Comparing the Memory Effects of 50-Hz Low-Frequency and 10-kHz High-Frequency Thoracic Spinal Cord Stimulation on Spinal Neural Network in a Myocardial Infarction Porcine Model.

OBJECTIVE: This study evaluated the effects of cessation of both conventional low-frequency (50 Hz) and high-frequency (10 kHz) spinal cord stimulation (SCS) on the cardiospinal neural network activity in pigs with myocardial infarction (MI). The objective is to provide an insight into the memory effect of SCS. MATERIALS AND METHODS: In nine Yorkshire pigs, chronic MI was created by delivering microspheres to the left circumflex coronary artery. Five weeks after MI, anesthetized pigs underwent sternotomy to expose the heart for performing acute ischemia intervention, and laminectomy to expose the T1-T4 spinal regions for extracellular in vivo neural recording and SCS. Cardiac ischemic-sensitive neurons were identified by selective responsiveness to left anterior descending (LAD) coronary artery occlusion. SCS episodes were delivered in a random order between low- (50 Hz) and high- (10 kHz) frequency, for 1 minute, at 90% of the motor threshold current. Neural firing and synchrony of ischemic-sensitive spinal neurons were evaluated before vs after SCS. RESULTS: Using a 64-channel microelectrode array, 2711 spinal neurons were recorded extracellularly. LAD ischemia excited 228 neurons that were labeled as ischemic-responsive neurons. The cessation of 50-Hz SCS caused a higher activation than did inhibition of ischemic-responsive neurons (41 activated vs 19 inhibited), whereas the cessation of 10-kHz SCS caused an opposite response with higher inhibition (11 activated vs 28 inhibited, p < 0.01 vs 50 Hz). Termination of low-frequency SCS caused an increase in ischemic-responsive neuronal firing rate compared with high-frequency SCS (50 Hz: 0.39 Hz ± 0.16 Hz, 10 kHz: -0.11 Hz ± 0.057 Hz, p < 0.01). In addition, SCS delivered at 50 Hz increased the number of synchronized pairs of neurons by 205 pairs, whereas high-frequency SCS decreased the number of synchronized pairs by 345 pairs (p < 0.01). CONCLUSIONS: High-frequency (10 kHz) stimulation provides persistent suppression of the ischemia-sensitive neurons after termination of SCS. In contrast, the spinal neural network reverted to excitatory state after termination of low-frequency (50 Hz) stimulation.

Effect of high-frequency stimulation on the complexity of low-Mg2+-induced epileptiform discharge rhythm waves in the CA3 region of rat hippocampal slices.

High-frequency stimulation (HFS) is a crucial therapeutic approach for neurodegenerative conditions, such as epilepsy. However, its underlying mechanism of inhibition remains unclear. In this study, a rat model of epileptiform discharges (EDs) was constructed by perfusing brain slices with magnesium-free artificial cerebrospinal fluid (aCSF), where after HFS was used to stimulate the CA3 area of the hippocampus. The EDs signals of each sub-region of hippocampal slices before and after HFS were recorded based on a multi-electrode Array (MEA). Secondly, the changes of approximate entropy (ApEn) complexity of rhythms in different regions of hippocampal slices before and after HFS were deeply analyzed The results showed that different rhythm characteristics of EDs signals exhibited significant differences before and after HFS. Here HFS significantly inhibited the delta rhythm of field potential and enhanced the beta rhythm. Finally, the changing rhythm of the EDs signal in the propagation path before and after HFS was analyzed, and it was found that the inhibitory target of HFS on EDs signal was in the CA3b sub-region. The rhythm would gradually decline with the propagation of EDs signal in the hippocampal neural pathway. This study shows that HFS can modulate the local field potential, thus inhibiting the pathological rhythm caused by epilepsy, which provides a novel research incentive for HFS to inhibit EDs.

Comparison of clinical outcomes associated with spinal cord stimulation (SCS) or conventional medical management (CMM) for chronic pain: a systematic review and meta-analysis.

