Combination of waveforms in modern spinal cord stimulation

Background After the surge of burst stimulation, different waveforms were developed to optimize results in spinal cord stimulation. Studies have shown higher responder rates for multiwave therapy, but since the launch of such multiwave systems, little is known about the patients’ preference regarding waveforms in the long-term follow-up. No study connected particular waveforms to specific pain etiologies or required stimulation parameters so far. Method Thirty-four patients with refractory chronic neuropathic pain were treated with spinal cord stimulation systems providing multiwave therapy between September 2018 and October 2019. Patients with a follow-up of at least 6 months were selected; 10 subjects were excluded due to revision surgery, infection, and loss to follow-up. Data regarding pain intensity and preferred waveform for the trial, the implantation, 3-month and 6-month follow-up were recorded. Results During the trial phase, 10 patients (43.5%) achieved significant pain relief using tonic stimulation, 5 using burst (21.7%), 3 using microburst (13.0%), and 4 using a combination of tonic and microburst (17.4%). One single patient preferred Contour stimulation during the trial. After 3 months, 6 patients preferred microburst (25%), 6 preferred tonic (25%), 5 used a combination of tonic and microburst (20.8%), and 5 patients used burst (20.8%). After 6 months, similar results were obtained. Contour and Whisper were used in complex cases failing to other waveforms. Conclusions Tonic stimulation, isolated or in combination, remains an important component in spinal cord stimulation, being used by almost half of the patients. Over time, the usage of microburst increased considerably. Whisper and Contour, although battery-consuming, are good salvage options in complex cases.

Practical Closed-Loop Strategies for Deep Brain Stimulation: Lessons From Chronic Pain

Deep brain stimulation (DBS) is a plausible therapy for various neuropsychiatric disorders, though continuous tonic stimulation without regard to underlying physiology (open-loop) has had variable success. Recently available DBS devices can sense neural signals which, in turn, can be used to control stimulation in a closed-loop mode. Closed-loop DBS strategies may mitigate many drawbacks of open-loop stimulation and provide more personalized therapy. These devices contain many adjustable parameters that control how the closed-loop system operates, which need to be optimized using a combination of empirically and clinically informed decision making. We offer a practical guide for the implementation of a closed-loop DBS system, using examples from patients with chronic pain. Focusing on two research devices from Medtronic, the Activa PC+S and Summit RC+S, we provide pragmatic details on implementing closed- loop programming from a clinician’s perspective. Specifically, by combining our understanding of chronic pain with data-driven heuristics, we describe how to tune key parameters to handle feature selection, state thresholding, and stimulation artifacts. Finally, we discuss logistical and practical considerations that clinicians must be aware of when programming closed-loop devices.

Influence of Spinal Cord Stimulation on Insulin Sensitivity in Chronic Pain Patients

Background and Objective This prospective, sham-controlled, randomized, cross-over study (NCT03637075), was designed to test the hypothesis that spinal cord stimulation (SCS) for the treatment of pain can also improve glucose metabolism and insulin sensitivity when compared to sham stimulation. Methods Ten non-diabetic participants (5 females, mean age 48.8 years) who had an SCS system implanted for the treatment of chronic neuropathic pain were studied. Whilst applying a hyperinsulinemic-euglycemic clamp, sham-stimulation and tonic stimulation were performed for 45 min (n=4) or 60 min (n=6) in each case randomly. The insulin sensitivity index and pain levels were determined. A second investigation, BurstDR stimulation was also conducted and the result was compared to that of sham stimulation (cross-over design). Results The insulin sensitivity improved significantly under the tonic stimulation when compared to the sham stimulation (p=0.037). BurstDR stimulation independently did not lead to a significantly improved insulin sensitivity compared to that after sham stimulation (p=0.16). We also examined the pain during the test and found no significant difference between sham and tonic stimulation (p=0.687). Conclusion The results of this study show that tonic stimulation used for the treatment of pain could also improve glucose metabolism and insulin sensitivity. Further investigations are required to investigate the clinical relevance of the role of glucose metabolism in diabetic chronic pain participants and its underlying mechanisms.

