medicare Supplemental claims data bases from April 2008 through March 2013. The predictor variable was the time from the first diagnosis of chronic pain to permanent SCS implant. Using multivariable analysis, we studied the impact of pain-to-SCS time on HCRU in the first year post-implant. For some regression tests, patients were grouped into terciles by HCRU., Results: A total of 762 patients met inclusion criteria, with a median pain-to-SCS time of 1.35 years (Q1: 0.8, Q3: 1.9). For every one-year increase in pain-to-SCS time, the odds increased by 33% for being in the high medical expenditures group (defined using the upper tercile: $4133 over above) over the low group (first lower: $603 or less). The odds increased by 39% for being in the high opioid prescriptions group (10-58 prescriptions) over the low group (0-1). The odds increased by 44% and 55%, respectively, for being in the high office visits (8-77) or hospitalizations (3-28) group over the low office visits (0-2) or hospitalizations (0) group., Conclusions: HCRU increased in the year following SCS implantation with longer pain-to-SCS time. These results suggest that considering SCS earlier in the care continuum for chronic pain may improve patient outcomes, with reductions in hospitalizations, clinic visits, and opioid usage., (© 2016 International Neuromodulation Society.)

The effectiveness of spinal cord stimulation (SCS) for chronic pain treatment depends on selection of appropriate stimulation settings, which can be especially challenging following posture change or SCS lead migration. The objective of this work was to investigate the feasibility of using SCS lead impedance for determining the location of a SCS lead and for detecting lead migration, as well as the impact of axial movement and rotation of the St. Jude Medical PENTA™ paddle in the dorsal-ventral or medial-lateral directions on dorsal column (DC) stimulation thresholds and neural activation regions. We used a two-stage computational model, including a finite element method model of field potentials in the spinal cord during stimulation, coupled to a biophysical cable model of mammalian, myelinated nerve fibers to calculate tissue impedance and nerve fiber activation within the DC. We found that SCS lead impedance was highly sensitive to the distance between the lead and cerebrospinal fluid (CSF) layer. In addition, among all the lead positions studied, medial-lateral movement resulted in the most substantial changes to SC activation regions. These results suggest that impedance can be used for detecting paddle position and lead migration, and therefore for guiding SCS programming.