OBJECTIVE: This study aims to evaluate the efficacy and safety of spinal cord stimulation (SCS) compared to conventional medical management (CMM) for patients diagnosed with chronic pain. Furthermore, the study seeks to compare the utilization of analgesics, as well as the long-term outcomes in terms of quality of life and functional capacity. DATA SOURCES: We systematically searched Cochrane Library, Web of Science, PubMed, and EMBASE for randomized controlled trials from inception up to February 2022. REVIEW METHODS: Inclusion and exclusion criteria were set according to the PICOS criteria. We searched for studies in which SCS was compared with CMM alone for chronic pain. Two reviewers independently identified eligible studies and extracted data. Risk of bias assessments were performed according to Cochrane review criteria and Interventional Pain Management Techniques-quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) criteria. RESULTS: The present meta-analysis comprised eight studies and included a total of 893 patients. Our findings demonstrate that spinal cord stimulation (SCS) in combination with conventional medical management (CMM) is associated with a significant reduction in visual analogue scale (VAS) pain intensity (P = 0.0005) and decreased scores on the McGill Pain Questionnaire (MPQ) (P < 0.0001). Moreover, SCS plus CMM was found to improve patients' quality of life, as evidenced by improvements in SF-36 scores (P < 0.00001), EQ-5D utility index (P = 0.008), and Oswestry Disability Index (ODI) (P < 0.00001). Based on the results of four high-quality randomized controlled trials (RCTs), the level of evidence supporting the efficacy of SCS for the treatment of painful neuropathy is graded as level I to II. In contrast, there is currently only low-level evidence to support the use of high-frequency stimulation and other chronic pain conditions, which can be attributed to a lack of sufficient randomized controlled trials. LIMITATIONS: The principal limitation of our study is the significant heterogeneity observed among the cohorts investigated. The primary source of this heterogeneity is the fact that spinal cord stimulation is indicated for the treatment of multiple chronic pain conditions. Moreover, variations in the stimulation parameters, differences among manufacturers, and the specific surgical implantation settings contribute to the increased heterogeneity observed in our analyses. To address this issue, we conducted a subgroup analysis based on specific situations and performed evidence synthesis to mitigate the potential impact of heterogeneity. These approaches allow for a more precise interpretation of the results and a more accurate evaluation of the quality of the included studies. CONCLUSIONS: SCS is an effective treatment to relieve the pain level of chronic pain, decrease analgesic usage, and increase long-term quality of life and functional capacity.

Behavior and electrophysiological effects on striatum-nigra circuit after high frequency stimulation. Relevance to Parkinson and epilepsy.

The phenomenon of plasticity in the striatum, and its relation with the striatum-nigra neuronal circuit has clinical and neurophysiological relevance to Parkinson and epilepsy. High frequency stimulation (HFS) can induce neural plasticity. Furthermore, it is possible to induce plasticity in the dorsal striatum and this can be modulated by substantia nigra activity. But it has not been shown yet what would be the effects in the striatum-nigra circuit after plasticity induction in striatum with HSF. Literature also misses a detailed description of the way back loop of the circuit: the striatal firing rate after substantia nigrás inhibition. We here conducted: First Experiment, application of HFS in dorsomedial striatum and measure of spontaneous and longlasting behavior expression in the open field three days later; Second, application of single pulses on dorsomedial striatum and measure of the evoked potentials in substantia nigra before and after HFS; Third Experiment: inhibition of substantia nigra and recording of the firing rate of dorsomedial striatum. HFS in dorsomedial striatum caused increased locomotion behaviors, but not classical stereotypy. However, rats had either an increase or decrease in substantia nigrás evoked potentials. Also, substantia nigrás inhibition caused an increase in dorsomedial striatum firing rate. Present data are suggestive of a potential application of HFS in striatum, as an attempt to modulate behavior rigidity and hypokinesia of diseases involving the basal ganglia, especially Parkinson´s Disease.

Effects of 10-kHz Subthreshold Stimulation on Human Peripheral Nerve Activation.

OBJECTIVE: The mechanisms of action of high-frequency stimulation (HFS) are unknown. We investigated the possible mechanism of subthreshold superexcitability of HFS on the excitability of the peripheral nerve. MATERIALS AND METHODS: The ulnar nerve was stimulated at the wrist in six healthy participants with a single (control) stimulus, and the responses were compared with the responses to a continuous train of 5 seconds at frequencies of 500 Hz, 2.5 kHz, 5 kHz, and 10 kHz. Threshold intensity for compound muscle action potential (CMAP) was defined as intensity producing a 100-µV amplitude in ten sequential trials and "subthreshold" as 10% below the CMAP threshold. HFS threshold was defined as stimulation intensity eliciting visible tetanic contraction. RESULTS: Comparing the threshold of single pulse stimulation for eliciting CMAP vs threshold for HFS response and pooling data at different frequencies (500 Hz-10 kHz) revealed a significant difference (p = 0.00015). This difference was most obvious at 10 kHz, with a mean value for threshold reduction of 42.2%. CONCLUSIONS: HFS with a stimulation intensity below the threshold for a single pulse induces axonal superexcitability if applied in a train. It can activate the peripheral nerve and produce a tetanic muscle response. Subthreshold superexcitability may allow new insights into the mechanism of HFS.

