Electrical stimulation of cranial nerves in cognition and disease.

The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy and biophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behavioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose-response stimulation parameters is defined here. Given that afferent cranial nerve axons project directly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher order brain networks, potent effects on cognition are plausible. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specific higher cognitive processes. State-of-the-art current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict that some non-invasive electrical or magnetic stimulation approaches that do not intend to modulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranial nerve stimulation work was conceptually limited to the production of sensory perception, with individual titration of intensity based on the level of perception and tolerability. However, disregarding sensory emulation allows consideration of temporal stimulation patterns (axon recruitment) that modulate the tone of cortical networks independent of sensory cortices, without necessarily titrating perception. For example, leveraging the role of the thalamus as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state. We show that properly parameterized computational models at multiple scales are needed to rationally optimize neuromodulation that target sets of cranial nerves, determining which and how specific brain circuitries are modulated, which can in turn influence cognition in a designed manner.

History of Cranial Nerve-Implanted Stimulators in Otolaryngology.

This article aims to clearly understand the historical development of cranial nerve-implanted stimulators in otolaryngology. The authors also discuss cranial nerve history; initial theory of the functional concept of animal spirit; electrical nerve impulse theory; first electrical otolaryngology cranial nerve stimulation devices; and the development of implanted stimulators.

Occipital Nerve Stimulation Attenuates Neuronal Firing Response to Mechanical Stimuli in the Ventral Posteromedial Thalamus of a Rodent Model of Chronic Migraine.

BACKGROUND: Chronic migraine (CM) is a highly debilitating disease, and many patients remain refractory to medicinal therapy. Given the convergent nature of neuronal networks in the ventral posteromedial nucleus (VPM) and the evidence of sensitization of pain circuitry in this disease, we hypothesize CM rats will have increased VPM neuronal firing, which can be attenuated using occipital nerve stimulation (ONS). OBJECTIVE: To determine whether VPM firing frequency differs between CM and sham rats, and whether ONS significantly alters firing rates during the application of mechanical stimuli. METHODS: Fourteen male Sprague-Dawley rats were infused with inflammatory media once daily through an epidural cannula for 2 wk to induce a CM state. Sham animals (n = 6) underwent cannula surgery but received no inflammatory media. ONS electrodes were implanted bilaterally and single-unit recordings were performed in the VPM of anesthetized rats during mechanical stimulation of the face and forepaw in the presence and absence of ONS. RESULTS: CM rats had significantly higher neuronal firing rates (P < .001) and bursting activity (P < .01) in response to mechanical stimuli when compared to shams. ONS significantly reduced neuronal firing in the VPM of CM rats during the application of 0.8 g (P = .04), 4.0 g (P = .04), and 15.0 g (P = .02) Von Frey filaments. ONS reduced bursting activity in CM rats during the 4.0 and 15 g filaments (P < .05). No significant changes in bursting activity or firing frequency were noted in sham animals during ONS. CONCLUSION: We demonstrate that neuronal spike frequencies and bursting activity in the VPM are increased in an animal model of CM compared to shams. Our results suggest that the mechanism of ONS may involve attenuation of neurons in the VPM of CM rats during the application of mechanical stimuli.

Long-Term Pain Reduction Does Not Imply Improved Functional Outcome in Patients Treated With Combined Supraorbital and Occipital Nerve Stimulation for Chronic Migraine.

BACKGROUND: Dual supraorbital and occipital nerve stimulation (SONS and ONS) have shown promising efficacy in treating primary headaches. However, its functional outcome is not well studied. OBJECTIVE: To present functional outcome studies of combined SONS and ONS for chronic migraine using verified metrics. METHOD: Consecutive patients with both SONS and ONS assessed with Migraine Disability Assessment (MIDAS) and Beck Depression Index (BDI) both preoperatively and postoperatively were studied. Selected predictor variables included patients with ≥50% improvement of pain, disability status, number of years from diagnosis to implantation, and narcotic use. Functional outcome variables included net improvement of ranked MIDAS and BDI scores. Multivariate analysis of variance was performed to assess the correlation between the outcome and predictor variables. RESULTS: Sixteen patients (12 female; average age 52 years old) were studied. Follow-up ranged from 5 to 80 months (average 44.5; σ = 21.4 months). At most recent follow-up, eight patients had a positive response (≥50% improvement in headache), which was the only predictor of functional outcome (total MIDAS, MIDAS-B, and BDI) (p = 0.021). Of note, improvement in functional outcome was only significant during the perioperative 3-6 months period and not throughout long-term follow-up. Among the predictor variables, a strong inverse correlation was found between disability status and positive response to stimulation (r = -0.582). CONCLUSION: There is a paucity of studies in quality of life, productivity, and psychosocial aspects with peripheral nerve stimulation therapy for headache. Patients with a positive response to SONS and ONS also reported overall improvement in their functional status as reflected by MIDAS and BDI in the perioperative period. Unfortunately, this effect waned over the long-term follow-up.