Background: Deep brain stimulation (DBS) treats the symptoms of several movement disorders, but optimal selection of stimulation parameters remains a challenge. The evoked compound action potential (ECAP) reflects synchronized neural activation near the DBS lead, and may be useful for feedback control and automatic adjustment of stimulation parameters in closed-loop DBS systems., Objectives: Determine the feasibility of recording ECAPs in the clinical setting, understand the neural origin of the ECAP and sources of any stimulus artifact, and correlate ECAP characteristics with motor symptoms., Methods: The ECAP and tremor response were measured simultaneously during intraoperative studies of thalamic DBS, conducted in patients who were either undergoing surgery for initial lead implantation or replacement of their internal pulse generator., Results: There was large subject-to-subject variation in stimulus artifact amplitude, which model-based analysis suggested may have been caused by glial encapsulation of the lead, resulting in imbalances in the tissue impedance between the contacts. ECAP recordings obtained from both acute and chronically implanted electrodes revealed that specific phase characteristics of the signal varied systematically with stimulation parameters. Further, a trend was observed in some patients between the energy of the initial negative and positive ECAP phases, as well as secondary phases, and changes in tremor from baseline. A computational model of thalamic DBS indicated that direct cerebellothalamic fiber activation dominated the clinically measured ECAP, suggesting that excitation of these fibers is critical in DBS therapy., Conclusions: This work demonstrated that ECAPs can be recorded in the clinical setting and may provide a surrogate feedback control signal for automatic adjustment of stimulation parameters to reduce tremor amplitude., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Closed-loop deep brain stimulation (DBS) systems have the potential to optimize treatment of movement disorders by enabling automatic adjustment of stimulation parameters based on a feedback signal. Evoked compound action potentials (ECAPs) and local field potentials (LFPs) recorded from the DBS electrode may serve as suitable closed-loop control signals. The objective of this study was to understand better the factors that influence ECAP and LFP recording, including the physical presence of the electrode, the geometrical dimensions of the electrode, and changes in the composition of the peri-electrode space across recording conditions., Approach: Coupled volume conductor-neuron models were used to calculate single-unit activity as well as ECAP responses and LFP activity from a population of model thalamic neurons., Main Results: Comparing ECAPs and LFPs measured with and without the presence of the highly conductive recording contacts, we found that the presence of these contacts had a negligible effect on the magnitude of single-unit recordings, ECAPs (7% RMS difference between waveforms), and LFPs (5% change in signal magnitude). Spatial averaging across the contact surface decreased the ECAP magnitude in a phase-dependent manner (74% RMS difference), resulting from a differential effect of the contact on the contribution from nearby or distant elements, and decreased the LFP magnitude (25% change). Reductions in the electrode diameter or recording contact length increased signal energy and increased spatial sensitivity of single neuron recordings. Moreover, smaller diameter electrodes (500 µm) were more selective for recording from local cells over passing axons, with the opposite true for larger diameters (1500 µm). Changes in electrode dimensions had phase-dependent effects on ECAP characteristics, and generally had small effects on the LFP magnitude. ECAP signal energy and LFP magnitude decreased with tighter contact spacing (100 µm), compared to the original dimensions (1500 µm), with the opposite effect on the ECAP at longer contact-to-contact distances (2000 µm). Finally, acute edema reduced the single neuron and population ECAP signal energy, as well as LFP magnitude, and glial encapsulation had the opposite effect, after accounting for loss of cells in the peri-electrode space., Significance: This study determined recording conditions and electrode designs that influence ECAP and LFP recording fidelity.

Spinal cord stimulation (SCS) is an effective therapy for treating chronic pain. The St. Jude Medical PENTA(TM) paddle lead features a 4 × 5 contact array for achieving broad, selective coverage of dorsal column (DC) fibers. The objective of this work was to evaluate DC activation regions that correspond to dermatomal coverage with use of the PENTA lead in conjunction with a lateral sweep programming algorithm. We used a two-stage computational model, including a finite element method model of field potentials in the spinal cord during stimulation, coupled to a biophysical cable model of mammalian, myelinated nerve fibers to determine fiber activation within the DC. We found that across contact configurations used clinically in the sweep algorithm, the activation region shifted smoothly between left and right DC, and could achieve gapless medio-lateral coverage in dermatomal fiber tract zones. Increasing stimulation amplitude between the DC threshold and discomfort threshold led to a greater area of activation and number of dermatomal zones covered on the left and/or right DC, including L1-2 zones corresponding to dermatomes of the lower back. This work demonstrates that the flexibility in contact selection offered by the PENTA lead may enable patient-specific tailoring of SCS.

A recently published computational modeling study of spinal cord stimulation (SCS) predicted that a multiple current source (MCS) system could generate a greater number of central points of stimulation in the dorsal column (DC) than a single current source (1 CS) system. However, the clinical relevance of this finding has not been established. The objective of this work was to compare the dermatomal zone selectivity of MCS and 1 CS systems. A finite element method (FEM) model was built with a representation of the spinal cord anatomy and a 2 × 8 paddle electrode array. Using a contact configuration with two aligned tripoles, the FEM model was used to solve for DC field potentials across incremental changes in current between the two cathodes, modeling the MCS and 1 CS systems. The activation regions within the DC were determined by coupling the FEM output to a biophysical nerve fiber model, and coverage was mapped to dermatomal zones. Results showed marginal differences in activated dermatomal zones between 1 CS and MCS systems. This indicates that a MCS system may not provide incremental therapeutic benefit as suggested in prior analysis.

