Ultrahigh frequency transcutaneous electrical nerve stimulation for neuropathic pain alleviation and neuromodulation.

A challenging complication in patients with peripheral compressive neuropathy is neuropathic pain. Excessive neuroinflammation at the injury site worsens neuropathic pain and impairs function. Currently, non-invasive modulation techniques like transcutaneous electrical nerve stimulation (TENS) have shown therapeutic promise with positive results. However, the underlying regulatory molecular mechanism for pain relief remains complex and unexplored. This study aimed to validate the therapeutic effect of ultrahigh frequency (UHF)-TENS in chronic constriction injury of the rat sciatic nerve. Alleviation of mechanical allodynia was achieved through the application of UHF-TENS, lasting for 3 days after one session of therapy and 4 days after two sessions, without causing additional damage to the myelinated axon structure. The entire tissue collection schedule was divided into four time points: nerve exposure surgery, 7 days after nerve ligation, and 1 and 5 days after one session of UHF therapy. Significant reductions in pain-related neuropeptides, MEK, c-Myc, c-FOS, COX2, and substance P, were observed in the injured DRG neurons after UHF therapy. RNA sequencing of differential gene expression in sensory neurons revealed significant downregulation in Cables, Pik3r1, Vps4b, Tlr7, and Ezh2 after UHF therapy, while upregulation was observed in Nfkbie and Cln3. UHF-TENS effectively and safely relieved neuropathic pain without causing further nerve damage. The decreased production of pain-related neuropeptides within the DRG provided the therapeutic benefit. Possible molecular mechanisms behind UHF-TENS may result from the modulation of the NF-κB complex, toll-like receptor-7, and phosphoinositide 3-kinase/Akt signaling pathways. These results suggest the neuromodulatory effects of UHF-TENS in rat sciatic nerve chronic constriction injury, including alleviation of neuropathic pain, amelioration of pain-related neuropeptides, and regulation of neuroinflammatory gene expression. In combination with the regulation of related neuroinflammatory genes, UHF-TENS could become a new modality for enhancing the treatment of neuropathic pain in the future.

Novel Pulsed Ultrahigh-frequency Spinal Cord Stimulation Inhibits Mechanical Hypersensitivity and Brain Neuronal Activity in Rats after Nerve Injury.

BACKGROUND: Spinal cord stimulation (SCS) is an important pain treatment modality. This study hypothesized that a novel pulsed ultrahigh-frequency spinal cord stimulation (pUHF-SCS) could safely and effectively inhibit spared nerve injury-induced neuropathic pain in rats. METHODS: Epidural pUHF-SCS (± 3V, 2-Hz pulses comprising 500-kHz biphasic sinewaves) was implanted at the thoracic vertebrae (T9 to T11). Local field brain potentials after hind paw stimulation were recorded. Analgesia was evaluated by von Frey-evoked allodynia and acetone-induced cold allodynia. RESULTS: The mechanical withdrawal threshold of the injured paw was 0.91 ± 0.28 g lower than that of the sham surgery (24.9 ± 1.2 g). Applying 5-, 10-, or 20-min pUHF-SCS five times every 2 days significantly increased the paw withdrawal threshold to 13.3 ± 6.5, 18.5 ± 3.6, and 21.0 ± 2.8 g at 5 h post-SCS, respectively (P = 0.0002, < 0.0001, and < 0.0001; n = 6 per group) and to 6.1 ± 2.5, 8.2 ± 2.7, and 14.3 ± 5.9 g on the second day, respectively (P = 0.123, 0.013, and < 0.0001). Acetone-induced paw response numbers decreased from pre-SCS (41 ± 12) to 24 ± 12 and 28 ± 10 (P = 0.006 and 0.027; n = 9) at 1 and 5 h after three rounds of 20-min pUHF-SCS, respectively. The areas under the curve from the C component of the evoked potentials at the left primary somatosensory and anterior cingulate cortices were significantly decreased from pre-SCS (101.3 ± 58.3 and 86.9 ± 25.5, respectively) to 39.7 ± 40.3 and 36.3 ± 20.7 (P = 0.021, and 0.003; n = 5) at 60 min post-SCS, respectively. The intensity thresholds for pUHF-SCS to induce brain and sciatic nerve activations were much higher than the therapeutic intensities and thresholds of conventional low-frequency SCS. CONCLUSIONS: Pulsed ultrahigh-frequency spinal cord stimulation inhibited neuropathic pain-related behavior and paw stimulation evoked brain activation through mechanisms distinct from low-frequency SCS.

Reversible Spasticity Suppression and Locomotion Change After Pulsed Radiofrequency on the Dorsal Root Ganglia of Rats With Spinal Cord Injury.

