Standard Stimulation Parameters Research Articles

Tonic and phasic transcutaneous auricular vagus nerve stimulation (taVNS) both evoke rapid and transient pupil dilation

BackgroundTranscutaneous auricular vagus nerve stimulation (tVNS or taVNS) is a non-invasive method of electrical stimulation of the afferent pathway of the vagus nerve, suggested to drive changes in putative physiological markers of noradrenergic activity, including pupil dilation. ObjectiveHowever, it is unknown whether different taVNS modes can map onto the phasic and tonic modes of noradrenergic activity. The effects of taVNS on pupil dilation in humans are inconsistent, largely due to differences in stimulation protocols. Here, we attempted to address these issues. MethodsWe investigated pupil dilation under phasic (1 s) and tonic (30 s) taVNS, in a pre-registered, single-blind, sham-controlled, within-subject cross-over design, in the absence of a behavioural task. ResultsPhasic taVNS induced a rapid increase in pupil size over baseline, significantly greater than under sham stimulation, which rapidly declined after stimulation offset. Tonic taVNS induced a similarly rapid (and larger than sham) increase in pupil size over baseline, returning to baseline within 5 s, despite the ongoing stimulation. Thus, both active and sham tonic modes closely resembled the phasic effect. There were no differences in tonic baseline pupil size, and no sustained effects of stimulation on tonic baseline pupil size. ConclusionsThese results suggest that both phasic- and tonic-like taVNS under the standard stimulation parameters may modulate primarily the phasic mode of noradrenergic activity, as indexed by evoked pupil dilation, over and above somatosensory effects. This result sheds light on the temporal profile of phasic and tonic stimulation, with implications for their applicability in further research.

Vagus nerve stimulation for pediatric patients with intractable epilepsy between 3 and 6\u2009years of age: study protocol for a double-blind, randomized control trial

BackgroundRecent clinical observations have reported the potential benefit of vagus nerve stimulation (VNS) as an adjunctive therapy for pediatric epilepsy. Preliminary evidence suggests that VNS treatment is effective for seizure reduction and mental development in young participants between 3 and 6 years of age who suffer from intractable epilepsy. However, robust clinical evidence for quantifying the difference of the efficacy and safety of VNS treatment in this specific patient population has yet to be reported.Methods/designA two-armed, multicenter, randomized, double-blind, prospective trial will be carried out to evaluate whether VNS is beneficial and safe for pediatric epilepsy. Pediatric participants aged between 3 to 6 years old with intractable epilepsy will be recruited and randomly assigned to experimental and control groups with a 1:1 allocation using a computer-generating randomization schedule. Before enrollment, informed consent will be signed by the parents of the participants and the study researchers. Participants in the experimental group will receive electrical stimulation over 24 weeks under standard stimulation parameters. Participants in the control group will not receive any stimulation during the 12 weeks of the double-blind period. The guardians of the participants are required to keep a detailed diary to record seizure activity. Outcome assessments including seizure frequency, Gesell Mental Developmental Scale scores, use of antiepileptic drugs and dosages, and adverse events will be collected at baseline, 6, 12, 18 and/or 24 weeks after electrical stimulation is initiated. The effects of treatment will be analyzed with time and treatment group comparisons.DiscussionThis trial will evaluate quantitative differences in efficacy and safety with/without VNS treatment for pediatric participants aged between 3 to 6 years with intractable epilepsy and will explore whether the current age range of VNS therapy can be expanded.Trial registrationClinicalTrials.gov, ID: NCT03062514, Registered on 23 February 2017.