Closed-loop deep brain stimulation (DBS) systems could provide automatic adjustment of stimulation parameters and improve outcomes in the treatment of Parkinson's disease and essential tremor. The evoked compound action potential (ECAP), generated by activated neurons near the DBS electrode, may provide a suitable feedback control signal for closed-loop DBS. The objectives of this work were to characterize the ECAP across stimulation parameters and determine the neural elements contributing to the signal. We recorded ECAPs during thalamic DBS in anesthetized cats and conducted computer simulations to calculate the ECAP of a population of thalamic neurons. The experimental and computational ECAPs were similar in shape and had characteristics that were correlated across stimulation parameters (R(2) = 0.80-0.95, P < 0.002). The ECAP signal energy increased with larger DBS amplitudes (P < 0.0001) and pulse widths (P < 0.002), and the signal energy of secondary ECAP phases was larger at 10-Hz than at 100-Hz DBS (P < 0.002). The computational model indicated that these changes resulted from a greater extent of neural activation and an increased synchronization of postsynaptic thalamocortical activity, respectively. Administration of tetrodotoxin, lidocaine, or isoflurane abolished or reduced the magnitude of the experimental and computational ECAPs, glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and D(-)-2-amino-5-phosphonopentanoic acid (APV) reduced secondary ECAP phases by decreasing postsynaptic excitation, and the GABAA receptor agonist muscimol increased the latency of the secondary phases by augmenting postsynaptic hyperpolarization. This study demonstrates that the ECAP provides information about the type and extent of neural activation generated during DBS, and the ECAP may serve as a feedback control signal for closed-loop DBS.

Objective: Electrical stimulation of the pudendal nerve (PN) is being developed as a means to restore bladder function in persons with spinal cord injury. A single nerve cuff electrode placed on the proximal PN trunk may enable selective stimulation of distinct fascicles to maintain continence or evoke micturition. The objective of this study was to design a nerve cuff that enabled selective stimulation of the PN., Approach: We evaluated the performance of both flat interface nerve electrode (FINE) cuff and round cuff designs, with a range of FINE cuff heights and number of contacts, as well as multiple contact orientations. This analysis was performed using a computational model, in which the nerve and fascicle cross-sectional positions from five human PN trunks were systematically reshaped within the nerve cuff. These cross-sections were used to create finite element models, with electric potentials calculated and applied to a cable model of a myelinated axon to evaluate stimulation selectivity for different PN targets. Subsequently, the model was coupled to a genetic algorithm (GA) to identify solutions that used multiple contact activation to maximize selectivity and minimize total stimulation voltage., Main Results: Simulations did not identify any significant differences in selectivity between FINE and round cuffs, although the latter required smaller stimulation voltages for target activation due to preserved localization of targeted fascicle groups. Further, it was found that a ten contact nerve cuff generated sufficient selectivity for all PN targets, with the degree of selectivity dependent on the relative position of the target within the nerve. The GA identified solutions that increased fitness by 0.7-45.5% over single contact activation by decreasing stimulation of non-targeted fascicles., Significance: This study suggests that using an optimal nerve cuff design and multiple contact activation could enable selective stimulation of the human PN trunk for restoration of bladder function.

The clinical efficacy of deep brain stimulation (DBS) for the treatment of movement disorders depends on the identification of appropriate stimulation parameters. Since the mechanisms of action of DBS remain unclear, programming sessions can be time consuming, costly and result in sub-optimal outcomes. Measurement of electrically evoked compound action potentials (ECAPs) during DBS, generated by activated neurons in the vicinity of the stimulating electrode, could offer insight into the type and spatial extent of neural element activation and provide a potential feedback signal for the rational selection of stimulation parameters and closed-loop DBS. However, recording ECAPs presents a significant technical challenge due to the large stimulus artefact, which can saturate recording amplifiers and distort short latency ECAP signals. We developed DBS-ECAP recording instrumentation combining commercial amplifiers and circuit elements in a serial configuration to reduce the stimulus artefact and enable high fidelity recording. We used an electrical circuit equivalent model of the instrumentation to understand better the sources of the stimulus artefact and the mechanisms of artefact reduction by the circuit elements. In vitro testing validated the capability of the instrumentation to suppress the stimulus artefact and increase gain by a factor of 1000 to 5000 compared to a conventional biopotential amplifier. The distortion of mock ECAP (mECAP) signals was measured across stimulation parameters, and the instrumentation enabled high fidelity recording of mECAPs with latencies of only 0.5 ms for DBS pulse widths of 50 to 100 µs/phase. Subsequently, the instrumentation was used to record in vivo ECAPs, without contamination by the stimulus artefact, during thalamic DBS in an anesthetized cat. The characteristics of the physiological ECAP were dependent on stimulation parameters. The novel instrumentation enables high fidelity ECAP recording and advances the potential use of the ECAP as a feedback signal for the tuning of DBS parameters.