OBJECTIVES: Radiofrequency has been used to suppress spasticity affecting motion in patients with cerebral palsy and spinal cord injury. This study tested spasticity suppression and locomotion change after pulsed radiofrequency (PRF) at the dorsal root ganglion of rats with spasticity. MATERIALS AND METHODS: Twenty-four rats that survived for 28 days after thoracic spinal cord injury and showed spasticity in the right hind limb were separated randomly to a PRF group or Sham operation group. PRF consisted of 2 Hz biphasic 25 msec trains of PRF (500 kHz, 5 V intensity) applied on the right L5 dorsal root ganglion for 300 sec. Muscle tension of the right triceps surae was measured at 450 deg/sec of passive ankle dorsiflexion on the day before and 3, 7, and 14 days after PRF or sham operation. Locomotive function was evaluated by obtaining Basso, Beattie, and Bresnahan (BBB) scores. RESULTS: Muscle tension of the triceps surae decreased significantly three days after PRF, and gradually returned to baseline 14 days later. In the sham operation group, muscle tension increased significantly more than 14 days. The BBB scores declined from 10 to 8 after PRF and returned to pre-PRF levels 14 days later, while scores remained constant after sham operation. CONCLUSIONS: PRF produced significant and reversible suppression in spasticity, but this was accompanied by deterioration in locomotive function. Thus, caution should be exercised in considering the benefits and costs in suppressing spasticity in ambulatory patients, and implanted devices that apply titratable doses of PRF may be best to optimize patients' needs.

Rapid and Delayed Effects of Pulsed Radiofrequency on Neuropathic Pain: Electrophysiological, Molecular, and Behavioral Evidence Supporting Long-Term Depression.

BACKGROUND: Pulsed radiofrequency (PRF) has been widely employed for ameliorating clinical neuropathic pain. How PRF alters electrophysiological transmission and modulates biomolecular functions in neural tissues has yet to be clarified. We previously demonstrated that an early application of low-voltage bipolar PRF adjacent to the dorsal root ganglion (DRG) reduced acute neuropathic pain in animals. By contrast, the present study investigated how PRF alters postsynaptic sensitization to produce early and delayed effects on neuropathic pain. OBJECTIVES: Our objective was to test the hypothesis that a 5-minute session of PRF could rapidly produce selective long-term depression (LTD) on C-fiber-mediated spinal sensitization and sustain the effect through the long-lasting inhibition of injury-induced ERK-MAPK activation. This may explain the prolonged analgesic effect of PRF on chronic neuropathic pain. STUDY DESIGN: Experiments were conducted on both normal rats and neuropathic pain rats that received spinal nerve ligation (SNL) 8 days prior. SETTING: An animal laboratory in a medical center of a university in Taiwan. METHODS: We first compared changes in field potentials in the L5 superficial spinal dorsal horn (SDH) that were evoked by conditioning electrical stimuli in the sciatic nerve in male adult rats before (as the baseline) and after PRF stimulation for at least 2 hours. Bipolar PRF was applied adjacent to the L5 DRG at an intensity of 5 V for 5 minutes, whereas the control rats were treated with sham applications. The electrophysiological findings were tested for any correlation with induction of spinal phospho-ERK (p-ERK) in normal and neuropathic pain rats. We then investigated the delayed effect of PRF on SNL-maintained pain behaviors for 2 weeks as well as p-ERK in SDH among the control, SNL, and PRF groups. Finally, potential injury in the DRGs after PRF stimulation was evaluated through behavioral observations and ATF-3, a neuronal stress marker. RESULTS: In the evoked field-potential study, the recordings mediated through A- and C-afferent fibers were identified as A-component and C-component, respectively. PRF significantly reduced the C-components over 2 hours in both the normal and SNL rats, but it did not affect the A-components. In the SNL rats, the C-component was significantly depressed in the PRF group compared with the sham group. PRF also inhibited acute p-ERK induced by mechanical nociception in both the control and SNL rats. For a longer period, PRF ameliorated SNL-maintained mechanical allodynia for 10 days and thermal analgesia for 14 days, and it significantly reduced late ERK activation within spinal neurons and astrocytes 14 days afterward. Moreover, PRF in the normal rats did not alter basal withdrawal thresholds or increase the expression and distribution of ATF-3 in the DRGs. LIMITATIONS: Several issues should be considered before translating the animal results to clinical applications. CONCLUSIONS: Low-voltage bipolar PRF produces LTD through selective suppression on the C-component, but not on the A-component. It also inhibits ERK activation within neurons and astrocytes in SDHs. The findings suggest that PRF alleviates long-lasting neuropathic pain by selectively and persistently modulating C-fiber-mediated spinal nociceptive hypersensitivity.Key words: Pulsed radiofrequency (PRF), dorsal root ganglion (DRG), neuropathic pain, ERK activation, evoked field potential, ATF-3, long-term depression (LTD), spinal nerve ligation (SNL).