EP 39. Clinical experience with deep brain stimulation in Huntington’s disease

Introduction Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) are well-established standard procedures for various movement disorders, e.g. Parkinson’s disease or dystonia. Until now, application of DBS in Huntington’s disease (HD) has been performed only as an individual and experimental treatment option reported in a few cases. Objective We present a prospective controlled case series of six patients with HD and bilateral DBS of the GPi. Material and Methods Indication for DBS was stated in six patients with severe, treatment-refractory chorea. The procedure was performed in general, intravenous anaesthesia. Bilateral lead placement in the GPi was achieved with stereotactic MRI-coordinates and intraoperative microrecordings. Stereotactic coordinates were as follows: (x) 19–20 mm lateral the midline of the intercommissural line, (y) 3 mm anterior and (z) 2–3 mm inferior the midpoint of the intercommissural line. Also intraoperative stimulation via the implanted leads was performed to evaluate stimulation induced-side effects like dystonic movements, eye movements etc. After insertion of the leads a second stereotactic MRI was performed to rule out any intracerebral complications and to document the definite position of the lead. Clinical evaluation included the motor score of the Unified Huntington‘s disease rating scale (UHDRS), Total Functional Capacity score (TFC), the Functional Assessment score (FA) and the 26-item version of the World Health Organisation questionnaire (WHO Bref) preoperatively and six months postoperatively. Results In all 6 patients leads were successfully implanted bilaterally in general anaesthesia. In one case one lead needed to be revised due to dislocation detected in the control, second MRI. Also in one case, second MRI revealed a small local haemorrhage in the course of one lead, but no clinical neurological deficits were observed in the patient postoperatively. Standard stimulation parameters were programmed and adjusted individually (mono- or bipolar mode, 30–130 hertz, 50–100 microseconds, amplitude 2–5.0 milliampere). The chorea subscore of the UHDRS motor score improved by 47% (range 21–86%; p Conclusion DBS of the GPi is an additional invasive treatment option for well-selected patients with HD. Risks and complications of the procedure and related to the implanted materials are low and acceptable. Continuous clinical experience and long-term follow-up of these patients are needed to evaluate the significance and evidence of DBS in HD.

Peripheral Neuromodulation to Treat Postamputation Pain.

Some of the more common peripherally mediated pain disorders are postamputation stump pain and phantom pain. These disabling conditions have proven difficult to treat. Here we aim to illustrate an option to treat postamputation pain using peripheral neurostimulation techniques. Traditional peripheral neuromodulation techniques use standard stimulation parameters and work by stimulation of nerve tissues which are then felt by the patient as a tingling sensation or paresthesia. Recently introduced high-frequency (10 kHz) electrical nerve block [HFAC (high-frequency alternating current) block] via a surgically implanted peripheral nerve cuff electrode results in true conduction block which actually blocks action potentials emanating from the painful neuroma and thus suppresses pain without tingling or paresthesia felt by the patient. In a recently completed 10-patient pilot study, the average pain level decreased from a score of 5.7 to 1.4 (out of 10) after HFAC block therapy with 85% of all testing sessions yielding a >50% pain reduction; a very significant reduction in the use of opioid and other analgesics was also noted, with all tested patients either stopping or decreasing their analgesic intake significantly. Patients achieved meaningful and significant pain reduction throughout the study, and patients who had phantom pain (in addition to stump pain) that responded to local anesthetic injections also responded favorably with HFAC block, presumably because in these particular patients, the phantom symptoms were peripherally generated. Each of the tested patients reported that HFAC block provided the most significant amount of pain reduction they had ever experienced when compared to other pain modalities tried since their amputations. The high-frequency electric nerve block technique is currently investigational pending FDA clearance. The next step for this modality is a pivotal trial, with the goal of having this therapy available to the mass market upon FDA clearance.

