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Abstract Accumulation of α-synuclein (α-Syn) has been implicated in proteasome and autophagy dysfunction in Parkinson’s disease (PD). High frequency electrical stimulation (HFS) mimicking clinical parameters used for deep brain stimulation (DBS) in vitro or DBS in vivo in preclinical models of PD have been found to reduce levels of α-Syn and, in certain cases, provide possible neuroprotection. However, the mechanisms by which this reduction in α-Syn improves cellular dysfunction associated with α-Syn accumulation remains elusive. Using HFS parameters that recapitulate DBS in vitro, we found that HFS led to a reduction of mutant α-Syn and thereby limited proteasome and autophagy impairments due to α-Syn. Additionally, we observed that HFS modulates via the ATP6V0C subunit of V-ATPase and mitigates α-Syn mediated autophagic dysfunction. This study highlights a role for autophagy in reduction of α-Syn due to HFS which may prove to be a viable approach to decrease pathological protein accumulation in neurodegeneration.

Background: Deep brain stimulation (DBS) has been widely used to manage debilitating neurological symptoms in movement disorders such as Parkinson's disease (PD). Despite its well-established symptomatic benefits, our understanding of the mechanisms underlying DBS and its possible effect on the accumulation of pathological proteins in neurodegeneration remains limited. Accumulation and oligomerization of the protein alpha-synuclein (α-Syn) are implicated in the loss of dopaminergic neurons in the substantia nigra in PD, making α-Syn a potential therapeutic target for disease modification. Objective: We examined the effects of high frequency electrical stimulation on α-Syn levels and oligomerization in cell and rodent models. Methods: High frequency stimulation, mimicking DBS parameters used for PD, was combined with viral-mediated overexpression of α-Syn in cultured rat primary cortical neurons or in substantia nigra of rats. Bimolecular protein complementation with split fluorescent protein reporters was used to detect and quantify α-Syn oligomers. Results: High frequency electrical stimulation reduced the expression of PD-associated mutant α-Syn and mitigated α-Syn oligomerization in cultured neurons. Furthermore, DBS in the substantia nigra, but not the subthalamic nucleus, decreased overall levels of α-Syn, including oligomer levels, in the substantia nigra. Conclusions: Taken together, our results demonstrate that direct high frequency stimulation can reduce accumulation and pathological forms of α-Syn in cultured neurons in vitro and in substantia nigra in vivo. Thus, DBS therapy could have a role beyond symptomatic treatment, with potential disease-modifying properties that can be exploited to target pathological proteins in neurodegenerative diseases.

Deep brain stimulation (DBS) has been widely used to manage debilitating neurological symptoms in movement disorders such as Parkinson's disease (PD). Despite its well-established symptomatic benefits, our understanding of the mechanisms underlying DBS and its possible effect on the accumulation of pathological proteins in neurodegeneration remains limited. Accumulation and oligomerization of the protein alpha-synuclein ( α -Syn) are implicated in the loss of dopaminergic neurons in the substantia nigra in PD, making α -Syn a potential therapeutic target for disease modification. We examined the effects of high frequency electrical stimulation on α -Syn levels and oligomerization in cell and rodent models. High frequency stimulation, mimicking DBS parameters used for PD, was combined with viral-mediated overexpression of α -Syn in cultured rat primary cortical neurons or in substantia nigra of rats. Bimolecular protein complementation with split fluorescent protein reporters was used to detect and quantify α -Syn oligomers. High frequency electrical stimulation reduced the expression of PD-associated mutant α -Syn and mitigated α -Syn oligomerization in cultured neurons. Furthermore, DBS in the substantia nigra, but not the subthalamic nucleus, decreased overall levels of α -Syn, including oligomer levels, in the substantia nigra. Taken together, our results demonstrate that direct high frequency stimulation can reduce accumulation and pathological forms of α -Syn in cultured neurons in vitro and in substantia nigra in vivo. Thus, DBS therapy could have a role beyond symptomatic treatment, with potential disease-modifying properties that can be exploited to target pathological proteins in neurodegenerative diseases. • High frequency stimulation reduces α -synuclein accumulation in cultured neurons. • Deep brain stimulation of the substantia nigra reduces α -synuclein accumulation in rats. • Deep brain stimulation could have a role beyond symptomatic treatment, with potential disease-modifying properties. One sentence summary: Electrical stimulation reduces α -synuclein accumulation in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Coupled neural network models are playing an increasingly important part in the modulation of absence seizures today. However, it is currently unclear how basal ganglia, corticothalamic network and pedunculopontine nucleus can coordinate with each other to develop a whole coupling circuit, theoretically. In addition, it is still difficult to select effective parameters of electrical stimulation on the regulation of absence seizures in clinical trials. Therefore, to develop a coupled model and reduce computation cost, a new model constructed by a simplified basal ganglion, two corticothalamic circuits and a pedunculopontine nucleus was proposed. Further, to seek better inhibition therapy, three electrical stimulations, high frequency stimulation (HFS), 1:0 coordinate reset stimulation (CRS) and 3:2 CRS, were applied to the thalamic reticular nucleus (RE) in the first corticothalamic circuit in the coupled model. The simulation results revealed that increasing the frequency and pulse width of an electrical stimulation within a certain range can also suppress seizures. Under the same parameters of electrical stimulation, the inhibitory effect of HFS on seizures was better than that of 1:0 CRS and 3:2 CRS. The research established a reduced corticothalamic-basal ganglion-pedunculopontine nucleus model, which lays a theoretical foundation for future optimal parameters selection of electrical stimulation. We hope that the findings will provide new insights into the role of theoretical models in absence seizures.

Abstract Background The purpose of this study was to evaluate if kilohertz frequency alternating current (KHFAC) stimulation of peripheral nerve could serve as a treatment for lumbar radiculopathy. Prior work shows that KHFAC stimulation can treat sciatica resulting from chronic sciatic nerve constriction. Here, we evaluate if KHFAC stimulation is also beneficial in a more physiologic model of low back pain which mimics nucleus pulposus (NP) impingement of a lumbar dorsal root ganglion (DRG). Methods To mimic a lumbar radiculopathy, autologous tail NP was harvested and placed upon the right L5 nerve root and DRG. During the same surgery, a cuff electrode was implanted around the sciatic nerve with wires routed to a headcap for delivery of KHFAC stimulation. Male Lewis rats (3 mo., n = 18) were separated into 3 groups: NP injury + KHFAC stimulation (n = 7), NP injury + sham cuff (n = 6), and sham injury + sham cuff (n = 5). Prior to surgery and for 2 weeks following surgery, animal tactile sensitivity, gait, and static weight bearing were evaluated. Results KHFAC stimulation of the sciatic nerve decreased behavioral evidence of pain and disability. Without KHFAC stimulation, injured animals had heightened tactile sensitivity compared to baseline (p