Deep brain stimulation (DBS) and lesioning are two surgical techniques used in the treatment of advanced Parkinson's disease (PD) in patients whose symptoms are not well controlled by drugs, or who experience dyskinesias as a side effect of medications. Although these treatments have been widely practiced, the mechanisms behind DBS and lesioning are still not well understood. The subthalamic nucleus (STN) and globus pallidus pars interna (GPi) are two common targets for both DBS and lesioning. Previous studies have indicated that DBS not only affects local cells within the target, but also passing axons within neighboring regions. Using a computational model of the basal ganglia-thalamic network, we studied the relative contributions of activation and silencing of local cells (LCs) and fibers of passage (FOPs) to changes in the accuracy of information transmission through the thalamus (thalamic fidelity), which is correlated with the effectiveness of DBS. Activation of both LCs and FOPs during STN and GPi-DBS were beneficial to the outcome of stimulation. During STN and GPi lesioning, effects of silencing LCs and FOPs were different between the two types of lesioning. For STN lesioning, silencing GPi FOPs mainly contributed to its effectiveness, while silencing only STN LCs did not improve thalamic fidelity. In contrast, silencing both GPi LCs and GPe FOPs during GPi lesioning contributed to improvements in thalamic fidelity. Thus, two distinct mechanisms produced comparable improvements in thalamic function: driving the output of the basal ganglia to produce tonic inhibition and silencing the output of the basal ganglia to produce tonic disinhibition. These results show the importance of considering effects of activating or silencing fibers passing close to the nucleus when deciding upon a target location for DBS or lesioning.

Closed-loop deep brain stimulation (DBS) systems offer promise in relieving the clinical burden of stimulus parameter selection and improving treatment outcomes. In such a system, a feedback signal is used to adjust automatically stimulation parameters and optimize the efficacy of stimulation. We explored the feasibility of recording electrically evoked compound action potentials (ECAPs) during DBS for use as a feedback control signal. A novel instrumentation system was developed to suppress the stimulus artifact and amplify the small magnitude, short latency ECAP response during DBS with clinically relevant parameters. In vitro testing demonstrated the capabilities to increase the gain by a factor of 1,000× over a conventional amplifier without saturation, reduce distortion of mock ECAP signals, and make high fidelity recordings of mock ECAPs at latencies of only 0.5 ms following DBS pulses of 50 to 100 μs duration. Subsequently, the instrumentation was used to make in vivo recordings of ECAPs during thalamic DBS in cats, without contamination by the stimulus artifact. The signal characteristics were similar across three experiments, suggesting common neural activation patterns. The ECAP recordings enabled with this novel instrumentation may provide insight into the type and spatial extent of neural elements activated during DBS, and could serve as feedback control signals for closed-loop systems.

