Selective neural inhibition via photobiomodulation alleviates behavioral hypersensitivity associated with small sensory fiber activation.

OBJECTIVE: Photobiomodulation at higher irradiances has great potential as a pain-alleviating method that selectively inhibits small diameter nerve fibers and corresponding sensory experiences, such as nociception and heat sensation. The longevity and magnitude of these effects as a function of laser irradiation parameters at the nerve was explored. METHODS: In a rodent chronic pain model (spared nerve injury-SNI), light was applied directly at the sural nerve with four delivery schemes: two irradiance levels (7.64 and 2.55 W/cm2 ) for two durations each, corresponding to either 4.8 or 14.4 J total energy, and the effect on sensory hypersensitivities was evaluated. RESULTS: At emitter irradiances of 7.64 W/cm2 (for 240 s), 2.55 W/cm2 (for 720 s), and 7.64 W/cm2 (for 80 s) the heat hypersensitivity was relieved the day following photobiomodulation (PBM) treatment by 37 ± 8.1% (statistically significant, p < 0.001), 26% ± 6% (p = 0.072), and 28 ± 6.1% (statistically significant, p = 0.032), respectively, and all three treatments reduced the hypersensitivity over the course of the experiment (13 days) at a statistically significant level (mixed-design analysis of variance, p < 0.05). The increases in tissue temperature (5.3 ± 1.0 and 1.3 ± 0.4°C from 33.3°C for the higher and lower power densities, respectively) at the neural target were well below those typically associated with permanent action potential disruption. CONCLUSIONS: The data from this study support the use of direct PBM on nerves of interest to reduce sensitivities associated with small-diameter fiber activity.

Selective Infrared Neural Inhibition Can Be Reproduced by Resistive Heating.

OBJECTIVES: Small-diameter afferent axons carry various sensory signals that are critical for vital physiological conditions but sometimes contribute to pathologies. Infrared (IR) neural inhibition (INI) can induce selective heat block of small-diameter axons, which holds potential for translational applications such as pain management. Previous research suggested that IR-heating-induced acceleration of voltage-gated potassium channel kinetics is the mechanism for INI. Therefore, we hypothesized that other heating methods, such as resistive heating (RH) in a cuff, could reproduce the selective inhibition observed in INI. MATERIALS AND METHODS: We conducted ex vivo nerve-heating experiments on pleural-abdominal connective nerves of Aplysia californica using both IR and RH. We fabricated a transparent silicone nerve cuff for simultaneous IR heating, RH, and temperature measurements. Temperature elevations (ΔT) on the nerve surface were recorded for both heating modalities, which were tested over a range of power levels that cover a similar ΔT range. We recorded electrically evoked compound action potentials (CAPs) and segmented them into fast and slow subcomponents on the basis of conduction velocity differences between the large and small-diameter axonal subpopulations. We calculated the normalized inhibition strength and inhibition selectivity index on the basis of the rectified area under the curve of each subpopulation. RESULTS: INI and RH showed a similar selective inhibition effect on CAP subcomponents for slow-conducting axons, confirmed by the inhibition probability vs ΔT dose-response curve based on approximately 2000 CAP measurements. The inhibition selectivity indexes of the two heating modalities were similar across six nerves. RH only required half the total electrical power required by INI to achieve a similar ΔT. SIGNIFICANCE: We show that selective INI can be reproduced by other heating modalities such as RH. RH, because of its high energy efficiency and simple design, can be a good candidate for future implantable neural interface designs.

Exploratory evaluation of spinal cord stimulation with dynamic pulse patterns: a promising approach to improve stimulation sensation, coverage of pain areas, and expected pain relief.