Background: The purpose of this study was to evaluate if kilohertz frequency alternating current (KHFAC) stimulation of peripheral nerve could serve as a treatment for lumbar radiculopathy. Prior work shows that KHFAC stimulation can treat sciatica resulting from chronic sciatic nerve constriction. Here, we evaluate if KHFAC stimulation is also beneficial in a more physiologic model of low back pain which mimics nucleus pulposus (NP) impingement of a lumbar dorsal root ganglion (DRG). Methods: To mimic a lumbar radiculopathy, autologous tail NP was harvested and placed upon the right L5 nerve root and DRG. During the same surgery, a cuff electrode was implanted around the sciatic nerve with wires routed to a headcap for delivery of KHFAC stimulation. Male Lewis rats (3 mo., n = 18) were separated into 3 groups: NP injury + KHFAC stimulation (n = 7), NP injury + sham cuff (n = 6), and sham injury + sham cuff (n = 5). Prior to surgery and for 2 weeks following surgery, animal tactile sensitivity, gait, and static weight bearing were evaluated. Results: KHFAC stimulation of the sciatic nerve decreased behavioral evidence of pain and disability. Without KHFAC stimulation, injured animals had heightened tactile sensitivity compared to baseline (p < 0.05), with tactile allodynia reversed during KHFAC stimulation (p < 0.01). Midfoot flexion during locomotion was decreased after injury but improved with KHFAC stimulation (p < 0.05). Animals also placed more weight on their injured limb when KHFAC stimulation was applied (p < 0.05). Electrophysiology measurements at end point showed decreased, but not blocked, compound nerve action potentials with KHFAC stimulation (p < 0.05). Conclusions: KHFAC stimulation decreases hypersensitivity but does not cause additional gait compensations. This supports the idea that KHFAC stimulation applied to a peripheral nerve may be able to treat chronic pain resulting from sciatic nerve root inflammation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D 2 R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D 2 R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals. The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus. Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP. Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation. Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation. These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D 2 Rs in the regulation of limbic information flow. • The intra-VP D 2 R agonist quinpirole induces LTP on the NAC shell-VP synapses. • Intra-VP quinpirole inhibits VP LFP response and LTP evoked by BLA stimulation. • Quinpirole increases the amplitude of the gamma frequency band in the VP LFP. • BLA tonically suppresses the NAC's HFS-induced gamma facilitation. • BLA plays a prominent role in the generation of the delta oscillations. [ABSTRACT FROM AUTHOR]

Abstract Nerve conduction block is an appealing way to selective target the nervous system for treating pathological conditions. Several modalities were described in the past, with the kilohertz frequency stimulation generating an enormous interest and tested successfully in clinical settings. Some shortcomings associated with different modalities of nerve blocking can limit its clinical use, as the “onset response”, the high demand of energy supply, among others. A recent study by Muzquiz and colleagues describes the efficacy and reversibility of low frequency alternating currents in blocking the cervical vagus in the pig, in the absence of an onset effect and apparent lack of neuronal damage.

Deep brain stimulation is an emerging treatment for brain disorders. However, the mechanisms of high-frequency brain stimulation are unclear. Recent studies have suggested that high-frequency stimulation might produce therapeutic effects by eliminating pathological rhythms in neuronal firing. To test the hypothesis, the present study investigated whether stimulation of axonal afferent fibers might alter firing rhythms of downstream neurons in in-vivo experiments with Sprague-Dawley rats. Stimulation trains of 100 Hz with one minute duration were applied to the Schaffer collaterals of hippocampus Area CA1 in anaesthetized rats. Spikes of single interneurons and pyramidal neurons in the downstream region were analyzed. The spike rhythms before, during, and after the stimulations were evaluated by analyzing the power spectrum density of autocorrelograms of the spiking sequences. The rhythms of local field potentials were also evaluated by power spectrum density. During baseline recordings, theta rhythms were obvious in the spiking sequences of both types of neuron and in the local field potentials of the stratum radiatum. However, these theta rhythms were all suppressed significantly during the stimulations. Additionally, the results of Pearson's correlation analysis showed that 20-30% variation in the theta rhythms of neuronal firing could be explained by changes of the theta rhythms in local field potentials. High-frequency axonal stimulation might prevent the original rhythmic excitation in afferent fibers and generate new excitation by stimulation pulses per se, thereby suppressing the theta rhythms of individual neuron firing and of local field potentials in the region downstream from stimulation. The results provide new evidence to support the hypothesis that high-frequency stimulation can alter the firing rhythms of neurons, which may underlie the therapeutic effects of deep brain stimulation.

Background: High frequency stimulation (HFS) may provide pain relief without the paresthesias typical of traditional low-frequency Spinal cord stimulation (SCS). Methods: A consecutive single-center series of patients was retrospectively reviewed to evaluate safety and efficacy of HF10 therapy. In this 24-month study, 62 patients with variables pathologies (44 patients with back failure surgery syndrome (FBSS), 18 patients with chronic peripheral neuropathic pain in the lower limbs (NeppL) were included to be treated with HF10. Pain outcomes were compared from preoperative baseline and at the conclusion of each study period. Clinical features, outcomes and complications were reviewed. Results: 62 patients completed this study. All patients had a successful trial before the definitive implantation of a spinal cord stimulator at the low dorsal level. The mean follow-up period was 11 months, ranging from 6 to 24 months. 6 patients showed no change from baseline visual analogue scale (VAS) after permanent implant and 2 had improved during the trial but was aggravated after the permanent implant placement. At 1 month, 63% of implanted HF10 therapy subjects were responders and 77% at 6 months. The average baseline, trial and postoperative Visual Analogue Scale (VAS) was 8.1, 3.6 and 4.2 respectively. When compared to the baseline, the average reduction achieved during the VAS trial was 4.5 points, accounting for a 56% pain reduction. The long-term failure rate was 22%. Conclusions: This study generated preliminary evidence showing improved VAS current pain scores in absence of paresthesias and increase patient satisfaction with HF10 spinal cord stimulation.

Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) is a promising therapy for treatment-resistant depression. Pre-clinical models have been widely used to investigate the neural mechanisms underlying its antidepressant benefit. The ventral division of the medial prefrontal cortex (vmPFC), particularly the infralimbic cortex (IL), is the homologous region in rat and DBS applied to vmPFC shows antidepressant-like effects in the forced swim test. Therefore we investigated the cellular mechanisms of simulated DBS (sDBS) in layer 5 IL neurons, using in vitro whole-cell patch clamp recordings. sDBS in IL layer 5 induced a prolonged after-depolarization (ADP) in both pyramidal and fast spiking neurons, which was dependent on current amplitude and pulse width. In contrast, sDBS applied in the forebrain white matter fibers, although delivered at a higher intensity, failed to induce any persistent depolarization in layer 5 IL pyramidal neurons. Cholinergic blockade (atropine, 2.0 µM) decreased both the ADP amplitude and duration in pyramidal neurons, but left those in fast spiking neurons unchanged. These data suggest that: (i) sDBS in IL gray and white matter produced different cellular effects on pyramidal neurons; (ii) sDBS-induced ADP in pyramidal, but not fast spiking neurons, was mediated by acetylcholine; and (iii) different neuromodulators may contribute to sDBS-induced ADP in IL. In summary, cholinergic mediated ADP in pyramidal neurons may contribute to the antidepressant effects of DBS in IL. [ABSTRACT FROM AUTHOR]

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.

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

In recent years, electroceuticals have been spotlighted as an emerging treatment for various severe chronic brain diseases, owing to their intrinsic advantage of electrical interaction with the brain, which is the most electrically active organ. However, the majority of research has verified only the short-term efficacy through acute studies in laboratory tests owing to the lack of a reliable miniaturized platform for long-term animal studies. The construction of a sufficient integrated system for such a platform is extremely difficult because it requires multi-disciplinary work using state-of-the-art technologies in a wide range of fields. In this study, we propose a complete system of an implantable platform for long-term preclinical brain studies. Our proposed system, the extra-cranial brain activator (ECBA), consists of a titanium-packaged implantable module and a helmet-type base station that powers the module wirelessly. The ECBA can also be controlled by a remote handheld device. Using the ECBA, we performed a long-term non-anesthetic study with multiple canine subjects, and the resulting PET-CT scans demonstrated remarkable enhancement in brain activity relating to memory and sensory skills. Furthermore, the histological analysis and high-temperature aging test confirmed the reliability of the system for up to 31 months. Hence, the proposed ECBA system is expected to lead a new paradigm of human neuromodulation studies in the near future. [ABSTRACT FROM AUTHOR]

Spinal cord stimulation (SCS) is an effective treatment for chronic, intractable neuropathic pain. There have been relatively few high-level studies that suggest its unequivocal use. The decay of stimulation efficacy over time have opened opportunity for the entrance of new pulse trains and waveforms. In this state-of-the-art review, we focused on many of the major studies published in the last 10 years that were considered level one evidence. A retrospective narrative approach was taken to conceptualize foundation studies as they pertain to current evidence. A special focus was taken on reported safety outcomes in comparison to foundation studies especially as they pertain to our 5-year outlook on the use of spinal cord stimulation. We find there are still significant limitations in the body of reviewed evidence and suggest that long-term data beyond 24 months are lacking in the literature. In addition, adverse event rates, device explantation rates and the sham effect looms as important concepts to address in the future in spite of the existing novel stimulation paradigms. [ABSTRACT FROM AUTHOR]

Long-term potentiation (LTP) at glutamatergic synapses is an extensively studied form of long-lasting synaptic plasticity widely regarded as the cellular basis for learning and memory. At the CA1 synapse, there are multiple forms of LTP with distinct properties. Although AMPA glutamate receptors (AMPARs) are a key target of LTP expression, whether they are required in all forms of LTP remains unclear. To address this question, we have used our recently developed mouse line, GluA1C2KI, where the c-terminal domain (CTD) of the endogenous GluA1 is replaced by that of GluA2. Unlike traditional GluA1 global or conditional KO mice, GluA1C2KI mice have no changes in basal AMPAR properties or synaptic transmission allowing a better assessment of GluA1 in synaptic plasticity. We previously showed that these mice are impaired in LTP induced by high-frequency stimulation (HFS-LTP), but whether other forms of LTP are also affected in these mice is unknown. In this study, we compared various forms of LTP at CA1 synapses between GluA1C2KI and wild-type littermates by using several induction protocols. We show that HFS-LTP is impaired in both juvenile and adult GluA1C2KI mice. The LTP induced by theta-burst stimulation (TBS-LTP) is also abolished in juvenile GluA1C2KI mice. Interestingly, TBS-LTP can still be induced in adult GluA1C2KI mice, but its mechanisms are altered becoming more sensitive to protein synthesis and the extracellular signal-regulated kinase (ERK) inhibitors compared to wild type (WT) control. The GluA1C2KI mice are also differentially altered in several forms of LTP induced under whole-cell recording paradigms. These results indicate that the CTD of GluA1 is differentially involved in different forms of LTP at CA1 synapse highlighting the complexity and adaptative potential of LTP expression mechanisms in the hippocampus.

Background. Pulmonary vein isolation (PVI) is the gold standard of interventional atrial fibrillation (AF) treatment, however, it doesn't provide a stable clinical effect and durable PVI in the long-term follow-up due to reconnections within the ablation line. To increase the efficacy of surgery, modulation of the autonomic nervous system can be combined with pulmonary vein isolation. Aim. The study was focused on the evaluation of efficacy of ganglionated plexi (GP) ablation combined with PVI, and intraoperative drug testing of dormant pulmonary vein conduction and exclusion of non-pulmonary vein triggers in patients with paroxysmal atrial fibrillation. Methods. There hundred sixty-seven patients with paroxysmal AF scheduled for catheter ablation were initially screened. PVI was performed in all patients. After testing with adenosine triphosphate and isoprenaline for dormant conduction following PVI and exclusion of non-pulmonary vein triggers, 194 patients with a positive response to high-frequency stimulation in the main GP sites of the left atrium were randomized in two groups: PVI (group I, n = 97), PVI with anatomical GP ablation (group II, n = 97). To perform continuous ECG monitoring, 53 patients received implantable cardiac monitors. The primary endpoint of the study was the freedom from any atrial tachyarrhythmias after 12 months of follow- up as recorded by 24-hour Holter monitoring. The secondary endpoints included AF burden based on implantable cardiac monitors data and predictors of AF recurrences. The patients were followed 3, 6, 9, 12 months after the ablation procedure. Results. The mean follow-up was 12.5±2.2 months. By the end of the follow-up, 79 (81.4%) patients in the PVI with GP ablation group and 58 (59.8%) patients in the PVI only group were free from any atrial tachyarrhythmia (р=0.0012; log-rank test, HR 0.41, 95% CI [0.23–0.72], р=0.002; Cox regression). Implantable cardiac monitors data revealed that AF burden was significantly lower in the PVI with GP group as compared with the PVI only group (14.8±1.7% and 5.4±0.7%, р