Purpose: The aim of this study was to determine the vitreous brimonidine concentration of topically applied brimonidine-Purite 0.15%., Methods: Patients scheduled for a pars plana vitrectomy were invited to participate in this study after institutional review board (IRB) approval was obtained. Each patient was asked to apply brimonidine-Purite (0.15%) drops in the designated eye either every 12 h (b.i.d.; 9 patients) or every 8 h (t.i.d.; 10 patients) for the 2 weeks proceeding scheduled surgery. The importance of the last topical dose being 12 h (b.i.d. group) or 8 h (t.i.d. group) before the scheduled surgery, was emphasized. Four (4) patients served as controls and did not receive any drops. Vitreous (approximately 0.5-1.0 mL) was aspirated prior to opening the infusion line. Specimens were frozen at -68 degrees C until analyzed., Results: In the b.i.d. group, the mean concentration of brimonidine was 16.74 nM+/-10.33 standard deviation (range, 0.42-34.68 nM; median, 16.38); in the t.i.d. group, the mean concentration of brimonidine was 19.16 nM+/-15.40 standard deviation (range, 0.22-39.48 nM; median, 16.98). A significant difference was observed between the (no drug) control vitreous brimonidine levels and b.i.d. or t.i.d. vitreous levels (P<0.01, <0.01, respectively; n=4, 9, and 10, respectively); and in brimonidine levels between t.i.d. phakic patients and t.i.d. patients with posterior chamber lens (P=0.04; n=4 and 6, respectively)., Conclusions: Brimonidine-Purite 0.15%, topically applied b.i.d. or t.i.d. for 2 weeks prior to collection, acquired vitreous levels of brimonidine at or above the 2-nM concentration known to activate the neuroprotective alpha-2 receptor in animals.

Purpose: To determine outflow resistance of the Baerveldt glaucoma implant using different tube configurations., Methods: Outflow resistance of 6 tube configurations (C1- C6) of Baerveldt implants was measured under conditions of constant pressure perfusion. Pressures ranged from 2 to 55 mm Hg. Venting slits were created using a 7-0 Vicryl, spatulated suture-needle. Seton tubes were occluded by threading a retrograde suture approximately 1.5 cm into the lumen., Results: At pressures between 2 and 55 mm Hg, mean outflow resistance of the normally configured seton (ie, open tube; C1) was 0.41 (+/- 0.6) mm Hg/microL/min. Resistance was unchanged (mean 0.41 (+/- 0.4) mm Hg/microL/min) by the addition of 4 venting slits (C2) to the seton tube. Occlusion of the open seton tube with a 3-0 Supramid suture (C3) significantly increased (P < 0.001) mean outflow resistance to 14.99 (+/- 0.6) mm Hg/microL/min. Occlusion of the tube with a 4-0 Supramid suture (C4) significantly increased (P < 0.001) mean outflow resistance to 1.09 (+/- 0.5) mm Hg/microL/min. In implants where tubes were occluded with a 3-0 Supramid suture, the addition of venting slits (C5) significantly decreased (P = 0.038) mean outflow resistance to 8.98 (+/- 0.4) mm Hg/microL/min. In tubes occluded with a 4-0 Supramid suture, the addition of venting slits (C6) decreased mean outflow resistance to 0.98 (+/- 0.6) mm Hg/microL/min., Conclusions: Although these results cannot be directly correlated to the clinical setting, they do show that outflow resistance can be modified at the time of surgery by changing tube configuration of the Baerveldt glaucoma implant. Configuration C5 (3-0 Supramid with venting slits) closely approximates the outflow rate in the normal intraocular pressure range.