Background: The societal burden of chronic pain and the contribution-in-part to the opioid crisis, is a strong motivation to improve and expand non-addictive treatments, including spinal cord stimulation (SCS). For several decades standard SCS has consisted in delivery of tonic pulses with static parameter settings in frequency, pulse width, and amplitude. These static parameters have limited ability to personalize the quality of paresthesia, the dermatomal coverage, and thus may affect SCS efficacy. Further, static settings may contribute to the build-up of tolerance or loss of efficacy of the therapy over time in some patients. Methods: We conducted an acute exploratory study to evaluate the effects of SCS using time-dynamic pulses as compared to time-static (conventional tonic) stimulation pulses, with the hypotheses that dynamic pulse SCS may enable beneficial tailoring of the sensation and the patient's expectation for better pain relief with SCS. During a single clinic visit, consented subjects undergoing a standard SCS trial had their implanted leads temporarily connected to an investigational external stimulator capable of delivering time-static and six categories of time-dynamic pulse sequences, each characterized by continuously varying a stimulation parameter. Study subjects provided several assessments while blinded to the stimulation pattern, including: drawing of paresthesia maps, descriptions of sensation, and ratings for comfort and helpfulness to pain relief. Results: Even without optimization of the field location, a majority of subjects rated sensations from dynamic stimulation as better or equal to that of static stimulation for comfortableness and for helpfulness to pain relief. The initial data showed a gender and/or pain dermatomal location related preference to a stimulation pattern. In particular, female subjects and subjects with pain at higher dermatomes tended to rank the sensation from dynamic stimulation better. Dynamic stimulation produced greater pain coverage without optimization; in 70% (9/13) of subjects, maximal pain coverage was achieved with a dynamic stimulation pattern. There was also greater variety in the words used by patients to describe stimulation sensation in the free text and free form verbal descriptions associated with dynamic stimulation. Conclusions: With the same electrode configuration and comparable parameter settings, acute SCS using dynamic pulses produced more positive ratings, expanded paresthesia coverage, and greater variation in sensation as compared to SCS using static pulses, suggesting that dynamic stimulation has the potential to improve capabilities of SCS for the treatment of chronic pain. Further study is warranted. Trial Registration: This study was registered at ClinicalTrials.gov under ID NCT02988713, November 2016 (URL: https://clinicaltrials.gov/ct2/show/NCT02988713).

A novel fast-acting sub-perception spinal cord stimulation therapy enables rapid onset of analgesia in patients with chronic pain.

Background: Treating chronic pain using sub-perception Spinal Cord Stimulation (SCS) does not elicit paresthesia but is associated with long analgesic 'wash-in' (i.e. duration until maximum pain relief) and prolonged assessment of therapy. We describe the attainment of clinically meaningful and rapid-onset analgesic outcomes using a novel sub-perception SCS approach.Methods: This observational case-series evaluated patients implanted with an SCS device for chronic pain, who underwent re-programming utilizing a new methodology in which paresthesia was used to guide sub-perception stimulation field targeting at specific parameters including charge-balanced symmetrical pulses at 90 Hz (termed Fast-Acting Sub-Perception Therapy, FAST). Pain scores (NRS) were collected as reported per standard-of-care from patient charts.Results: Mean overall pain score at baseline was 8.4 ± 0.2 (n = 41). After activation of FAST, a 7.1-point reduction in overall pain score was (1.3 ± 0.2, p < 0.0001) reported within 11.2 ± 1.9 minutes (n = 34). This decrease in pain score was sustained out to 3-month (1.6 ± 0.3, n = 26) and 6-month follow-up (1.7 ± 0.4, n = 18). At last follow up (mean = 223 ± 132 days), a pain score of 1.6 ± 0.3, n = 30 was determined.Conclusions: After FAST implementation, a profound analgesic response, requiring substantially less energy than conventional sub-perception methodologies, was observed. This rapid analgesic onset achieved with the novel FAST technique suggests the potential for an alternative mechanism of action(s) of sub-perception SCS.

Assessment of axonal recruitment using model-guided preclinical spinal cord stimulation in the ex vivo adult mouse spinal cord.