Background. Catheter pulmonary vein isolation (PVI) is the main interventional procedure for treatment of atrial fibrillation (AF). Recurrences of arrhythmia paroxysms in the postoperative period are mainly determined by reconnection of conduction from the pulmonary veins. However, non-pulmonary vein triggers and a positive vagal response of ganglionated plexi (GP) to high frequency stimulation after PVI confirmed by drug testing may affect the long-term efficacy of catheter AF ablation. Aim. To evaluate the efficacy of PVI isolation after drug testing and a negative response to high-frequency stimulation and a positive response to high-frequency stimulation but without subsequent ablation in patients with paroxysmal AF, as well as the efficacy of PVI confirmed by drug testing in patients having nonpulmonary vein triggers. Methods. The present analysis is a part of the randomized study on the comparison of PVI confirmed by drug testing with the absence of non-pulmonary vein triggers and a positive response of GP to high-frequency stimulation with and without GP ablation. PVI was performed in 311 patients. Ninety-six patients were excluded because they required additional GP ablation. Two hundred and fourteen patients were divided into three groups: PVI with a positive GP response (posGP) to high-frequency stimulation without GP ablation (group I, n = 97), PVI with a negative GP response (negGP) to high-frequency stimulation (group II, n = 79) and PVI with non-pulmonary vein triggers (group III, n = 38). The primary endpoint of the study was the freedom from any atrial tachyarrhythmias after 12 months of follow-up confirmed by 24-hour Holter monitoring. The secondary endpoints included the frequency of detecting dormant pulmonary vein conduction, non-pulmonary vein triggers, negative GP response to high-frequency stimulation after catheter PVI. The patients were followed 3, 6, 9, 12 months after the ablation procedure. Results. At the end of the follow-up 57 (72.2%) patients in the PVI + negGP group (group II), 58 (59.8%) patients in the PVI + posGP group (group I) and 20 (52.6%) patients in the PVI + NPT (group III) were free from any atrial tachyarrhythmia (р=0.07; log-rank test). A statistical significance in the efficacy was observed when group II was compared with group III (72.2% and 52.6%, р = 0.028, log-rank test). In the course of primary ablation following PVI, when performing drug testing, dormant atriovenous conduction sites were observed in 105 (33.8%) patients, while non-pulmonary vein triggers (n = 79) were recorded in 38 (12.2%) patients. The frequency of negative GP responses to high-frequency stimulation after PVI accounted for 28.3%. Conclusion. Pulmonary vein isolation confirmed by drug testing, without a response of GP to high-frequency stimulation tends to provide higher efficacy in maintaining the sinus rhythm as compared with PVI and a positive GP response to high-frequency stimulation, but without a statistical significance, whereas nonpulmonary vein triggers after PVI are associated with lower efficacy in the long-term follow-up.

Repetitive activation of skeletal muscle fibers leads to a reduced transmembrane K+ gradient. The resulting membrane depolarization has been proposed to play a major role in the onset of muscle fatigue. Nevertheless, raising the extracellular K+ ( $$ {\text{K}}_{\text{o}}^{ + } $$ ) concentration ( $$ [ {\text{K}}^{ + } ]_{\text{o}} $$ ) to 10 mM potentiates twitch force of rested amphibian and mammalian fibers. We used a double Vaseline gap method to simultaneously record action potentials (AP) and Ca2+ transients from rested frog fibers activated by single and tetanic stimulation (10 pulses, 100 Hz) at various $$ [ {\text{K}}^{ + } ]_{\text{o}} $$ and membrane potentials. Depolarization resulting from current injection or raised $$ [ {\text{K}}^{ + } ]_{\text{o}} $$ produced an increase in the resting [Ca2+]. Ca2+ transients elicited by single stimulation were potentiated by depolarization from −80 to −60 mV but markedly depressed by further depolarization. Potentiation was inversely correlated with a reduction in the amplitude, overshoot and duration of APs. Similar effects were found for the Ca2+ transients elicited by the first pulse of 100 Hz trains. Depression or block of Ca2+ transient in response to the 2nd to 10th pulses of 100 Hz trains was observed at smaller depolarizations as compared to that seen when using single stimulation. Changes in Ca2+ transients along the trains were associated with impaired or abortive APs. Raising $$ [ {\text{K}}^{ + } ]_{\text{o}} $$ to 10 mM potentiated Ca2+ transients elicited by single and tetanic stimulation, while raising $$ [ {\text{K}}^{ + } ]_{\text{o}} $$ to 15 mM markedly depressed both responses. The effects of 10 mM $$ {\text{K}}_{\text{o}}^{ + } $$ on Ca2+ transients, but not those of 15 mM $$ {\text{K}}_{\text{o}}^{ + } $$ , could be fully reversed by hyperpolarization. The results suggests that the force potentiating effects of 10 mM $$ {\text{K}}_{\text{o}}^{ + } $$ might be mediated by depolarization dependent changes in resting [Ca2+] and Ca2+ release, and that additional mechanisms might be involved in the effects of 15 mM $$ {\text{K}}_{\text{o}}^{ + } $$ on force generation.

Abstract Background Deep brain stimulation (DBS) has shown wide clinical applications for treating various disorders of central nervous system. High frequency stimulation (HFS) of pulses with a constant intensity and a constant frequency is typically used in DBS. However, new stimulation paradigms with time-varying parameters provide a prospective direction for DBS developments. To meet the research demands for time-varying stimulations, we designed a new stimulation system with a technique of LabVIEW-based virtual instrument. Methods The system included a LabVIEW program, a NI data acquisition card, and an analog stimulus isolator. The output waveforms of the system were measured to verify the time-varying parameters. Preliminary animal experiments were run by delivering the HFS sequences with time-varying parameters to the hippocampal CA1 region of anesthetized rats. Results Verification results showed that the stimulation system was able to generate pulse sequences with ramped intensity and hyperbolic frequency accurately. Application of the time-varying HFS sequences to the axons of pyramidal cells in the hippocampal CA1 region resulted in neuronal responses different from those induced by HFS with constant parameters. The results indicated important modulations of time-varying stimulations to the neuronal activity that could prevent the stimulation from inducing over-synchronized firing of population neurons. Conclusions The stimulation system provides a useful technique for investigating diverse stimulation paradigms for the development of new DBS treatments.