P84. High-frequency anterior thalamus stimulation interrupts cortical midline theta rhythm during drowsiness in an epileptic patient

Deep brain stimulation (DBS) of anterior thalamic nuclei (ANT) reduces frequency and intensity of epileptic partial and secondarily-generalized seizures. However, exact mechanisms of action and the effects of ANT-DBS on cortical activity are unknown. Recently, we demonstrated in one of our patients who had non-lesional epilepsy the correlation of ANT-DBS with bilateral frontal epileptic patterns ( Bucurenciu et al., 2014 ). We report the case of a 27-years old male epileptic patient with dyscognitive focal seizures, due to a left-hemispheric inoperable lesion, interpreted as focal cortical dysplasia and polymicrogyria, comprising the upper temporal lobe, the insula and the entire parietal lobe. At the age of 25, quadripolar DBS-electrodes (Model 3389, Medtronic®, Minneapolis, MN, USA), connected to a subclavicular dual-channel programmable stimulation device (Activa PC, Medtronic®), were stereotactically implanted in both ANTs. The stimulation parameters were 5 V and 5.5 V, 180 Hz, 150 μ s pulse width, cycling mode with 1min on/3min off. Stimulation on-phases were identified based on periodical reduction of QRS-complex-amplitudes in electrocardiograms. A 20% reduction of seizure frequencies with no side effects were reported after initiation of ANT-DBS. In several long-term EEGs of the patient, prominent non-specific midline-theta frontal rhythms of uncertain significance were observed during drowsiness. During bilateral stimulation via the most upper (superior-lateral) electrode-contacts (3 and 11) a reliable interruption of midline-theta rhythm was observed in EEGs, density-spectral-arrays and power-spectra, similarly to the effect of activating the patient. When the lowest (inferio-medial) electrode contacts (0 and 8) were used for stimulation the midline-theta rhythm was less affected. Other cortical rhythms, such as occipital-alpha or sleep-spindles, were only unspecifically reduced in amplitude by stimulation of both the most upper and the lowest contact-pairs, respectively. The contact-specificity and the selective inhibition of midline-theta rhythm, associated with changes of the power-spectra shape, prove that the observed EEG-amplitude reduction during stimulation is a real desynchronization of midline-theta rhythm and not an artefact. This is the first direct proof of an acute, electrode-contact specific influence of high-frequency ANT-DBS with standard stimulation-parameters on a cortical rhythm and might be relevant for epilepsies involving frontal cortical regions.

Intraoperative neurophysiological responses in epileptic patients submitted to hippocampal and thalamic deep brain stimulation

Purpose Deep brain stimulation (DBS) has been used in an increasing frequency for treatment of refractory epilepsy. Acute deep brain macrostimulation intraoperative findings were sparsely published in the literature. We report on our intraoperative macrostimulation findings during thalamic and hippocampal DBS implantation. Methods Eighteen patients were studied. All patients underwent routine pre-operative evaluation that included clinical history, neurological examination, interictal and ictal EEG, high resolution 1.5T MRI and neuropsychological testing. Six patients with temporal lobe epilepsy were submitted to hippocampal DBS (Hip-DBS); 6 patients with focal epilepsy were submitted to anterior thalamic nucleus DBS (AN-DBS) and 6 patients with generalized epilepsy were submitted to centro-median thalamic nucleus DBS (CM-DBS). Age ranged from 9 to 40 years (11 males). All patients were submitted to bilateral quadripolar DBS electrode implantation in a single procedure, under general anesthesia, and intraoperative scalp EEG monitoring. Final electrode's position was checked postoperatively using volumetric CT scanning. Bipolar stimulation using the more proximal and distal electrodes was performed. Final standard stimulation parameters were 6 Hz, 4 V, 300 μs (low frequency range: LF) or 130 Hz, 4 V, 300 μs (high frequency range: HF). Key findings Bilateral recruiting response (RR) was obtained after unilateral stimulation in all patients submitted to AN and CM-DBS using LF stimulation. RR was widespread but prevailed over the fronto-temporal region bilaterally, and over the stimulated hemisphere. HF stimulation led to background slowing and a DC shift. The mean voltage for the appearance of RR was 4 V (CM) and 3 V (AN). CM and AN-DBS did not alter inter-ictal spiking frequency or morphology. RR obtained after LF Hip-DBS was restricted to the stimulated temporal lobe and no contralateral activation was noted. HF stimulation yielded no visually recognizable EEG modification. Mean intensity for initial appearance of RR was 3 V. In 5 of the 6 patients submitted to Hip-DBS, an increase in inter-ictal spiking was noted unilaterally immediately after electrode insertion. Intraoperative LF stimulation did not modify temporal lobe spiking; on the other hand, HF was effective in abolishing inter-ictal spiking in 4 of the 6 patients studied. There was no immediate morbidity or mortality in this series. Significance Macrostimulation might be used to confirm that the hardware was working properly. There was no typical RR derived from each studied thalamic nuclei after LF stimulation. On the other hand, absence of such RRs was highly suggestive of hardware malfunction or inadequate targeting. Thalamic-DBS (Th-DBS) RR was always bilateral after unilateral stimulation, although they somehow prevailed over the stimulated hemisphere. Contrary to Th-DBS, Hip-DBS gave rise to localized RR over the ipsolateral temporal neocortex, and absence of this response might very likely be related to inadequate targeting or hardware failure. Increased spiking was seen over temporal neocortex during hippocampal electrode insertion; this might point to the more epileptogenic hippocampal region in each individual patient. We did not notice any intraoperative response difference among patients with temporal lobe epilepsy with or without MTS. The relationship between these intraoperative findings and seizure outcome is not yet clear and should be further evaluated.