Spinal cord stimulation (SCS) is used clinically to limit chronic pain, but fundamental questions remain on the identity of axonal populations recruited. We developed an ex vivo adult mouse spinal cord preparation to assess recruitment following delivery of clinically analogous stimuli determined by downscaling a finite element model of clinical SCS. Analogous electric field distributions were generated with 300-µm × 300-µm electrodes positioned 200 µm above the dorsal column (DC) with stimulation between 50 and 200 µA. We compared axonal recruitment using electrodes of comparable size and stimulus amplitudes when contacting the caudal thoracic DC and at 200 or 600 µm above. Antidromic responses recorded distally from the DC, the adjacent Lissauer tract (LT), and in dorsal roots (DRs) were found to be amplitude and site dependent. Responses in the DC included a unique component not seen in DRs, having the lowest SCS recruitment amplitude and fastest conduction velocity. At 200 µm above, mean cathodic SCS recruitment threshold for axons in DRs and LT were 2.6 and 4.4 times higher, respectively, than DC threshold. SCS recruited primary afferents in all (up to 8) caudal segments sampled. Whereas A and C fibers could be recruited at nearby segments, only A fiber recruitment and synaptically mediated dorsal root reflexes were observed in more distant (lumbar) segments. In sum, clinically analogous SCS led to multisegmental recruitment of several somatosensory-encoding axonal populations. Most striking is the possibility that the lowest threshold recruitment of a nonprimary afferent population in the DC are postsynaptic dorsal column tract cells (PSDCs) projecting to gracile nuclei.NEW & NOTEWORTHY Spinal cord stimulation (SCS) is used clinically to control pain. To identify axonal populations recruited, finite element modeling identified scaling parameters to deliver clinically analogous SCS in an ex vivo adult mouse spinal cord preparation. Results showed that SCS first recruited an axonal population in the dorsal column at a threshold severalfold lower than primary afferents. These putative postsynaptic dorsal column tract cells may represent a previously unconsidered population responsible for SCS-induced paresthesias necessary for analgesia.

Dependence of c-fos Expression on Amplitude of High-Frequency Spinal Cord Stimulation in a Rodent Model.

OBJECTIVES: Clinical high-frequency spinal cord stimulation (hfSCS) (>250 Hz) applied at subperception amplitudes reduces leg and low back pain. This study investigates, via labeling for c-fos-a marker of neural activation, whether 500 Hz hfSCS applied at amplitudes above and below the dorsal column (DC) compound action potential (CAP) threshold excites dorsal horn neurons. MATERIALS AND METHODS: DC CAP thresholds in rats were determined by applying single biphasic pulses of SCS to T12 -T13 segments using pulse widths of 40 or 200 µsec via a ball electrode placed over the left DC and increasing amplitude until a short latency CAP was observed on the L5 DC and sciatic nerve. The result of this comparison allowed us to substitute sciatic nerve CAP for DC CAP. SCS at T12 -T13 was applied continuously for two hours using: sham or hfSCS at 500 Hz SCS, 40 µsec pulse width, and 50, 70, 90, or 140% CAP threshold. Spinal cord slices from T11 -L1 were immunolabeled for c-fos, and the number of c-fos-positive cells was quantified. RESULTS: 500 Hz hfSCS applied at 90 and 140% CAP threshold produced substantial (≥6 c-fos + neurons on average per slice per segment) c-fos expression in more segments between T11 and L1 than did sham stimulation (p < 0.025, 90% CAP; p < 0.001, 140% CAP, Fisher's Exact Tests) and resulted in more c-fos-positive neurons on average per slice per segment ipsilateral to than contralateral to the SCS electrode at 70, 90, and 140% CAP threshold (p < 0.01, Wilcoxon Signed Rank Tests). CONCLUSIONS: The finding of enhanced c-fos expression in the ipsilateral superficial dorsal horn provides evidence for activation/modulation of neuronal circuitry associated with subperception hfSCS.

Effects of Rate on Analgesia in Kilohertz Frequency Spinal Cord Stimulation: Results of the PROCO Randomized Controlled Trial.