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. [ABSTRACT FROM AUTHOR]

• Intraoperative EEG changes in chronic pain patients under spinal cord stimulation are investigated. • Spectral and topographical differences between high frequency and tonic stimulation are observed. • High frequency stimulation-induced spatio-spectral features are associated to pain relief. To investigate the differences in neural patterns between spinal cord stimulation (SCS) waveforms (60-Hz tonic vs 10-KHz high frequency stimulation, HFS) and their correlation to stimulation-induced pain relief. We recorded 10-channel electroencephalogram (EEG) in response to stimulation ON and OFF in 9 chronic pain patients (4 women, 5 men) during SCS surgery and examined the intraoperative spatio-spectral EEG features. We discovered stronger relative alpha power in the somatosensory region and higher trend in alpha/theta peak power ratio in frontal cortex with HFS. We also observed a shift in peak frequency from theta to alpha rhythms in HFS as compared to baseline and tonic stimulation, where slower theta activity was maintained. Further, a positive correlation was found between changes in Oswestry disability index (ODI) scores (from preoperative to postoperative) and HFS-induced alpha/theta peak power ratio in frontal and somatosensory regions. Altogether, our findings suggest that dynamic spectral interactions in theta-alpha band and their spatial distributions might be the first intraoperative neural signatures of pain relief induced by HFS in chronic pain. Examining electrophysiological changes intraoperatively has a potential to elucidate response to SCS therapy prior to device selection, reducing the healthcare expenditures associated with failed implants. [ABSTRACT FROM AUTHOR]

The β-adrenergic receptor stimulation improves endurance in fast twitch muscles and these effects are sensitive to extracellular Ca2+ influx. Present study is aimed to determine the effects of adrenaline, with different concentrations of extracellular Ca2+ Ca ECF 2 + , on the contractility and endurance of slow twitch muscles during high frequency stimulations (HFS). Isolated soleus of rabbit was electrically stimulated (strength; 50 Hz, duration; 0.5 ms) in the presence (Test) of adrenaline (1 × 10−7 mM) or without adrenaline (CTL). Fatigue was induced with HFS (80 Hz) for the duration of 20 s. Contractions were recorded through isometric transducer connected with Powerlab. Kreb's buffer was used with three compositions: standard with 2.5 mM Ca2+ (Ca-S), Ca2+ free buffer (Ca-F) and buffer with raised Ca2+ i.e., 10 mM (Ca-R). Muscles endurance was assessed by measuring the decline in tetanic tension in the terms of percentage (%Pmax) and rate of decline in tetanic tension (dP/dt). During 20 s, %Pmax showed reduction of only 10% in Ca-S. This decline was enhanced in Ca-F (50%) and reduced in Ca-R (6%). Effect of adrenaline was observed only in Ca-F where %Pmax was about 20% greater in Test than CTL. These effects were not observed in both Ca-S and Ca-R during 20 s. However, when duration of stimulation was increased to 120 or 150 s in Ca-S and Ca-R respectively, decline in %Pmax was less in Test as compared to CTL. Thus, Ca ECF 2 + plays protective role against fatigue during continuous HFS in slow twitch muscles. In addition, adrenaline improves the muscles endurance during fatiguing contraction but these effects are not mediated through Ca ECF 2 + influx. [ABSTRACT FROM AUTHOR]

Brief-pulse stimulation at 50 Hz has been shown to terminate afterdischarges observed in epilepsy patients. However, the optimal pulse stimulation parameters for terminating cortical electrical stimulation-induced afterdischarges remain unclear. In the present study, we examined the effects of different brief-pulse stimulation frequencies (5, 50 and 100 Hz) on cortical electrical stimulation-induced afterdischarges in 10 patients with refractory epilepsy. Results demonstrated that brief-pulse stimulation could terminate cortical electrical stimulation-induced afterdischarges in refractory epilepsy patients. In conclusion, (1) a brief-pulse stimulation was more effective when the afterdischarge did not extend to the surrounding brain area. (2) A higher brief-pulse stimulation frequency (especially 100 Hz) was more likely to terminate an afterdischarge. (3) A low current intensity of brief-pulse stimulation was more likely to terminate an afterdischarge

Introduction: Spinal cord stimulation has emerged as a state-of-the-art evidence-based treatment for chronic neuropathic pain and mixed nociceptive-neuropathic pain. In recent years, several newer devices and treatment algorithms have provided unique and effective ways of treating chronic pain by spinal cord stimulation. In a previous review, the authors commented on the 5-year forecast for high frequency and Burst waveforms, as the only two paresthesia independent SCS strategies. Over the last 5 years, there has been considerable addition to the outcome data related to these modalities. Additionally, new treatment algorithms and modalities for spinal cord stimulation have emerged. In this review, the authors provide an up to date summary of these modalities of treatment, indications, and evidence on all different modalities and programming paradigms that are available today. Areas covered: A literature review was performed using key bibliographic databases to find outcomes related studies pertaining to spinal cord stimulation, limited to the English language and human data, between 2010 and 2018. The literature search yielded the following based on our inclusion criteria; six articles on burst stimulation, three articled on high density/high dose stimulation, six articles on Dorsal Root Ganglion stimulation, nine articles on high-frequency stimulation, and one article on closed-loop stimulation. We have also included in the discussion some smaller and anecdotal studies. Expert commentary: The evidence to support outcomes of spinal cord stimulation has evolved considerably since our last review in 2014. New targets, frequencies and pulse trains, and feedback appear to have advanced the efficacy of spinal cord stimulation. Future developments aim to continue to refine patient selection and maintenance of patients in therapy. [ABSTRACT FROM AUTHOR]

The subcallosal cingulate (SCC) region, or its rodent homologue the medial prefrontal cortex (mPFC), and midbrain dorsal raphe (DR) are crucial nodes of the widespread network implicated in emotional regulation. Stimulation of the SCC is being explored as a potential treatment for depression. Because modulation of the 5-HT system is the most common pharmacological means of treating depression, we sought to establish 5-HT's role in the mPFC-DR projection. Using anaesthetized mice, we recorded neuronal activity in 49 neurons of the DR before, during, and after high frequency stimulation (HFS) of the mPFC. The majority of DR cells (74%) significantly decreased firing rate during HFS (p

Deep brain stimulation (DBS) has been used for treating many brain disorders. Clinical applications of DBS commonly require high-frequency stimulations (HFS, ∼100 Hz) of electrical pulses to obtain therapeutic efficacy. It is not clear whether the electrical energy of HFS functions other than generating firing of action potentials in neuronal elements. To address the question, we investigated the reactions of downstream neurons to pulse sequences with a frequency in the range 50–200 Hz at afferent axon fibers in the hippocampal CA1 region of anesthetized rats. The results show that the mean rates of neuronal firing induced by axonal HFS were similar even for an up to fourfold difference (200:50) in the number and thereby in the energy of electrical pulses delivered. However, HFS with a higher pulse frequency (100 or 200 Hz) generated more randomness in the firing pattern of neurons than a lower pulse frequency (50 Hz), which were quantitatively evaluated by the significant changes of two indexes, namely, the peak coefficients and the duty ratios of excitatory phase of neuronal firing, induced by different frequencies (50–200 Hz). The findings indicate that a large portion of the HFS energy might function to generate a desynchronization effect through a possible mechanism of intermittent depolarization block of neuronal membranes. The present study addresses the demand of high frequency for generating HFS-induced desynchronization in neuronal activity, which may play important roles in DBS therapy.