Ganglionated Plexus Ablation Procedures to Treat Vasovagal Syncope.

Vasovagal syncope (VVS) refers to a heterogeneous group of conditions whereby the cardiovascular reflexes normally controlling the circulation are interrupted irregularly in response to a trigger, resulting in vasodilation, bradycardia, or both. VVS affects one-third of the population at least once in their lifetime or by the age of 60, reduces the quality of life, and may cause disability affecting certain routines. It poses a considerable economic burden on society, and, despite its prevalence, there is currently no proven pharmacological treatment for preventing VVS. The novel procedure of ganglionated plexus (GP) ablation has emerged rapidly in the past two decades, and has been proven successful in treating syncope. Several parameters influence the success rate of GP ablation, including specific ablation sites, localization and surgical techniques, method of access, and the integration of other interventions. This review aims to provide an overview of the existing literature on the physiological aspects and clinical effectiveness of GP ablation in the treatment of VVS. Specifically, we explore the association between GPs and VVS and examine the impact of GP ablation procedures as reported in human clinical trials. Our objective is to shed light on the therapeutic significance of GP ablation in eliminating VVS and restoring normal sinus rhythm, particularly among young adults affected by this condition.

High and Low-Frequency Stimulation Effect on Epileptiform Activity in Brain Slices.

Background: Neurostimulation is one of the new therapeutic approaches in patients with drug-resistant epilepsy, and despite its high efficiency, its mechanism of action is still unclear. On the one hand, electrical stimulation in the human brain is immoral; on the other hand, the creation of the epilepsy model in laboratory animals affects the entire brain network. As a result, one of the ways to achieve the neurostimulation mechanism is to use epileptiform activity models In vitro. In vitro models, by accessing the local network from the whole brain, we can understand the mechanisms of action of neurostimulation. Methods: A literature search using scientific databases including PubMed, Google Scholar, and Scopus, using "Neurostimulation" and "epileptiform activity" combined with "high-frequency stimulation", " low-frequency stimulation ", and "brain slices" as keywords were conducted, related concepts to the topic gathered and are used in this paper. Results: Electrical stimulation causes neuronal depolarization and the release of GABAA, which inhibits neuronal firing. Also, electrical stimulation inhibits the nervous tissue downstream of the stimulation site by preventing the passage of nervous activity from the upstream to the downstream of the axon. Conclusion: Neurostimulation techniques consisting of LFS and HFS have a potential role in treating epileptiform activity, with some studies having positive results. Further investigations with larger sample sizes and standardized outcome measures can be conducted to validate the results of previous studies.

Sensory tetanisation to induce long-term-potentiation-like plasticity: A review and reassessment of the approach.

There is great interest in developing non-invasive approaches for studying cortical plasticity in humans. High-frequency presentation of auditory and visual stimuli, or sensory tetanisation, can induce long-term-potentiation-like (LTP-like) changes in cortical activity. However, contrasting effects across studies suggest that sensory tetanisation may be unreliable. We review these contrasting effects, conduct our own study of auditory and visual tetanisation, and perform meta-analyses to determine the average effect of sensory tetanisation across studies. We measured auditory-evoked amplitude changes in a group of younger (18-29 years of age) and older (55-83 years of age) adults following tetanisation to 1 and 4 kHz tone bursts and following a slow-presentation control. We also measured visual-evoked amplitude changes following tetanisation to horizontal and vertical sign gradients. Auditory and visual response amplitudes decreased following tetanisation, consistent with some studies but contrasting with others finding amplitude increases (i.e. LTP-like changes). Older adults exhibited more modest auditory-evoked amplitude decreases, but visual-evoked amplitude decreases like those of younger adults. Changes in response amplitude were not specific to tetanised stimuli. Importantly, slow presentation of auditory tone bursts produced response amplitude changes approximating those observed following tetanisation in younger adults. Meta-analyses of visual and auditory tetanisation studies found that the overall effect of sensory tetanisation was not significant across studies or study sites. The results suggest that sensory tetanisation may not produce reliable changes in cortical responses and more work is needed to determine the validity of sensory tetanisation as a method for inducing human cortical plasticity in vivo.