OBJECTIVE: The PROCO RCT is a multicenter, double-blind, crossover, randomized controlled trial (RCT) that investigated the effects of rate on analgesia in kilohertz frequency (1-10 kHz) spinal cord stimulation (SCS). MATERIALS AND METHODS: Patients were implanted with SCS systems and underwent an eight-week search to identify the best location ("sweet spot") of stimulation at 10 kHz within the searched region (T8-T11). An electronic diary (e-diary) prompted patients for pain scores three times per day. Patients who responded to 10 kHz per e-diary numeric rating scale (ED-NRS) pain scores proceeded to double-blind rate randomization. Patients received 1, 4, 7, and 10 kHz SCS at the same sweet spot found for 10 kHz in randomized order (four weeks at each frequency). For each frequency, pulse width and amplitude were titrated to optimize therapy. RESULTS: All frequencies provided equivalent pain relief as measured by ED-NRS (p ≤ 0.002). However, mean charge per second differed across frequencies, with 1 kHz SCS requiring 60-70% less charge than higher frequencies (p ≤ 0.0002). CONCLUSIONS: The PROCO RCT provides Level I evidence for equivalent pain relief from 1 to 10 kHz with appropriate titration of pulse width and amplitude. 1 kHz required significantly less charge than higher frequencies.

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

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

Theoretical analysis of intracortical microelectrode recordings.

Advanced fabrication techniques have now made it possible to produce microelectrode arrays for recording the electrical activity of a large number of neurons in the intact brain for both clinical and basic science applications. However, the long-term recording performance desired for these applications is hindered by a number of factors that lead to device failure or a poor signal-to-noise ratio (SNR). The goal of this study was to identify factors that can affect recording quality using theoretical analysis of intracortical microelectrode recordings of single-unit activity. Extracellular microelectrode recordings were simulated with a detailed multi-compartment cable model of a pyramidal neuron coupled to a finite-element volume conductor head model containing an implanted recording microelectrode. Recording noise sources were also incorporated into the overall modeling infrastructure. The analyses of this study would be very difficult to perform experimentally; however, our model-based approach enabled a systematic investigation of the effects of a large number of variables on recording quality. Our results demonstrate that recording amplitude and noise are relatively independent of microelectrode size, but instead are primarily affected by the selected recording bandwidth, impedance of the electrode-tissue interface and the density and firing rates of neurons surrounding the recording electrode. This study provides the theoretical groundwork that allows for the design of the microelectrode and recording electronics such that the SNR is maximized. Such advances could help enable the long-term functionality required for chronic neural recording applications.

Students learn systems-based care and facilitate system change as stakeholders in a free clinic experience.

Systems-based practice (SBP) is rarely taught or evaluated during medical school, yet is one of the required competencies once students enter residency. We believe Texas A&M College of Medicine students learn about systems issues informally, as they care for patients at a free clinic in Temple, TX. The mandatory free clinic rotation is part of the Internal Medicine clerkship and does not include formal instruction in SBP. During 2008-2009, a sample of students (n = 31) on the IMED clerkship's free clinic rotation participated in a program evaluation/study regarding their experiences. Focus groups (M = 5 students/group) were held at the end of each outpatient rotation. Students were asked: "Are you aware of any system issues which can affect either the delivery of or access to care at the free clinic?" Data saturation was reached after six focus groups, when investigators noted a repetition of responses. Based upon investigator consensus opinion, data collection was discontinued. Based upon a content analysis, six themes were identified: access to specialists, including OB-GYN, was limited; cost containment; lack of resources affects delivery of care; delays in care due to lack of insurance; understanding of larger healthcare system and free clinic role; and delays in tests due to language barriers. Medical students were able to learn about SBP issues during free clinic rotations. Students experienced how SBP issues affected the health care of uninsured individuals. We believe these findings may be transferable to medical schools with mandatory free clinic rotations.

Viral clostridial light chain gene-based control of penicillin-induced neocortical seizures.