Female Wistar rats were instrumented to record bladder pressure and to stimulate the left pelvic nerve. Repeated voids were induced by continuous infusion of saline into the bladder (11.2 ml/h) via a T-piece in the line to the bladder catheter. In each animal tested (n = 6) high frequency pelvic nerve stimulation (1–3 kHz, 1–2 mA sinusoidal waveform for 60 s) applied within 2 s of the onset of a sharp rise in bladder pressure signaling an imminent void was able to inhibit micturition. Voiding was modulated in three ways: (1) Suppression of voiding (four rats, n = 13 trials). No fluid output or a very small volume of fluid expelled (

The disruption of coordination between smooth muscle contraction in the bladder and the relaxation of the external urethral sphincter (EUS) striated muscle is a common issue in dysfunctional bladders. It is a significant challenge to overcome for neuromodulation approaches to restore bladder control. Bladder-sphincter dyssynergia leads to undesirably high bladder pressures, and poor voiding outcomes, which can pose life-threatening secondary complications. Mixed pelvic nerves are potential peripheral targets for stimulation to treat dysfunctional bladders, but typical electrical stimulation of pelvic nerves activates both the parasympathetic efferent pathway to excite the bladder, as well as the sensory afferent pathway that causes unwanted sphincter contractions. Thus, a novel pelvic nerve stimulation paradigm is required. In anesthetized female rats, we combined a low frequency (10 Hz) stimulation to evoke bladder contraction, and a more proximal 20 kHz stimulation of the pelvic nerve to block afferent activation, in order to produce micturition with reduced bladder-sphincter dyssynergia. Increasing the phase width of low frequency stimulation from 150 to 300 μs alone was able to improve voiding outcome significantly. However, low frequency stimulation of pelvic nerves alone evoked short latency (19.9–20.5 ms) dyssynergic EUS responses, which were abolished with a non-reversible proximal central pelvic nerve cut. We demonstrated that a proximal 20 kHz stimulation of pelvic nerves generated brief onset effects at lower current amplitudes, and was able to either partially or fully block the short latency EUS responses depending on the ratio of the blocking to stimulation current. Our results indicate that ratios >10 increased the efficacy of blocking EUS contractions. Importantly, we also demonstrated for the first time that this combined low and high frequency stimulation approach produced graded control of the bladder, while reversibly blocking afferent signals that elicited dyssynergic EUS contractions, thus improving voiding by 40.5 ± 12.3%. Our findings support advancing pelvic nerves as a suitable neuromodulation target for treating bladder dysfunction, and demonstrate the feasibility of an alternative method to non-reversible nerve transection and sub-optimal intermittent stimulation methods to reduce dyssynergia.

Nerve block waveforms require the passage of large amounts of electrical energy at the neural interface for extended periods of time. It is desirable that such waveforms be applied chronically, consistent with the treatment of protracted immune conditions, however current metal electrode technologies are limited in their capacity to safely deliver ongoing stable blocking waveforms. Conductive hydrogel (CH) electrode coatings have been shown to improve the performance of conventional bionic devices, which use considerably lower amounts of energy than conventional metal electrodes to replace or augment sensory neuron function. In this study the application of CH materials was explored, using both a commercially available platinum iridium (PtIr) cuff electrode array and a novel low-cost stainless steel (SS) electrode array. The CH was able to significantly increase the electrochemical performance of both array types. The SS electrode coated with the CH was shown to be stable under continuous delivery of 2 mA square pulse waveforms at 40,000 Hz for 42 days. CH coatings have been shown as a beneficial electrode material compatible with long-term delivery of high current, high energy waveforms.

Coupled neural network models are playing an increasingly important part in the modulation of absence seizures today. However, it is currently unclear how basal ganglia, corticothalamic network and pedunculopontine nucleus can coordinate with each other to develop a whole coupling circuit, theoretically. In addition, it is still difficult to select effective parameters of electrical stimulation on the regulation of absence seizures in clinical trials. Therefore, to develop a coupled model and reduce computation cost, a new model constructed by a simplified basal ganglion, two corticothalamic circuits and a pedunculopontine nucleus was proposed. Further, to seek better inhibition therapy, three electrical stimulations, high frequency stimulation (HFS), 1:0 coordinate reset stimulation (CRS) and 3:2 CRS, were applied to the thalamic reticular nucleus (RE) in the first corticothalamic circuit in the coupled model. The simulation results revealed that increasing the frequency and pulse width of an electrical stimulation within a certain range can also suppress seizures. Under the same parameters of electrical stimulation, the inhibitory effect of HFS on seizures was better than that of 1:0 CRS and 3:2 CRS. The research established a reduced corticothalamic-basal ganglion-pedunculopontine nucleus model, which lays a theoretical foundation for future optimal parameters selection of electrical stimulation. We hope that the findings will provide new insights into the role of theoretical models in absence seizures.

Deep brain stimulation (DBS) has been used for treating many brain disorders. Clinical applications of DBS commonly require high-frequency stimulations (HFS, ∼100 Hz) of electrical pulses to obtain therapeutic efficacy. It is not clear whether the electrical energy of HFS functions other than generating firing of action potentials in neuronal elements. To address the question, we investigated the reactions of downstream neurons to pulse sequences with a frequency in the range 50–200 Hz at afferent axon fibers in the hippocampal CA1 region of anesthetized rats. The results show that the mean rates of neuronal firing induced by axonal HFS were similar even for an up to fourfold difference (200:50) in the number and thereby in the energy of electrical pulses delivered. However, HFS with a higher pulse frequency (100 or 200 Hz) generated more randomness in the firing pattern of neurons than a lower pulse frequency (50 Hz), which were quantitatively evaluated by the significant changes of two indexes, namely, the peak coefficients and the duty ratios of excitatory phase of neuronal firing, induced by different frequencies (50–200 Hz). The findings indicate that a large portion of the HFS energy might function to generate a desynchronization effect through a possible mechanism of intermittent depolarization block of neuronal membranes. The present study addresses the demand of high frequency for generating HFS-induced desynchronization in neuronal activity, which may play important roles in DBS therapy. [ABSTRACT FROM AUTHOR]