Pulse Dosing of 10-kHz Paresthesia-Independent Spinal Cord Stimulation Provides the Same Efficacy with Substantial Reduction of Device Recharge Time.

OBJECTIVE: This study was designed to assess whether using pulse dosing (PD) (regularly cycled intermittent stimulation) of high-frequency 10-kHz spinal cord stimulation (10-kHz SCS) can reduce device recharge time while maintaining efficacy in patients with chronic intractable back pain with or without leg pain. DESIGN: Prospective, multicenter, observational study. METHODS: Patients successfully using 10-kHz SCS at 100%ON (i.e., continuously with no PD) for >3 months were consecutively enrolled. After a 1-week baseline period of documenting their pain twice daily on a 0-10 numerical rating scale (NRS) using 100%ON of their "favorite" program, all subjects were reprogrammed to 14%PD for 10-14 days. If subjects preferred 14%PD to 100%ON, they were programmed to 3%PD; otherwise, they were programmed to 50%PD. Subjects used this next program for another 10-14 days. Subjects then entered a 3-month observational period during which they were requested to use but not limited to their most preferred %PD program. Toward the end of 3 months, subjects completed a 7-day NRS diary and indicated a final %PD program preference. Study endpoints included %PD preference, mean diary NRS by %PD, and daily minutes and patterns of charging. RESULTS: Of 31 subjects completing the study, 81% preferred less than 100%ON. Among the subjects, 39% preferred 3%PD, 32% preferred 14%PD, 10% preferred 50%PD, and 19% preferred 100%ON. Average daily charge durations were 8.3 ± 3.1 minutes for 3%PD, 13.9 ± 4.9 minutes for 14%PD, 26.2 ± 7.4 minutes for 50%PD, and 43.8 ± 10.9 minutes for 100%ON. Regression modeling suggested that pain relief was weighted as more than twice as influential as charging in preference for reduced %PD. CONCLUSIONS: This prospective study suggests that 10-kHz SCS therapy with PD may be successfully used in a large majority of 10-kHz SCS responders, maintaining efficacy while reducing device charging time by nearly two thirds.

Orientation-selective and directional deep brain stimulation in swine assessed by functional MRI at 3T.

Functional MRI (fMRI) has become an important tool for probing network-level effects of deep brain stimulation (DBS). Previous DBS-fMRI studies have shown that electrical stimulation of the ventrolateral (VL) thalamus can modulate sensorimotor cortices in a frequency and amplitude dependent manner. Here, we investigated, using a swine animal model, how the direction and orientation of the electric field, induced by VL-thalamus DBS, affects activity in the sensorimotor cortex. Adult swine underwent implantation of a novel 16-electrode (4 rows x 4 columns) directional DBS lead in the VL thalamus. A within-subject design was used to compare fMRI responses for (1) directional stimulation consisting of monopolar stimulation in four radial directions around the DBS lead, and (2) orientation-selective stimulation where an electric field dipole was rotated 0°-360° around a quadrangle of electrodes. Functional responses were quantified in the premotor, primary motor, and somatosensory cortices. High frequency electrical stimulation through leads implanted in the VL thalamus induced directional tuning in cortical response patterns to varying degrees depending on DBS lead position. Orientation-selective stimulation showed maximal functional response when the electric field was oriented approximately parallel to the DBS lead, which is consistent with known axonal orientations of the cortico-thalamocortical pathway. These results demonstrate that directional and orientation-selective stimulation paradigms in the VL thalamus can tune network-level modulation patterns in the sensorimotor cortex, which may have translational utility in improving functional outcomes of DBS therapy.

High-frequency electrical stimulation of cutaneous nociceptors differentially affects pain perception elicited by homotopic and heterotopic electrical stimuli.