Novel attempts to optimize vagus nerve stimulation parameters on serotonin neuronal firing activity in the rat brain

Vagus nerve stimulation (VNS) is indicated for treatment-resistant epilepsy and depression. Electrophysiologic recordings in the rat brain have shown that VNS promptly increases the firing rate of NE neurons and subsequently that of 5-HT neurons. Thus far, it appears that the standard stimulation parameters currently used in depressed patients produce an optimal activation of 5-HT neurons. This study was therefore aimed at investigating additional alterations of stimulation parameters to optimize VNS efficacy to further increase 5-HT neuronal activity. Rats were implanted with a VNS device and stimulated for 14 days using standard (0.25 mA/20 Hz/500 microseconds/30 seconds ON-5 minutes OFF, continuously) or various stimulation parameters: extension of the OFF period (30 seconds ON every 10 to 30 minutes), the OFF and ON periods, discontinuous stimulation (12 hours per day using standard parameters), and burst stimulation modes. Rat dorsal raphe 5-HT neurons were recorded under chloral hydrate anesthesia. Both 12-hour stimulation periods for 14 days, and the 30-second stimulation every 10 or 15 minutes significantly increased the firing activity of 5-HT neurons to the same extent as standard parameters while the 30-minute intervals were ineffective. Stimulations in a burst mode and the pseudo-one-pulse stimulations also significantly increased 5-HT neuronal activity. These results indicate that less stimulation is sufficient to achieve the same VNS efficacy on 5-HT neuronal firing. These data may be relevant for patients using VNS because these new parameters could minimize or prevent side effects and increase battery life of the stimulator.

Modulation of seizure threshold by vagus nerve stimulation in an animal model for motor seizures

The precise mechanism of action of vagus nerve stimulation (VNS) in suppressing epileptic seizures remains to be elucidated. This study investigates whether VNS modulates cortical excitability by determining the threshold for provoking focal motor seizures by cortical electrical stimulation before and after VNS. Male Wistar rats (n = 8) were implanted with a cuff-electrode around the left vagus nerve and with stimulation electrodes placed bilaterally on the rat motor cortex. Motor seizure threshold (MST) was assessed for each rat before and immediately after 1 h of VNS with standard stimulation parameters, during two to three sessions on different days. An overall significant increase of the MST was observed following 1 h of VNS compared to the baseline value (1420 microA and 1072 microA, respectively; P < 0.01). The effect was reproducible over time with an increase in MST in each experimental session. VNS significantly increases the MST in a cortical stimulation model for motor seizures. These data indicate that VNS is capable of modulating cortical excitability.