Key points: A recent animal study showed that high frequency electrical stimulation (HFS) of C‐fibres induces a gliogenic heterosynaptic long‐term potentiation at the spinal cord that is hypothesized to mediate secondary hyperalgesia in humans. Here this hypothesis was tested by predominantly activating C‐fibre nociceptors in the area of secondary mechanical hyperalgesia induced by HFS in humans. It is shown that heat perception elicited by stimuli predominantly activating C‐fibre nociceptors is greater, as compared to the control site, after HFS in the area of secondary mechanical hyperalgesia. This is the first study that confirms in humans the involvement of C‐fibre nociceptors in the changes in heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. Abstract: It has recently been shown that high frequency electrical stimulation (HFS) of C‐fibres induces a gliogenic heterosynaptic long‐term potentiation (LTP) at the spinal cord in animals, which has been hypothesized to be the underlying mechanism of secondary hyperalgesia in humans. Here we tested this hypothesis using a method to predominantly activate quickly responding C‐fibre nociceptors in the area of secondary hyperalgesia induced by HFS in humans. HFS was delivered to one of the two volar forearms in 18 healthy volunteers. Before, 20 min and 45 min after HFS, short‐lasting (10 ms) high‐intensity CO2 laser heat stimuli delivered to a very small area of the skin (0.15 mm2) were applied to the area of increased mechanical pinprick sensitivity at the HFS‐treated arm and the homologous area of the contralateral control arm. During heat stimulation the electroencephalogram, reaction times and intensity of perception (numerical rating scale 0–100) were measured. After HFS, we observed a greater heat sensitivity, an enhancement in the number of detected trials, faster reaction times and an enhancement of the N2 wave of C‐fibre laser‐evoked potentials at the HFS‐treated arm compared to the control arm. This is the first study that confirms in humans the involvement of C‐fibre nociceptors in enhanced heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. [ABSTRACT FROM AUTHOR]

Epilepsy has been classically seen as a brain disorder resulting from abnormally enhanced neuronal excitability and synchronization. Although it has been described since antiquity, there are still significant challenges achieving the therapeutic goal of seizure freedom. Deep brain stimulation of the anterior nucleus of the thalamus has emerged as a promising therapy for focal drug-resistant epilepsy; the basic mechanism of action, however, remains unclear. Here, we show that desynchronization is a potential mechanism of deep brain stimulation of the anterior nucleus of the thalamus by studying local field potentials recordings from the cortex during high-frequency stimulation (130 Hz) of the anterior nucleus of the thalamus in nine patients with drug-resistant focal epilepsy. We demonstrate that high-frequency stimulation applied to the anterior nucleus of the thalamus desynchronizes ipsilateral hippocampal background electrical activity over a broad frequency range, and reduces pathological epileptic discharges including interictal spikes and high-frequency oscillations. Furthermore, high-frequency stimulation of the anterior nucleus of the thalamus is capable of decoupling large-scale neural activity involving the hippocampus and distributed cortical areas. We found that stimulation frequencies ranging from 15 to 45 Hz were associated with synchronization of hippocampal local field potentials, whereas higher frequencies (>45 Hz) promoted desynchronization of ipsilateral hippocampal activity. Moreover, reciprocal effective connectivity between the anterior nucleus of the thalamus and the hippocampus was demonstrated by hippocampal-thalamic evoked potentials and thalamic-hippocampal evoked potentials. In summary, high-frequency stimulation of the anterior nucleus of the thalamus is shown to desynchronize focal and large-scale epileptic networks, and here is proposed as the mechanism for reducing seizure generation and propagation. Our data also demonstrate position-specific correlation between deep brain stimulation applied to the anterior nucleus of the thalamus and patients with temporal lobe epilepsy and seizure onset zone within the Papaz circuit or limbic system. Our observation may prove useful for guiding electrode implantation to increase clinical efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Long‐term potentiation is a form of synaptic plasticity thought to play an important role in learning and memory. Recently noninvasive methods have been developed to induce and measure activity similar to long‐term potentiation in humans. Sensory tetani (trains of quickly repeating auditory or visual stimuli) alter the electroencephalogram in a manner similar to electrical stimulation that results in long‐term potentiation. This review briefly covers the development of long‐term potentiation research before focusing on in vivo human studies that produce long‐term potentiation‐like effects using auditory and visual stimulation. Similarities and differences between traditional (animal and brain tissue) long‐term potentiation studies and human sensory tetanization studies will be discussed, as well as implications for perceptual learning. Although evidence for functional consequences of sensory tetanization remains scarce, studies involving clinical populations indicate that sensory induced plasticity paradigms may be developed into diagnostic and research tools in clinical settings. Individual differences in the effects of sensory tetanization are not well‐understood and provide an interesting avenue for future research. Differences in effects found between research groups that have emerged as the field has progressed are also yet to be resolved. [ABSTRACT FROM AUTHOR]

Background Ventricular tachycardia (VT) and ventricular premature complexes (VPCs) originating from the right ventricular outflow tract (RVOT) are generally considered as benign arrhythmias, with ECG morphology showing LBBB pattern and inferior axis. Pathogenic mechanisms in the genesis of RVOT VT/VPC remain largely unknown. We aimed to investigate the neural mechanism in RVOT ventricular arrhythmias in canine model. Methods Twelve mongrel dogs (13.7 ± 1.3 kg, 5 male dogs) were studied through midline thoracotomies. High-frequency stimulation (HFS) was applied to the proximal pulmonary artery (PA) to induce RVOT VT/VPC. An EnSite Array and a mapping catheter were used for electroanatomical mapping. The RVOT and PA were surgically excised for immunohistochemistry studies, including tyrosine hydroxylase (TH) stain for sympathetic nerves and choline acetyltransferase (ChAT) stain for parasympathetic nerves. Results In nine (75%) out of twelve dogs, HFS of the proximal PA induced RVOT VT/VPC. The density of TH-positive nerves was significantly higher than that of ChAT-positive nerves (6803 ± 700 vs. 670 ± 252 μm 2 /mm 2 , p  < 0.001). Furthermore, the density of TH-positive nerves was also significantly higher in the VT/VPC origin sites than that in the non-origin sites (18,044 ± 2866 vs. 5554 ± 565 μm 2 /mm 2 , p  = 0.002). Catheter ablation of the proximal PA eliminated the inducibility of RVOT VT/VPC successfully. Conclusions HFS of the proximal PA could induce RVOT VT/VPC. The sympathetic nerves were densely innervated to the origin of RVOT VT/VPC, indicating the critical role of sympathetic hyperactivity in the initiation and perpetuation of RVOT VT/VPC. [ABSTRACT FROM AUTHOR]

Female Wistar rats were instrumented to record bladder pressure and to stimulate the left pelvic nerve. Repeated voids were induced by continuous infusion of saline into the bladder (11.2 ml/h) via a T-piece in the line to the bladder catheter. In each animal tested (n = 6) high frequency pelvic nerve stimulation (1-3 kHz, 1-2 mA sinusoidal waveform for 60 s) applied within 2 s of the onset of a sharp rise in bladder pressure signaling an imminent void was able to inhibit micturition. Voiding was modulated in three ways: (1) Suppression of voiding (four rats, n = 13 trials). No fluid output or a very small volume of fluid expelled (<15% of the volume expected based on the mean of the previous 2 or 3 voids). Voiding suppressed for the entirety of the stimulation period (60 s) and resumed within 37 s of stopping stimulation. (2) Void deferred (four rats, n = 6 trials). The imminent void was suppressed (no fluid expelled) but a void occurred later in the stimulation period (12-44 s, mean 24.5 ± 5.2 s after the onset of the stimulation). (3) Reduction in voided volume (five rats, n = 20 trials). Voiding took place but the volume of fluid voided was 15-80% (range 21.8-77.8%, mean 45.3 ± 3.6%) of the volume expected from the mean of the preceding two or three voids. Spontaneous voiding resumed within 5 min of stopping stimulation. Stimulation during the filling phase in between voids had no effect. The experiments demonstrate that conditional high frequency stimulation of the pelvic nerve started at the onset of an imminent void can inhibit voiding. The effect was rapidly reversible and was not accompanied by any adverse behavioral side effects. [ABSTRACT FROM AUTHOR]