Animal studies have shown that high-frequency electrical stimulation (HFS) of peripheral C-fiber nociceptors induces both homosynaptic and heterosynaptic long-term potentiation (LTP) within spinal nociceptive pathways. In humans, when HFS is applied onto the skin to activate nociceptors, single electrical stimuli are perceived more intense at the HFS site compared with a control site, a finding that was interpreted as a perceptual correlate of homosynaptic LTP. The present study aimed to investigate if after HFS the pain elicited by electrical stimuli delivered at the skin next to the HFS site is perceived as more intense compared with the pain at a control site (contralateral arm). To test this, HFS was applied to one of the two ventral forearms of 24 healthy participants. Before and after HFS, single electrical stimuli were delivered through the HFS electrode, through an identical electrode next to the HFS electrode and an identical electrode at the contralateral arm. After HFS, the pain elicited by the single electrical stimuli was reduced at all three sites, with the largest reduction at the HFS site. Nevertheless, electrical stimuli delivered to the skin next to the HFS site were perceived as more intense than control stimuli. This result indicates that higher pain ratings to electrical stimuli after HFS at the HFS site cannot solely be interpreted as a perceptual correlate of homosynaptic changes. Furthermore, we show for the first time, in humans, that HFS can reduce pain elicited by single electrical stimuli delivered through the same electrode.NEW & NOTEWORTHY High-frequency electrical stimulation (HFS) of cutaneous nociceptors can reduce pain perception to single electrical stimuli delivered through the same electrode. Moreover, single electrical stimuli delivered to the skin next to the site at which HFS was applied are perceived as more intense compared with that at the contralateral control site, indicating the presence of heterosynaptic effects for electrical stimuli.

Deep brain stimulation by optimized stimulators in a phenotypic model of dystonia: Effects of different frequencies.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi, entopeduncular nucleus, EPN, in rodents) has become important for the treatment of generalized dystonia, a severe and often intractable movement disorder. It is unclear if lower frequencies of GPi-DBS or stimulations of the subthalamic nucleus (STN) are of advantage. In the present study, the main objective was to examined the effects of bilateral EPN-DBS at different frequencies (130 Hz, 40 Hz, 15 Hz) on the severity of dystonia in the dtsz mutant hamster. In addition, STN stimulations were done at a frequency, proven to be effective by the present EPN-DBS in dystonic hamsters. In order to obtain precise bilateral electrical stimuli with magnitude of 50 µA, a pulse width of 60 µs and defined frequencies, it was necessary to develop a new optimized stimulator prior to the experiments. Since the individual highest severity of dystonic episodes is known to be reached within three hours after induction in dtsz hamsters, the duration of DBS was 180 min. During DBS with 130 Hz the severity of dystonia was significantly lower within the third hour than without DBS in the same animals (p < 0.05). DBS with 40 Hz tended to exert antidystonic effects after three hours, while 15 Hz stimulations of the EPN and 130 Hz stimulations of the STN failed to show any effects on the severity. DBS of the EPN at 130 Hz was most effective against generalized dystonia in the dtsz mutant. The response to EPN-DBS confirms that the dtsz mutant is suitable to further investigate the effects of long-term DBS on severity of dystonia and neuronal network activities, important to give insights into the mechanisms of DBS.

Different effects of monophasic pulses and biphasic pulses applied by a bipolar stimulation electrode in the rat hippocampal CA1 region.