Improving the efficacy of sacral nerve stimulation for faecal incontinence by alteration of stimulation parameters

Sacral nerve stimulation (SNS) is an effective treatment for faecal incontinence, but only standard stimulation parameters have been used. This study assessed the clinical impact of altering the parameters. Twelve patients with partially improved faecal incontinence following SNS underwent acute testing to select optimal stimulation parameters; rectal compliance was used as a surrogate marker. Parameters tested were: stimulation off; frequency 14 (standard), 31 or 6.9 Hz; and pulse duration 210 (standard), 450 or 90 micros. Patients completed a 2-week bowel diary, St Mark's continence score (SMCS) and Rockwood faecal incontinence quality-of-life (FIQL) score before testing using standard settings, and after testing using optimized settings. Optimal settings, determined by greatest increase in rectal compliance, were shorter pulse width in five patients and higher frequency in seven. Optimized stimulation resulted in a decrease in mean episodes of incontinence from 2.3 to 1.2 per week (P = 0.031), soiling from 3.3 to 1.7 days per week (P = 0.016), faecal urgency from 31 to 18 per cent of all evacuations (P = 0.055) and SMCS from 12.3 to 8.7 (P = 0.008); the FIQL coping/behaviour score improved (P = 0.008). With a shorter pulse width and higher frequency, clinical efficacy in patients undergoing SNS for faecal incontinence can be improved.

Interdigitated Electrodes and Their Possibility to Determine the Excitation Region in Neurons in Cultured Networks

This report concerns investigations of the activation process of nerve cells cultured on large planar interdigitated electrodes. Cultured neurons from embryonic rat cerebral cortex form electrophysiologically active networks after one week in vitro. The treatment with antagonists to ionotropic glutamate and GABAA receptors blocks synaptic neurotransmission without affecting intrinsic excitability of neurons. Standard stimulation parameters,which were previously determined to trigger a generalized network response in control networks,were ineffective for activation of networks under a synaptic activity blockade. Here we show that in these conditions a pulse sequence of ten biphasic pulses with amplitude of ±2.2 V is adequate for global network stimulation,without cell damage. In specially designed compartment cultures we analyzed further the stimulation process in control and synaptically blocked networks with cell bodies spatially separated from the electrodes. Our results suggest that the direct stimulation of few neurons trigger network-wide responses by the activation of synaptic connections. Further,the stimulation of axonal neuritic extensions is sufficient to active single neurons.

Prejunctional opioid mu-receptors and adenosine A1-receptors on the sympathetic nerve endings of the rat tail artery interact with the alpha 2-adrenoceptors.

Experiments were designed to study the interaction between prejunctional alpha 2-adrenoceptors and both adenosine and opioid receptors at the postganglionic sympathetic nerve endings innervating the tail artery of the rat. Segments of this vessel were preincubated with [3H]-noradrenaline and then perfused/superfused with [3H]-noradrenaline-free medium. Their perivascular nerves were field stimulated with standard stimulation parameters: 24 pulses at 0.4 Hz, 0.3 ms, 200 mA. In some experiments, the stimulation parameters were adjusted in order to obtain similar reference release values despite the presence of a first release-modulating drug. The adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA; 0.3-10 mumol/l) and [D-Ala2,MePhe4,Glyol5]enkephalin (DAGO; 0.3-10 mumol/l) depressed the stimulation-evoked overflow of tritium in a concentration dependent manner. The release-inhibiting effect of both NECA and DAGO was enhanced in the presence of the alpha 2-adrenoceptor antagonist rauwolscine (3 mumol/1) while it was attenuated in the presence of the alpha 2-adrenoceptor agonist 5-bromo-6-[2-imidazolin-2yl-amino]-quinoxaline (UK-14,304; 0.1 mumol/l). These changes occurred both at standard and adjusted stimulation parameters. These results demonstrate that the prejunctional adenosine A1- and opioid mu-receptors interact with the prejunctional alpha 2-adrenoceptors. The level at which these interactions take place (receptors themselves or transduction mechanisms) as well as the physiological significance of the phenomenon remain to be determined.