Chaotic phase space differential algorithm for real-time detection of ventricular arrhythmias: application in animal model.

Life-threatening ventricular arrhythmias remain the main cause of death among patients with cardiovascular diseases. Efforts have been spent on early detection of such fatal cardiac signs. We have previously reported a novel chaotic phase space differential (CPSD) algorithm in discriminating VPC, VT, and VF from normal sinus rhythm with both good sensitivity and specificity. In this article, we apply this algorithm on the rat model of calcium induced ventricular tachycardia. Peaked CPSD values can be observed along with the occurrence of ventricular tachycardia. In addition, minor ECG changes such as new onset S wave or sinus arrhythmia can also be noted on CPSD tracing. We believe that the CPSD algorithm not only is capable of detecting lethal ventricular arrhythmias, but also is potentially a good tool for long-term monitoring the change of ECG signals.

A dual-mode highly efficient class-E stimulator controlled by a low-Q class-E power amplifier through duty cycle.

This paper presents the design flow of two high-efficiency class-E amplifiers for the implantable electrical stimulation system. The implantable stimulator is a high-Q class-E driver that delivers a sine-wave pulsed radiofrequency (PRF) stimulation, which was verified to have a superior efficacy in pain relief to a square wave. The proposed duty-cycle-controlled class-E PRF driver designed with a high-Q factor has two operational modes that are able to achieve 100% DC-AC conversion, and involves only one switched series inductor and an unchanged parallel capacitor. The measured output amplitude under low-voltage (LV) mode using a 22% duty cycle was 0.98 V with 91% efficiency, and under high-voltage (HV) mode using a 47% duty cycle was 2.95 V with 92% efficiency. These modes were inductively controlled by a duty-cycle detector, which can detect the duty-cycle modulated signal generated from the external complementary low-Q class-E power amplifier (PA). The design methodology of the low-Q inductive interface for a non-50% duty cycle is presented. The experimental results exhibits that the 1.5-V PA that consumes DC power of 14.21 mW was able to deliver a 2.9-V sine wave to a 500 Ω load. The optimal 60% drain efficiency of the system from the PA to the load was obtained at a 10-mm coupling distance.

In situ measurement of tissue impedance using an inductive coupling interface circuit.

In this work, a method of an inductive coupling impedance measurement (ICIM) is proposed for measuring the nerve impedance of a dorsal root ganglion (DRG) under PRF stimulation. ICIM provides a contactless interface for measuring the reflected impedance by an impedance analyzer with a low excitation voltage of 7 mV. The paper develops a calibration procedure involving a 50-Ω reference resistor to calibrate the reflected resistance for measuring resistance of the nerve in the test. A de-embedding technique to build the equivalent transformer circuit model for the ICIM circuit is also presented. A batteryless PRF stimulator with ICIM circuit demonstrated good accuracy for the acute measurement of DRG impedance both in situ and in vivo. Besides, an in vivo animal experiment was conducted to show that the effectiveness of pulsed radiofrequency (PRF) stimulation in relieving pain gradually declined as the impedance of the stimulated nerve increased. The experiment also revealed that the excitation voltage for measuring impedance below 25 mV can prevent the excitation of a nonlinear response of DRG.

A comparison between pulsed radiofrequency and electro-acupuncture for relieving pain in patients with chronic low back pain.

Many treatment options for chronic low back pain are available, including varied forms of electric stimulation. But little is known about the electricity effect between electro-acupuncture and pulsed radiofrequency. The objective of this study is to assess the difference in effectiveness of pain relief between pulsed radiofrequency and electro-acupuncture. Visual analog score (VAS) pain score, the Oswestry disability index (ODI) to measure a patient's permanent functional disability, and Short form 36 (SF-36) which is a survey used in health assessment to determine the cost-effectiveness of a health treatment, were used as rating systems to measure the pain relief and functional improvement effect of pulsed radiofrequency and electro-acupuncture, based on the methodological quality of the randomized controlled trials, the relevance between the study groups, and the consistency of the outcome evaluation. First, the baseline status before therapy shows no age and gender influence in the SF-36 and VAS score but it is significant in the ODI questionnaire. From ANOVA analyses, it is apparent that radiofrequency therapy is a significant improvement over electro-acupuncture therapy after one month. But electro-acupuncture also showed functional improvement in the lumbar spine from the ODI. This study provides sufficient evidence of the superiority of pulsed radiofrequency (PRF) therapy for low back pain relief compared with both electro-acupuncture (EA) therapy and the control group. But the functional improvement of the lumbar spine was proved under EA therapy only. Both therapies are related to electricity effects.