Locus Coeruleus Activation Patterns Differentially Modulate Odor Discrimination Learning and Odor Valence in Rats

The locus coeruleus (LC) produces phasic and tonic firing patterns that are theorized to have distinct functional consequences. However, how different firing modes affect learning and valence encoding of sensory information are unknown. Here we show bilateral optogenetic activation of rat LC neurons using 10-Hz phasic trains of either 300 msec or 10 sec accelerated acquisition of a similar odor discrimination. Similar odor discrimination learning was impaired by noradrenergic blockade in the piriform cortex (PC). However, 10-Hz phasic light-mediated learning facilitation was prevented by a dopaminergic antagonist in the PC, or by ventral tegmental area (VTA) silencing with lidocaine, suggesting a LC-VTA-PC dopamine circuitry involvement. Ten hertz tonic stimulation did not alter odor discrimination acquisition, and was ineffective in activating VTA DA neurons. For valence encoding, tonic stimulation at 25 Hz induced conditioned odor aversion, while 10-Hz phasic stimulations produced an odor preference. Both conditionings were prevented by noradrenergic blockade in the basolateral amygdala (BLA). Cholera Toxin B retro-labeling showed larger engagement of nucleus accumbens-projecting neurons in the BLA with 10-Hz phasic activation, and larger engagement of central amygdala projecting cells with 25-Hz tonic light. These outcomes argue that the LC activation patterns differentially influence both target networks and behavior.

Comparison of Spinal Cord Stimulation Waveforms for Treating Chronic Low Back Pain: Systematic Review and Meta-Analysis

Background: The treatment of chronic refractory low back pain (LBP) is challenging. Conservative and pharmacologic options have demonstrated limited efficacy. Spinal cord stimulation (SCS) has been shown to be effective in reducing chronic LBP in various contexts. With emerging SCS technologies, the collective evidence of novel waveforms relative to traditional tonic stimulation for treating chronic LBP has yet to be clearly characterized. Objectives: To provide evidence for various SCS waveforms—tonic, burst, and high frequency (HF)—relative to each other for treating chronic LBP. Study Design: Systematic review and meta-analysis. Methods: PubMed, Medline, Cochrane Library, prior systematic reviews, and reference lists were screened by 2 separate authors for all randomized trials and prospective cohort studies comparing different SCS waveforms for treatment of chronic LBP. Results: We identified 11 studies that included waveform comparisons for treating chronic LBP. Of these, 6 studies compared burst versus tonic, 2 studies compared burst versus HF, and 3 studies compared tonic versus HF. A meta-analysis of 5 studies comparing burst versus tonic was conducted and revealed pooled superiority of burst over tonic in pain reduction. One study comparing burst versus tonic was excluded given technical challenges in data extraction. Limitations: Both randomized controlled trials and prospective cohort studies were included for meta-analysis. Several studies included a high risk of bias in at least one domain. Conclusions: Burst stimulation is superior to tonic stimulation for treating chronic LBP. However, superiority among other waveforms has yet to be clearly established given some heterogeneity and limitations in evidence. Given the relative novelty of burst and HF SCS waveforms, evidence of longitudinal efficacy is needed. Key words: Chronic low back pain, spinal cord stimulation, tonic, burst, high frequency

10 kHz High-Frequency Spinal Cord Stimulation for Chronic Thoracic Pain: A Multicenter Case Series and a Guide for Optimal Anatomic Lead Placement

Background: Surgical options for thoracic pain are limited and carry significant risk and morbidity. Spinal cord stimulation has the potential to be used for treatment of thoracic pain, as it has been useful for treating multiple types of chronic pain. Conventional tonic stimulation is limited in the treatment of thoracic pain, as it can produce paresthesia that is difficult to localize. Conversely, high-frequency spinal cord stimulation (HF-SCS) does not activate dorsal column Aβ fibers and does not produce paresthesia, and thus may be more beneficial in treating thoracic back pain not manageable with tonic stimulation. Objectives: To evaluate (1) the efficacy of 10 kHz HF-SCS for patients with chronic thoracic pain; and (2) appropriate paresthesia-free lead placement and programming targets for 10 kHz HF-SCS for patients with chronic thoracic pain. Study Design: Retrospective case series. Setting: Multisite academic medical center or pain clinic. Methods: A retrospective chart review was performed on 19 patients with thoracic back pain who underwent HF-SCS implantation. These patients had lead placement and stimulation between the T1-T6 vertebral levels. Outcome measures collected include location of device implant, stimulation settings, and pain scores at baseline, end of trial, and 1, 6, and 12 months postimplant. Followup phone calls collected information on if the patient reported functional improvement, improved sleep, or decreased pain medication usage. A Wilcoxon signed-rank test compared differences in mean pain scores across time points. Results: Significantly decreased Visual Analog Scale scores were observed with 17/19 (89.5%) patients demonstrating response to therapy (> 50% reduction in pain scores). These results were sustained relative to baseline at 1, 6, and 12 months postimplant, depending on length of followup. Many patients also reported functional improvement (17/19), improved sleep (14/19), and reduction in use of pain medications after implantation (9/19). A total of 15/19 patients reported best relief when contacts over T1 or T2 vertebrae were used for stimulation. Limitations: This study is limited by its retrospective design. Additionally, including documentation from multiple sites may be prone to selection and abstraction bias. Data were also not available for all patients at all time points. Conclusions: HF-SCS may be a viable option for significant, long-lasting pain relief for thoracic back pain. There may also be evidence for anatomically based lead placement and programming for thoracic back pain. Randomized, controlled trials with extended follow-up are needed to further evaluate this therapy. Key words: Thoracic pain, back pain, spinal cord stimulation, high frequency, 10 kHz