Restraining excitatory neurotransmission within a seizure focus provides a nondestructive treatment strategy for intractable neocortical epilepsy. Clostridial toxin light chain (LC) inhibits synaptic transmission by digesting a critical vesicle-docking protein, synaptobrevin, without directly altering neuronal health. This study tests the treatment efficacy of adenoviral vector delivered LC (AdLC) on a model of seizures in rats induced by motor cortex penicillin (PCN) injection. LC expression significantly reduced electroencephalogram (EEG) frequency, amplitude, duration, and latency compared to control groups injected with either an adenoviral vector bearing green fluorescent protein (AdGFP) or phosphate buffered solution (PBS). Correspondingly, LC gene expression improved behavioral manifestations including seizure severity and latency. There was no statistical difference in motor function before and after vector administration between treatment and control groups. Histological analysis revealed spatially discrete LC expression with corresponding synaptobrevin depletion in the cortex surrounding the injection site. Thus, vector-mediated LC gene delivery is capable of improving both the EEG and behavioral manifestations of PCN-induced focal neocortical seizures through synaptobrevin depletion.

Optimization of microelectrode design for cortical recording based on thermal noise considerations.

Intracortical microelectrode recordings of neural activity show great promise as control signals for neuroprosthetic applications. However, faithful, consistent recording of single unit spiking activity with chronically implanted silicon-substrate microelectrode arrays has proven difficult. Many approaches seek to enhance the long-term performance of microelectrode arrays by, for example, increasing electrode biocompatibility, decreasing electrode impedance, or improving electrode interface properties through application of small voltage pulses. The purpose of this study was to use computational models to optimize the design of microelectrodes. We coupled detailed models of the neural source signal, silicon-substrate microelectrodes, and thermal noise to define the electrode contact size that maximized the signal-to-noise ratio (SNR). Model analysis combined a multi-compartment cable model of a layer V cortical pyramidal neuron with a 3D finite element model of the head and microelectrode to define the amplitude and time course of the recorded signal. A spatially-lumped impedance model was parameterized with in vitro and in vivo spectroscopy data and used to define thermal noise as a function of electrode contact size. Our results suggest that intracortical microelectrodes with a contact size of ~380 microm2 will provide an increased SNR in vivo and improve the long-term recording capabilities of silicon-substrate microelectrode arrays.

Model-based analysis of cortical recording with silicon microelectrodes.

OBJECTIVE: The purpose of this study was to use computational modeling to better understand factors that impact neural recordings with silicon microelectrodes used in brain-machine interfaces. METHODS: A non-linear cable model of a layer V pyramidal cell was coupled with a finite-element electric field model with explicit representation of the microelectrode. The model system enabled analysis of extracellular neural recordings as a function of the electrode contact size, neuron position, edema, and chronic encapsulation. RESULTS: The model predicted spike waveforms and amplitudes that were consistent with experimental recordings. Small (< 1000 microm2) and large (10 k microm2) electrode contacts had similar volumes of recording sensitivity, but small contacts exhibited higher signal amplitudes (approximately 50%) when neurons were in close proximity (50 microm) to the electrode. The model results support the notion that acute edema causes a signal decrease ( approximately 24%), and certain encapsulation conditions can result in a signal increase (approximately 17%), a mechanism that may contribute to signal increases observed experimentally in chronic recordings. CONCLUSIONS: Optimal electrode design is application-dependent. Small and large contact sizes have contrasting recording properties that can be exploited in the design process. In addition, the presence of local electrical inhomogeneities (encapsulation, edema, coatings) around the electrode shank can substantially influence neural recordings and requires further theoretical and experimental investigation. SIGNIFICANCE: Thought-controlled devices using cortical command signals have exciting therapeutic potential for persons with neurological deficit. The results of this study provide the foundation for refining and optimizing microelectrode design for human brain-machine interfaces.

Functional magnetic resonance imaging of the human lumbar spinal cord.