Occipital Nerve Stimulation for Migraine: Update from Recent Multicenter Trials.

Occipital nerve stimulation (ONS) continues to be investigated for the treatment of refractory chronic migraine. Results from case series and from prospective, sham-controlled clinical trials remain inconclusive regarding the efficacy of ONS for migraine treatment. Safety and implantation techniques require improvements since rates of lead migration, infection, and persistent stimulator-related pain continue to be high. Existing data justify further ONS trials with carefully chosen primary outcome(s), adequate statistical power, and improved surgical techniques.

Concordant occipital and supraorbital neurostimulation therapy for hemiplegic migraine; initial experience; a case series.

INTRODUCTION: Hemiplegic migraine is a particularly severe form of the disease that often evolves to a debilitating chronic illness that is resistant to commonly available therapies. Peripheral neurostimulation has been found to be a beneficial therapy for some patients among several diagnostic classes of migraine, but its potential has not been specifically evaluated for hemiplegic migraine. MATERIALS AND METHODS: Four patients with hemiplegic migraine were treated with concordant, combined occipital and supraorbital neurostimulation over periods ranging 6-92 months. The clinical indicators followed included assessments of headache frequency and severity, frequency of hemiplegic episodes, functional impairment, medication usage, and patient satisfaction. RESULTS: All reported a positive therapeutic response, as their average headache frequency decreased by 92% (30 to 2.5 headache days/month); Visual Analog Score by 44% (9.5 to 5.3); frequency of hemiplegic episodes by 96% (7.5 to 0.25 hemiplegic episodes/month); headache medication usage by 96% (6 to 0.25 daily medications); and Migraine Disability Assessment score by 98% (249 to 6). All were satisfied and would recommend the therapy, and all preferred combined occipital-supraorbital neurostimulation to occipital neurostimulation alone. CONCLUSIONS: Concordant combined occipital and supraorbital neurostimulation may provide effective therapy for both the pain and motor aura in some patients with hemiplegic migraine.

Analysis of adverse events in the management of chronic migraine by peripheral nerve stimulation.

OBJECTIVE: In this study, we analyze device- and procedure-related adverse events (AEs) from a recent prospective, multicenter, double-blinded controlled study that utilized peripheral nerve stimulation (PNS) of occipital nerves for management of chronic migraine. METHODS: PNS device characteristics (lead length and spacing), surgical techniques including lead orientation (parallel or perpendicular to the nerve), and implantable pulse generator (IPG) placement (upper buttock, abdomen, infraclavicular, or lower axilla) in 157 patients were analyzed to identify any relationship with the AE incidence rate. Number of prior PNS implants performed (NPPIP) by the implanter and its relationship with different AE categories (hardware-related, biological, and stimulation-related events) and frequently observed device/procedure-related AEs (lead migration/fracture/breakage, persistent pain at the lead/IPG location, unintended/undesirable changes in stimulation, infection) were also evaluated. Three-way ANOVA tests were utilized to evaluate the dependence of AE occurrence on the variables described above. RESULTS: IPG pocket locations closer to the lead (e.g. infraclavicular region) were associated with a lower AE incidence rate (p < 0.05). Higher NPPIP was related to lower stimulation- and hardware-related AEs (p < 0.05), frequently observed AEs like lead migration, pain, and infection (p < 0.05), and procedure-related additional surgeries (p < 0.05). CONCLUSION: Implantation of the IPG closer to the lead location was associated with reduced AEs. PNS is a relatively new procedure, and the skill and precision in performing these procedures improves with experience. Our results demonstrate that as the implanter gains more experience with these procedures, a significant reduction in device- and procedure-related AEs may be expected.

Dual occipital and supraorbital nerve stimulation for chronic migraine: a single-center experience, review of literature, and surgical considerations.