Locus coeruleus patterns differentially modulate learning and valence in rat via the ventral tegmental area and basolateral amygdala respectively

ABSTRACTThe locus coeruleus (LC), the main source of forebrain norepinephrine, produces phasic and tonic firing patterns that are theorized to have distinct functional consequences. However, how different firing modes affect learning and valence coding of sensory information are unknown. Here bilateral optogenetic activation of rat LC neurons using 10-Hz phasic trains of either 300 msec or 10 sec accelerates acquisition of a food-rewarded similar odor discrimination, but not a dissimilar odor discrimination, consistent with LC-supported enhanced pattern separation and plasticity. Similar odor discrimination learning is impaired by noradrenergic blockade in the piriform cortex (PC). However, here 10-Hz LC phasic light-mediated learning facilitation is prevented by a dopaminergic antagonist in the PC, or by ventral tegmental area (VTA) silencing with lidocaine, suggesting an LC-VTA-PC dopamine circuitry mediates 10-Hz phasic learning facilitation. Tonic stimulation at 10 Hz did not alter odor discrimination acquisition, and was less effective in activating VTA DA neurons. For valence encoding, tonic stimulation at 25 Hz induced freezing, anxiety and conditioned odor aversion, while 10-Hz phasic stimulation produced an odor preference consistent with positive valence. Noradrenergic blockade in the basolateral amygdala (BLA) prevented conditioned odor preference and aversion induced by 10-Hz phasic and 25-Hz tonic light respectively. CTB retro-labeling showed relatively larger engagement of nucleus accumbens projecting neurons over central amygdala projecting neurons in the BLA with 10-Hz LC phasic activation, compared to 25-Hz tonic. These outcomes argue that LC pauses, as well as LC firing frequencies, differentially influence both target networks and behaviour.

Fantastic Four: Age, Spinal Cord Stimulator Waveform, Pain Localization and History of Spine Surgery Influence the Odds of Successful Spinal Cord Stimulator Trial

Background: There is a dearth in our understanding of the factors that are predictive of successful spinal cord stimulator (SCS) trials and eventual conversion to permanent implants. Knowledge of these factors is important for appropriate patient selection and treatment optimization. Objectives: Although previous studies have explored factors predictive of trial success, few have examined the role of waveform in trial outcomes. This study sought to establish the relationship of neuraxial waveform and related measures to trial outcomes. Study Design: This study used a retrospective chart review design. Methods: Data were retrospectively collected on 174 patients undergoing SCS trials upon institutional review board approval of the study protocol. Indications for SCS were: complex regional pain syndrome, failed back surgery syndrome with radicular symptoms, peripheral neuropathy, and axial low back pain. Descriptive statistics and logistic regression analyses were used to assess the association of demographic and clinical variables with SCS trial outcomes. Results: The study population comprised 56% women, had a median age of 55 (interquartile range [IQR], 44-64), and 32 of 174 (18%) patients failed SCS trials. Individuals with successful trials (≥ 50% pain relief) were significantly younger and had a median age of 54 years (IQR, 42-60) compared to those who failed SCS trials (median age 66 years; IQR, 50-76; P = .005). Adjusting for age, gender, number of leads, pain category, and diagnoses: surgical history (odds ratio [OR] = 4.4; 95% confidence interval [CI], 1.3-15.8) and paresthesia-based tonic-stimulation (OR = 10.3; 95% CI, 1.7-62.0), but not burst or high frequency, were significantly associated with successful trials. Of note, the number of leads (whether dual or single), pain duration, characteristics, and category (nociceptive vs neuropathic) were not significant factors. An interaction between surgical spine history and lower extremity pain was significantly associated with a positive trial (P = .005). Limitations: This study was limited by its retrospective nature and focus on a patient population at a single major academic medical center. Conclusions: Paresthesia-based tonic stimulation, age, and surgical history have significant effects on SCS trials. Prospective and randomized controlled studies may provide deeper insights regarding impact on costs and overall outcomes. IRB Approval #: 2018P002216 Keywords: Pain duration, pain location, spinal cord stimulator trial, stimulator waveform, surgical history