The purpose of this study was to assess the efficacy of latanoprost 0.005% and timolol maleate 0.5% in black and white patients with elevated intraocular pressure (IOP). This double-masked, randomized, 2-period crossover study included 39 eyes in 22 patients with primary open-angle glaucoma or ocular hypertension. After a 2- to 4-week washout period, patients were randomly assigned to receive either vehicle placebo in the morning and latanoprost in the evening or timolol maleate twice daily for 6 weeks. Then, after a 4-week washout period, patients received the opposing treatment for 6 weeks. Both latanoprost and timolol maleate significantly lowered IOP from baseline in both black and white patients. Latanoprost treatment was associated with lower mean IOP compared with timolol treatment in black patients (P = .013 at 8 AM, P = .19 at 10 AM). At 10 AM at the end of the treatment period, the mean +/- SD change from baseline IOP in black patients receiving latanoprost was significantly greater than that of white patients (-10.2 +/- 7.0 and -5.9 +/- 2.5 mm Hg, respectively; P = .042). The mean +/- SD change from baseline IOPs in black patients was not significantly different from that in white patients at 8 AM at the end of the treatment period for the latanoprost group and at 8 AM and 10 AM at the end of the treatment period for the timolol maleate group. In white patients, the change from baseline IOP in light (grade 1) irises was not significantly different from dark (grade 5) irises after treatment with either latanoprost or timolol maleate. In summary, intraocular pressure after treatment with latanoprost was lower than that after timolol treatment in black patients with primary open-angle glaucoma or ocular hypertension, and at 1 of 2 timepoints, latanoprost caused a significantly greater reduction of IOP in black patients than in white patients.

Background: Numerous studies have reported neuropsychological impairment in schizophrenia and increasing evidence suggests that individuals with schizophrenia or schizophrenia spectrum disorders and their unaffected first-degree family members exhibit similar deficits in some neuropsychological domains. Substantial modifications to the Wechsler Memory Scale (WMS) have resulted in more sensitive and reliable indicators of various aspects of memory functioning in the WMS-III, which enables generation of auditory, visual and working memory indices., Objective: The aim of the present study was to examine the memory profile of individuals with schizophrenia or schizophrenia spectrum disorder (n = 19), their unaffected first-degree family members (n = 11), and healthy controls (n = 9)., Methods: The study involved neuropsychological testing, including the immediate and working memory subtests of the WMS-III, utilizing both auditory and visual domains. Symptom assessment was performed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN), version 2.0. Two multivariate analyses of covariance (mancova) were conducted: (i) comparing patients, relatives and controls; and (ii) comparing relatives and controls only., Results: The first analysis indicated that the patient group obtained significantly lower index scores than both relatives and controls on all three indices. The second analysis indicated that the performance of relatives was significantly lower than controls on the working memory index, although there were no significant differences on the auditory and visual immediate index scores., Conclusions: The differential impairment in working memory performance in clinically asymptomatic family members suggests that the WMS-III working memory index score may be a potential phenotypic marker of schizophrenia.

Purpose: Adenosine receptors modulate several ocular responses; however, our understanding of factors that influence ocular extracellular adenosine levels is limited. The objective of this study was to evaluate how changes in intraocular pressure (IOP) influence endogenous levels of the purines adenosine and inosine, in the aqueous humor of normal and ocular-hypertensive patients., Patients and Methods: Informed consent was obtained from 51 individuals undergoing cataract extraction or glaucoma surgical procedures. IOP was measured immediately prior to surgery. At the start of the surgical procedure, an aqueous sample of 75-100 microL was obtained. Purine levels were determined by reverse-phase HPLC., Results: In normotensive individuals, mean aqueous adenosine and inosine levels were 5.2 +/- 1.1 and 19.4 +/- 2.2 ng/100 microL, respectively. No significant correlation between IOP and purine concentration was measured in this group. In ocular hypertensive individuals, the mean aqueous adenosine and inosine concentration was significantly elevated when compared to normotensive individuals. In the ocular hypertensive individual, this elevation in adenosine level was significantly correlated with IOP (r(2) = 0.42)., Conclusions: These results demonstrate that in ocular hypertensive individuals, aqueous adenosine concentration is correlated with IOP. As the activation of adenosine receptors can modulate IOP and retinal blood flow, adenosine release during periods of ocular hypertension may play an important role in the physiological responses to elevated IOP.