PURPOSE: To determine whether consistent regions of activity could be observed in the lumbar spinal cord of single subjects with spin-echo functional MRI (fMRI) if several repeated experiments were performed within a single imaging session. MATERIALS AND METHODS: Repeated fMRI experiments of the human lumbar spinal cord were performed at 1.5 T with a single-shot spin-echo technique (half-Fourier single-shot turbo spin-echo (HASTE)) as used by previous investigators, and a modified method (fluid-attenuated inversion recovery (FLAIR)-HASTE) that nulled the otherwise highly variable signal from the cerebrospinal fluid (CSF). RESULTS: FLAIR-HASTE reduced the variability of the signal in the CSF region to background levels, and presumably reduced associated artifacts in the spinal cord. Consistent areas of activation in the spinal cord in response to a thermal stimulus just below the knee were not observed across the fMRI experiments with either method. CONCLUSION: FLAIR-HASTE was useful for removing artifact in the spinal cord signal induced by variability in the CSF signal. However, with the techniques used in this study, we were not able to confirm the presence of a consistent fMRI response in the lumbar spinal cord because of the signal enhancement by extravascular protons (SEEP) effect during thermal stimulation of the hindlimb.

Prediction of myelinated nerve fiber stimulation thresholds: limitations of linear models.

Computer models of neurons are used to simulate neural behavior, and are important tools for designing neural prostheses. Computation time remains an issue when simulating large numbers of neurons or applying models to real time applications. Warman et al. developed a method to predict excitation thresholds for axons using linear models and a predetermined critical voltage. We calculated threshold prediction error as a function of the location of an extracellular electrode using two different axon models to examine further threshold prediction using linear models. Threshold prediction error was low (<3% error) under the conditions examined by Warman et al., but under more general conditions, threshold prediction error was as high as 23.6%. Linear models were limited as effective tools for single fiber threshold prediction because accuracy was dependent on the nonlinear and linear models used, and any parameter that affected the extracellular potential distribution. Threshold prediction could be improved by appropriately choosing the membrane conductance of the linear model, but determination of an optimal conductance was computationally expensive. Finally, although single fiber threshold prediction error was partially masked when considering the input-output (I/O) properties of populations of axons, relatively large errors still occurred in population I/O curves generated with linear models.

Electrical localization of neural activity in the dorsal horn of the spinal cord: a modeling study.

Intraspinal microstimulation is a means of eliciting coordinated motor responses for restoration of function. However, detailed maps of the neuroanatomy of the human spinal cord are lacking, and it is not clear where electrodes should be implanted. We developed an electrical approach to localize active neurons in the spinal cord using potentials recorded from the surface of the spinal cord. We evaluated this localization method using an analytical model of the spinal cord and two previously developed inverse algorithms (standardized low resolution brain electromagnetic tomography (sLORETA) and a locally optimal source (LOS) method). The results support electrical source localization as a feasible imaging approach for localizing (within 300 microm) active neurons in the spinal cord. The LOS method could localize the source when 16 recording electrodes were placed on the dorsolateral aspect of the cord and the noise level was 2%. When recording electrodes were positioned around the entire circumference of the spinal cord, either localization method could localize the source, even at 15% noise. Finally, localization error was not sensitive to inaccuracies in the expected electrode positions or the electrical parameters of the forward model, but was sensitive to a geometrical modification of the forward model in one case.

Negociación del desarrollo sanitario

Este libro se ha organizado alrededor de dos conjuntos de ideas. El primer conjunto de ideas desglosa un proceso característico de desarrollo sanitario en cuatro componentes. Encontramos que es útil examinar el proceso de desarrollo sanitario de esta manera, en lugar de tratarlo como un todo. El segundo conjunto de ideas describe cuatro prácticas generalizadas de negociación que a menudo son útiles en el contexto de las negociaciones de desarrollo sanitario. En el contexto de cada uno de los componentes del proceso, se examinó estas prácticas de negociación y se tratará de ilustrar su aplicación. Los cuatro componentes son: Preparación para la adopción de decisiones; Adopción de decisiones sabias; Creación de las condiciones para la ejecución; Ejecución basada en los resultados y las lecciones aprendidas. (Au)