BACKGROUND: Electrical pulse stimulations have been applied in brain for treating certain diseases such as movement disorders. High-frequency stimulations (HFS) of biphasic pulses have been used in clinic stimulations, such as deep brain stimulation (DBS), to minimize the risk of tissue damages caused by the electrical stimulations. However, HFS sequences of monophasic pulses have often been used in animal experiments for studying neuronal responses to the stimulations. It is not clear yet what the differences of the neuronal responses to the HFS of monophasic pulses from the HFS of biphasic pulses are. METHODS: To investigate the neuronal responses to the two types of pulses, orthodromic-HFS (O-HFS) and antidromic-HFS (A-HFS) of biphasic and monophasic pulses (1-min) were delivered by bipolar electrodes, respectively, to the Schaffer collaterals (i.e., afferent fibers) and the alveus fibers (i.e., efferent fibers) of the rat hippocampal CA1 region in vivo. Evoked population spikes of CA1 pyramidal neurons to the HFSs were recorded in the CA1 region. In addition, single pulses of antidromic- and orthodromic-test stimuli were applied before and after HFSs to evaluate the baseline and the recovery of neuronal activity, respectively. RESULTS: Spreading depression (SD) appeared during sequences of 200-Hz monophasic O-HFS with a high incidence (4/5), but did not appear during corresponding 200-Hz biphasic O-HFS (0/6). A preceding burst of population spikes appeared before the SD waveforms. Then, the SD propagated slowly, silenced neuronal firing temporarily and resulted in partial recovery of orthodromically evoked population spikes (OPS) after the end of O-HFS. No SD events appeared during the O-HFS with a lower frequency of 100 Hz of monophasic or biphasic pulses (0/5 and 0/6, respectively), neither during the A-HFS of 200-Hz pulses (0/9). The antidromically evoked population spikes (APS) after 200-Hz biphasic A-HFS recovered to baseline level within ~ 2 min. However, the APS only recovered partially after the 200-Hz A-HFS of monophasic pulses. CONCLUSIONS: The O-HFS with a higher frequency of monophasic pulses can induce the abnormal neuron activity of SD and the A-HFS of monophasic pulses can cause a persisting attenuation of neuronal excitability, indicating neuronal damages caused by monophasic stimulations in brain tissues. The results provide guidance for proper stimulation protocols in clinic and animal experiments.

Long-Term Efficacy of a Novel Spinal Cord Stimulation Clinical Workflow Using Kilohertz Stimulation: Twelve-Month Results From the Vectors Study.

BACKGROUND AND OBJECTIVES: Multiple variables play a role in spinal cord stimulation (SCS) treatment outcomes, including patient anatomy, pain pattern, lead location, stimulation parameters, and so on. A wide range of stimulation parameters are considered safe and on-label, and as a result a growing number of new frequencies and frequency-combinations are being incorporated into standard practice. A standardized approach to therapy delivery may provide more consistent outcomes for more patients. The Vectors study evaluated whether there is significant sustained improvement in pain and functional outcomes when therapy is delivered using a standardized approach. MATERIALS AND METHODS: Vectors, a post-market, single-arm study evaluated the safety and efficacy of SCS with an implantable neurostimulator starting with 1 kHz stimulation, targeting the T9-T10 disc space following paresthesia mapping. Subjects with chronic intractable low back and leg pain (visual analogue scale [VAS] ≥ 50 mm) were enrolled. The primary endpoint was change in overall pain (VAS) at the three-month visit compared to baseline. Subjects were followed through 12 months. Secondary endpoints included changes in low back and leg pain, quality of life (European Quality of Life - Five Dimensions, EQ-5D-5L), disability (Oswestry Disability Index, ODI), individual subject goals, and subject satisfaction. RESULTS: There was a significant reduction in overall pain (VAS; 45.4 mm) through the three-month visit, which was sustained through 12 months. At 12 months, 79% of subjects had ≥50% improvement in at least one pain domain (overall, lowback or leg) with 85% of subjects reporting therapy satisfaction. There was a decrease in disability and an improvement in quality of life with 70% of subjects achieving a personal activity goal by the three-month visit. CONCLUSIONS: Long-term pain relief and improvement in quality of life and function were achieved when following a standardized workflow. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03345472.

1.2 kHz High-Frequency Stimulation as a Rescue Therapy in Patients With Chronic Pain Refractory to Conventional Spinal Cord Stimulation.

OBJECTIVES: We aimed to investigate the efficacy of new subperception stimulation paradigms including 1.2 kHz-high-frequency stimulation (HFS) and advanced-HFS field-shaping algorithm (dorsal horn HFS [DHHFS]) in refractory cases which initially benefited from conventional spinal cord stimulation (SCS) and lost the effect throughout time. MATERIALS AND METHODS: In the context of a rescue-therapy, patients underwent externalization of the implanted SCS-leads and were tested with multiple combinations of new SCS paradigms. Pain intensity was analyzed using the numeric rating scale (NRS), and data were collected preoperatively and at multiple postoperative follow-ups. RESULTS: Thirty-seven patients underwent externalization of the leads. Mean preoperative NRS-score was 8.1/10 points (SD ± 0.9) for the ON-stimulation period. Patients received a combination of either tonic, burst and 1.2 kHz-HFS, or burst and 1.2 kHz-HFS, DHHFS, or 1.2 kHz-HFS and DHHFS, or 1.2 kHz-HFS alone. The mean postoperative NRS-score after the testing-phase was 3.8/10 points (SD ± 2.5), showing a 48.0% mean reduction (p < 0.001). In total, 29 patients reported a significant reduction above 50% in NRS-scores and therefore were reimplanted with new generators that could deliver the new paradigms. Eight patients underwent full SCS-system explantation. The patients who continued with the new paradigms (n = 29) reported mean NRS-scores of 3.5/10 points (SD ± 1.7) 12 months postoperatively, still showing a significant reduction of 43.3% when compared to preoperative scores (p < 0.001). CONCLUSION: Rescue-therapy with combination of multiple waveforms, including tonic, burst, 1.2 kHz-HFS, and DHHFS, was associated with a significant pain relief in patients with failed conventional SCS. This approach is a safe and efficient and should be considered before explantation of the SCS-system.