Purpose: To study the injection of viscoelastic material into Schlemm's canal adjacent to and 6.0 mm from the scleral flap during viscocanalostomy in an autopsy eye model., Setting: Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA., Methods: Viscocanalostomy was performed in 8 postmortem human globes. Sodium hyaluronate (Healon GV or Healon5) was injected into 1 side of Schlemm's canal, with the other side serving as a control in some eyes. The eyes were prepared for light microscopic analysis, and serial pathologic sections were taken adjacent to the flap and 6.0 mm circumferentially from the flap. The area of Schlemm's canal was calculated and compared using t tests., Results: Injecting viscoelastic material enlarged the area of Schlemm's canal adjacent to and 6.0 mm from the flap significantly more than not injecting viscoelastic material. While there was no difference between the viscoelastic materials in dilating Schlemm's canal at the flap, with Healon5 there was a small but statistically significantly greater dilation 6.0 mm from the flap. No full-thickness breaks in the trabecular meshwork were noted adjacent to or 6.0 mm from the flap., Conclusion: Injecting viscoelastic material significantly increased the cross-sectional area of Schlemm's canal and may play a role in the success of viscocanalostomy. Further study is needed to elucidate the mechanism of this procedure.

Objective: To determine the vitreous concentration of brimonidine after topical administration of Alphagan., Design: Prospective observational case series., Participants: Eighteen patients scheduled for elective pars plana vitrectomy., Methods: Brimonidine tartrate, 0.2%, was topically administered twice or three times daily for 4 to 14 days preoperatively in 13 patients. Four patients served as controls, without application of brimonidine. A dry, undiluted vitrectomy specimen obtained intraoperatively was collected, frozen, and sent to an independent bioanalytical facility for quantitative determination of vitreous concentration of brimonidine using gas chromatography/mass spectrometry., Main Outcome Measures: The concentration of brimonidine in human vitreous., Results: All patients treated with brimonidine measured above the lower limit of quantitation with a mean vitreous concentration of 185 +/- 500 nM. All patients not treated with brimonidine measured at or below the lower limit of quantitation of 0.05 nM. There was a trend toward higher concentration in patients who were either aphakic or pseudophakic compared with those that were phakic., Conclusions: Topically applied brimonidine results in vitreous levels at or above 2 nM, the concentration shown to activate alpha(2)-receptors.

Objective: To assess the correlation of the bulbar conjunctival blood column (BCBC) with anemia., Design: A prospective, randomized, masked, two observer case series., Participants: Inpatients on hospital wards; outpatients in both the Hematology-Oncology and Ophthalmology Clinics., Methods: Observations of the palpebral conjunctival hue (PCH) and BCBC by two observers masked to the patient's diagnosis, laboratory test results, and other's observations. The PCH and BCBC were correlated by slit-lamp examination with serum hemoglobin values. Different threshold levels for anemia were defined as hemoglobin <10, <11, and <12 mg/dl., Main Outcome Measures: The parameters included determination of (1) the conjunctival hue, assessed as pink or pale and (2) the bulbar conjunctival blood column, assessed as full (normal), granular, or discontinuous. These data were compared against the patient's hemoglobin level., Results: Mean hemoglobin was 11.0+/-2.2 mg/dl. Sensitivity of the BCBC and PCH for anemia was 83%-94% and 38%, respectively, regardless of the definition of anemia. Specificity of BCBC improved with increasing hemoglobin threshold levels for anemia: 56% (hemoglobin <10 mg/dl) to 73% (hemoglobin <12 mg/dl); specificity for PCH ranged from 82% to 94%. The BCBC was significantly (P<0.03) associated with anemia for hemoglobin <11 mg/dl for both observers (logistic regression, Spearman correlation). There was a significant (P<0.05) association of PCH with anemia only for hemoglobin <10 mg/dl with logistic regression (one observer only) and with Spearman correlation (both observers)., Conclusions: The BCBC is significantly associated with anemia, with higher sensitivity and only slightly less specificity than PCH.