The disruption of coordination between smooth muscle contraction in the bladder and the relaxation of the external urethral sphincter (EUS) striated muscle is a common issue in dysfunctional bladders. It is a significant challenge to overcome for neuromodulation approaches to restore bladder control. Bladder-sphincter dyssynergia leads to undesirably high bladder pressures, and poor voiding outcomes, which can pose life-threatening secondary complications. Mixed pelvic nerves are potential peripheral targets for stimulation to treat dysfunctional bladders, but typical electrical stimulation of pelvic nerves activates both the parasympathetic efferent pathway to excite the bladder, as well as the sensory afferent pathway that causes unwanted sphincter contractions. Thus, a novel pelvic nerve stimulation paradigm is required. In anesthetized female rats, we combined a low frequency (10Hz) stimulation to evoke bladder contraction, and a more proximal 20 kHz stimulation of the pelvic nerve to block afferent activation, in order to produce micturition with reduced bladder-sphincter dyssynergia. Increasing the phase width of low frequency stimulation from 150 to 300 µs alone was able to improve voiding outcome significantly. However, low frequency stimulation of pelvic nerves alone evoked short latency (19.9-20.5ms) dyssynergic EUS responses, which were abolished with a non-reversible proximal central pelvic nerve cut. We demonstrated that a proximal 20 kHz stimulation of pelvic nerves generated brief onset effects at lower current amplitudes, and was able to either partially or fully block the short latency EUS responses depending on the ratio of the blocking to stimulation current. Our results indicate that ratios >10 increased the efficacy of blocking EUS contractions. Importantly, we also demonstrated for the first time that this combined low and high frequency stimulation approach produced graded control of the bladder, while reversibly blocking afferent signals that elicited dyssynergic EUS contractions, thus improving voiding by 40.5 ± 12.3%. Our findings support advancing pelvic nerves as a suitable neuromodulation target for treating bladder dysfunction, and demonstrate the feasibility of an alternative method to nonreversible nerve transection and sub-optimal intermittent stimulation methods to reduce dyssynergia. [ABSTRACT FROM AUTHOR]

In the striatum, long term potentiation (LTP) and long-term depression (LTD) of glutamatergic transmission are believed to underlie motor learning and are impaired in animal models of Parkinson’s disease. High frequency stimulation (HFS) is often used to induce synaptic plasticity in the brain. In the striatum, the polarity of HFS-induced plasticity is influenced by the recording conditions, which can differ between various studies. Here, we examined the ability of HFS to induce synaptic plasticity in the dorsolateral striatum in the presence of extracellular Mg 2+ ions, with no GABA A receptor blocker, and without membrane depolarization during HFS. We found that HFS induced a LTD of excitatory postsynaptic currents (EPSCs) mediated by AMPA receptors (AMPARs) in medium spiny neurons (MSNs) recorded with whole-cell voltage-clamp. However, HFS induced a LTP of field excitatory postsynaptic potentials/population spikes (fEPSP/PSs), which was dependent on the stimulation intensity applied. The rate of synaptically-evoked spiking in MSNs, measured with cell-attached recordings, showed LTP following HFS. LTD and LTP were impaired in the dopamine-depleted striatum of 6-hydroxydopamine (6-OHDA) lesioned mice, a model of Parkinson’s disease. This study shows that HFS induces opposing forms of dopamine-dependent synaptic plasticity in the striatum, i.e . LTD of AMPAR-EPSCs and LTP of both fEPSP/PS and synaptically-evoked firing in MSNs. [ABSTRACT FROM AUTHOR]

Nerve block waveforms require the passage of large amounts of electrical energy at the neural interface for extended periods of time. It is desirable that such waveforms be applied chronically, consistent with the treatment of protracted immune conditions, however current metal electrode technologies are limited in their capacity to safely deliver ongoing stable blocking waveforms. Conductive hydrogel (CH) electrode coatings have been shown to improve the performance of conventional bionic devices, which use considerably lower amounts of energy than conventional metal electrodes to replace or augment sensory neuron function. In this study the application of CH materials was explored, using both a commercially available platinum iridium (PtIr) cuff electrode array and a novel low-cost stainless steel (SS) electrode array. The CH was able to significantly increase the electrochemical performance of both array types. The SS electrode coated with the CH was shown to be stable under continuous delivery of 2mA square pulse waveforms at 40,000Hz for 42 days. CH coatings have been shown as a beneficial electrode material compatible with long-term delivery of high current, high energy waveforms. [ABSTRACT FROM AUTHOR]

Subcallosal Brodmann's Area 25 (Cg25) Deep Brain Stimulation (DBS) is a new promising therapy for treatment resistant major depressive disorder (TR-MDD). While different DBS stimulating parameters may have an impact on the efficacy and safety of the therapy, there is no data to support a protocol for optimal stimulation parameters for depression. Here we present a prospective multi-center double-blind randomized crossed-over 13-month study that evaluated the effects of High (130 Hz) vs Low (20 Hz) frequency Cg25 stimulation for nine patients with TR-MDD. Four out of nine patients achieved response criteria (≥40% reduction of symptom score) compared to mean baseline values at the end of the study. The mean percent change of MADRS score showed a similar improvement in the high and low frequency stimulation groups after 6 months of stimulation (−15.4 ± 21.1 and −14.7 ± 21.1 respectively). The mean effect at the end of the second period (6 months after cross-over) was higher than the first period (first 6 months of stimulation) in all patients (−23.4 ± 19.9 (n = 6 periods) and −13.0 ± 22 (n = 9 periods) respectively). At the end of the second period, the mean percent change of the MADRS scores improved more in the high than low frequency groups (−31.3 ± 19.3 (n = 4 patients) and −7.7 ± 10.9 (n = 2 patients) respectively). Given the small numbers, detailed statistical analysis is challenging. Nonetheless the results of this study suggest that long term high frequency stimulation might confer the best results. Larger scale, randomized double blind trials are needed in order to evaluate the most effective stimulation parameters. [ABSTRACT FROM AUTHOR]