Connectivity and Dynamics Underlying Synaptic Control of the Subthalamic Nucleus.

Adaptive motor control critically depends on the interconnected nuclei of the basal ganglia in the CNS. A pivotal element of the basal ganglia is the subthalamic nucleus (STN), which serves as a therapeutic target for deep brain stimulation (DBS) in movement disorders, such as Parkinson's disease. The functional connectivity of the STN at the microcircuit level, however, still requires rigorous investigation. Here we combine multiple simultaneous whole-cell recordings with extracellular stimulation and post hoc neuroanatomical analysis to investigate intrinsic and afferent connectivity and synaptic properties of the STN in acute brain slices obtained from rats of both sexes. Our data reveal an absence of intrinsic connectivity and an afferent innervation with low divergence, suggesting that STN neurons operate as independent processing elements driven by upstream structures. Hence, synchrony in the STN, a hallmark of motor processing, exclusively depends on the interactions and dynamics of GABAergic and glutamatergic afferents. Importantly, these inputs are subject to differential short-term depression when stimulated at high, DBS-like frequencies, shifting the balance of excitation and inhibition toward inhibition. Thus, we present a mechanism for fast yet transient decoupling of the STN from synchronizing afferent control. Together, our study provides new insights into the microcircuit organization of the STN by identifying its neurons as parallel processing units and thus sets new constraints for future computational models of the basal ganglia. The observed differential short-term plasticity of afferent inputs further offers a basis to better understand and optimize DBS algorithms.SIGNIFICANCE STATEMENT The subthalamic nucleus (STN) is a pivotal element of the basal ganglia and serves as target for deep brain stimulation, but information on the functional connectivity of its neurons is limited. To investigate the STN microcircuitry, we combined multiple simultaneous patch-clamp recordings and neuroanatomical analysis. Our results provide new insights into the synaptic organization of the STN identifying its neurons as parallel processing units and thus set new constraints for future computational models of the basal ganglia. We further find that synaptic dynamics of afferent inputs result in a rapid yet transient decoupling of the STN when stimulated at high frequencies. These results offer a better understanding of deep brain stimulation mechanisms, promoting the development of optimized algorithms.

Unraveling the Role of Astrocytes in Subthalamic Nucleus Deep Brain Stimulation in a Parkinson's Disease Rat Model.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for motor symptoms of Parkinson's disease (PD) when L-DOPA therapy induces disabling side effects. Classical inflammatory activation of glial cells is well established in PD, contributing to the progressive neurodegenerative state; however, the role of DBS in regulating the inflammatory response remains largely unknown. To understand the involvement of astrocytes in the mechanisms of action of DBS, we evaluated the effect of STN-DBS in regulating motor symptoms, astrocyte reactivity, and cytokine expression in a 6-OHDA-induced PD rat model. To mimic in vivo DBS, we investigate the effect of high-frequency stimulation (HFS) in cultured astrocytes regulating cytokine induction and NF-κB activation. We found that STN-DBS improved motor impairment, induced astrocytic hyperplasia, and reversed increased IFN-γ and IL-10 levels in the globus pallidus (GP) of lesioned rats. Moreover, HFS activated astrocytes and prevented TNF-α-induced increase of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in vitro. Our results indicate that DBS/HFS may act as a regulator of the inflammatory response in PD states, attenuating classical activation of astrocytes and cytokine induction, potentially through its ability to regulate NF-κB activation. These findings may help us understand the role of astrocyte signaling in HFS, highlighting its possible relationship with the effectiveness of DBS in neurodegenerative disorders.