Purpose: To study any interaction between pilocarpine and latanoprost when administered together, and to determine the optimal timing of dosage to maximize reduction of intraocular pressure (IOP)., Methods: Nineteen adult patients with either primary open-angle glaucoma or ocular hypertension participated in a single-center, prospective case study with masked observer. After a baseline measurement of IOP during treatment with latanoprost was obtained, initial treatment with pilocarpine three times daily was added without bedtime administration. This was followed by three different dose regimens in which pilocarpine was administered four times daily, altering the bedtime pilocarpine dose to precede the latanoprost dose by 1 hour, or to follow it by 10 minutes or 1 hour. Intraocular pressure was measured at 8:00 AM and 75 minutes after administration of the morning dose of pilocarpine., Results: Comparison of IOP at 8:00 AM with baseline showed no significant change when pilocarpine was taken three times daily, or when pilocarpine was taken four times daily when the bedtime dose preceded administration of latanoprost by 1 hour. There were significant decreases in IOP versus baseline when the bedtime dose of pilocarpine was taken simultaneously with or 1 hour after administration of latanoprost. Application of pilocarpine immediately after the 8:00 AM IOP measurement revealed a significant additional decrease in pressure. There were no significant differences between dosage schedules in the magnitude of the additional reduction in IOP., Conclusion: The order and timing of administration of pilocarpine and latanoprost can significantly alter their ocular hypotensive activity. Pilocarpine is most effective when administered four times daily, and when the bedtime dose is administered 1 hour after administration of latanoprost.

We examined the effects of a single exposure to a temperature elevation of 2 degrees C for a 2 h period on the developmental processes of cell division and cell death in the hippocampus and the amygdala of the quokka. Animals aged postnatal day (P) 4045 were injected with tritiated (3H-) thymidine and then exposed to either 37 degrees C (normal) or 39 degrees C (+/-0.2 degrees C) in an incubator for a duration of 2 h. The young were then returned to the nipple and, after a period of 24 h, were sacrificed. Brains were sectioned and selected sections processed for autoradiography, and some were counterstained. Cell division taking place at the time of heating was estimated by counting 3H-thymidine-labelled cells and at the time of sacrifice by counting mitotic figures. Dying cells were visualised as pyknotic profiles in cresyl-violet-stained sections. In both the amygdala and the hippocampus, the number of 3H-thymidine-labelled cells (cells dividing in situ during the heating period) was significantly lower in the experimental than the control group. Such cells were glia in the amygdala and granule cells and glia in the hippocampus. However, the number of dying cells or mitotic figures (cells dividing at the time of sacrifice) did not differ significantly between the two groups. By comparison, the number of 3H-thymidine-labelled cells, dying cells or mitotic figures did not significantly differ in the diencephalon. Therefore, a brief exposure to a slight elevation in temperature results in an immediate alteration in cell division in the hippocampus and amygdala. These findings have implications for the role played by raised temperature, such as during virus infection, in producing developmental anomalies of the brain.

Background and Objective: To evaluate the efficacy and safety of diclofenac 0.1% versus prednisolone acetate 1% following trabeculectomy with adjunctive mitomycin-C., Patients and Methods: The authors prospectively randomized chronic open-angle glaucoma patients who underwent trabeculectomy with adjunctive mitomycin-C to receive postoperatively either diclofenac 0.1% or prednisolone acetate 1% 4 times daily, to be tapered as inflammation resolved., Results: In the diclofenac group (n = 14), the preoperative intraocular pressure of 30.4 +/- 13.1 decreased to 12.4 +/- 6.5 mm Hg at 6 months postoperatively. In the prednisolone acetate group (n = 12), the preoperative intraocular pressure decreased from 29.1 +/- 10.4 to 12.8 +/- 4.2 mm Hg at 6 months postoperatively (P = .85). The average number of medicines used 6 months postoperatively was 0.50 +/- 0.8 in the diclofenac group and 0.24 +/- 0.6 in the prednisolone acetate group (P = .36). Adverse events were similar between groups (P = .51). One patient in the diclofenac group underwent reoperation at 1 month due to uncontrolled intraocular pressure., Conclusions: This study shows that following trabeculectomy with adjunctive mitomycin-C, a similar intraocular pressure result may be expected when either diclofenac or prednisolone acetate is prescribed postoperatively for intraocular inflammation.