Fiber Threshold Accommodation as a Mechanism of Burst and High-Frequency Spinal Cord Stimulation.

OBJECTIVES: Burst and high-frequency spinal cord stimulation (SCS), in contrast to low-frequency stimulation (LFS, < 200 Hz), reduce neuropathic pain without the side effect of paresthesia, yet it is unknown whether these methods' mechanisms of action (MoA) overlap. We used empirically based computational models of fiber threshold accommodation to examine the three MoA. MATERIALS AND METHODS: Waveforms used in SCS are composed of cathodic, anodic, and rest phases. Empirical studies of human peripheral sensory nerve fibers show different accommodation effects occurring in each phase. Notably, larger diameter fibers accommodate more than smaller fibers. We augmented our computational axon model to replicate fiber threshold accommodation behavior for diameters from 5 to 15 µm in each phase. We used the model to predict threshold change in variations of burst, high frequency, and LFS. RESULTS: The accommodation model showed that 1) inversion of larger and smaller diameter fiber thresholds produce a therapeutic window in which smaller fibers fire while larger ones do not and 2) the anodic pulses increase accommodation and perpetuate threshold inversion from burst to burst and between cathodic pulses in burst, high frequency, and variations, resulting in an amplitude "window" in which larger fibers are inactivated while smaller fibers fire. No threshold inversion was found for traditional LFS. CONCLUSIONS: The model, based on empirical data, predicts that, at clinical amplitudes, burst and high-frequency SCS do not activate large-diameter fibers that produce paresthesia while driving medium-diameter fibers, likely different from LFS, which produce analgesia via different populations of dorsal horn neural circuits.

Reaction of the Heart to High Frequency Stimulation against the Background of Acute Doxorubicin Treatment.

Short-term high frequency electrostimulation (8-10 Hz) of the isolated isovolumic rat heart rapidly increased the rate of pressure rise and drop and the diastolic pressure. At the same time, the relaxation rate constant (RRC), being independent of the developed pressure, remained unaltered. These findings suggested that diastolic pressure rise was not caused by incomplete myocardial relaxation. Doxorubicin (3 µM) moderately reduced the developed pressure, but the relaxation rate constant remained unchanged. The dynamics and degree of changes in all indicators of the cardiac contractile function in high-frequency stimulation were the same as in control. It can be hypothesized that the initial effect of doxorubicin was not related to ionic transport system disturbances in cardiomyocytes.

Heterosynaptic facilitation of mechanical nociceptive input is dependent on the frequency of conditioning stimulation.

High-frequency burstlike electrical conditioning stimulation (HFS) applied to human skin induces an increase in mechanical pinprick sensitivity of the surrounding unconditioned skin (a phenomenon known as secondary hyperalgesia). The present study assessed the effect of frequency of conditioning stimulation on the development of this increased pinprick sensitivity in humans. In a first experiment, we compared the increase in pinprick sensitivity induced by HFS, using monophasic non-charge-compensated pulses and biphasic charge-compensated pulses. High-frequency stimulation, traditionally delivered with non-charge-compensated square-wave pulses, may induce a cumulative depolarization of primary afferents and/or changes in pH at the electrode-tissue interface due to the accumulation of a net residue charge after each pulse. Both could contribute to the development of the increased pinprick sensitivity in a frequency-dependent fashion. We found no significant difference in the increase in pinprick sensitivity between HFS delivered with charge-compensated and non-charge-compensated pulses, indicating that the possible contribution of charge accumulation when non-charge-compensated pulses are used is negligible. In a second experiment, we assessed the effect of different frequencies of conditioning stimulation (5, 20, 42, and 100 Hz) using charge-compensated pulses on the development of increased pinprick sensitivity. The maximal increase in pinprick sensitivity was observed at intermediate frequencies of stimulation (20 and 42 Hz). It is hypothesized that the stronger increase in pinprick sensitivity at intermediate frequencies may be related to the stronger release of substance P and/or neurokinin-1 receptor activation expressed at lamina I neurons after C-fiber stimulation.NEW & NOTEWORTHY Burstlike electrical conditioning stimulation applied to human skin induces an increase in pinprick sensitivity in the surrounding unconditioned skin (a phenomenon referred to as secondary hyperalgesia). Here we show that the development of the increase in pinprick sensitivity is dependent on the frequency of the burstlike electrical conditioning stimulation.