Occipital nerve stimulation (ONS) has been studied in a few clinical trials for the treatment of chronic migraine (CM) with failure to prove sufficient efficacy. To date, peripheral nerve stimulation for the treatment of primary headache is limited to off-label use only. The authors report their institutional experience in CM therapy with combined ONS and supraorbital nerve stimulation (SONS). Fourteen patients treated with dual ONS and SONS for CM were studied with follow-up ranging from 3 to 60 months. Seventy-one percent achieved successful stimulation as defined by a 50% or greater decrease in pain severity. The mean reduction in headache-related visual analog scale (VAS) score was 3.92 ± 2.4. Half of the patients also had resolution of migraine-associated neurological symptoms and returned to normal functional capacity. The main adverse events included lead migration (42.8%), supraorbital lead allodynia (21.4%), and infection (14.2%) with a resulting high reoperation rate (35.7%). The authors' stimulation efficacy was superior to the combined 33% positive response rates (≥ 50% pain reduction) in the published studies of ONS for CM. This is likely due to the fact that topographical paresthesia induced by combined ONS and SONS covers the area of migraine pain better than ONS alone. The authors also discuss effective surgical techniques to prevent patient morbidity.

Neuropeptide RFRP inhibits the pacemaker activity of terminal nerve GnRH neurons.

The terminal nerve gonadotropin-releasing hormone (TN-GnRH) neurons show spontaneous pacemaker activity whose firing frequency is suggested to regulate the release of GnRH peptides and control motivation for reproductive behaviors. Previous studies of the electrophysiological properties of TN-GnRH neurons reported excitatory modulation of pacemaker activity by auto/paracrine and synaptic modulations, but inhibition of pacemaker activity has not been reported to date. Our recent study suggests that neuropeptide FF, a type of Arg-Phe-amide (RFamide) peptide expressed in TN-GnRH neurons themselves, inhibits the pacemaker activity of TN-GnRH neurons in an auto- and paracrine manner. In the present study, we examined whether RFamide-related peptides (RFRPs), which are produced in the hypothalamus, modulate the pacemaker activity of TN-GnRH neurons as candidate inhibitory synaptic modulators. Bath application of RFRP2, among the three teleost RFRPs, decreased the frequency of firing of TN-GnRH neurons. This inhibition was diminished by RF9, a potent antagonist of GPR147/74, which are candidate RFRP receptors. RFRP2 changed the conductances for Na(+) and K(+). The reversal potential for RFRP2-induced current was altered by inhibitors of the transient receptor potential canonical (TRPC) channel (La(3+) and 2-aminoethoxydiphenyl borate) and by a less selective blocker of voltage-independent K(+) channels (Ba(2+)). By comparing the current-voltage relationship in artificial cerebrospinal fluid with that under each drug, the RFRP2-induced current was suggested to consist of TRPC channel-like current and voltage-independent K(+) current. Therefore, synaptic release of RFRP2 from hypothalamic neurons is suggested to inhibit the pacemaker activity of TN-GnRH neurons by closing TRPC channels and opening voltage-independent K(+) channels. This novel pathway may negatively regulate reproductive behaviors.

Activated cranial cervical cord neurons affect left ventricular infarct size and the potential for sudden cardiac death.

To evaluate whether cervical spinal neurons can influence cardiac indices and myocyte viability in the acutely ischemic heart, the hearts of anesthetized rabbits subjected to 30 min of LAD coronary arterial occlusion (CAO) were studied 3h after reperfusion. Control animals were compared to those exposed to pre-emptive high cervical cord stimulation (SCS; the dorsal aspect of the C1-C2 spinal cord was stimulated electrically at 50 Hz; 0.2 ms; 90% of motor threshold, starting 15 min prior to and continuing throughout CAO). Four groups of animals were so tested: 1) neuroaxis intact; 2) prior cervical vagotomy; 3) prior transection of the dorsal spinal columns at C6; and 4) following pharmacological treatment [muscarinic (atropine) or adrenergic (atenolol, prazosin or yohimbine) receptor blockade]. Infarct size (IS) was measured by tetrazolium, expressed as percentage of risk zone. C1-C2 SCS reduced acute ischemia induced IS by 43%, without changing the incidence of sudden cardiac death (SCD). While SCS-induced reduction in IS was unaffected by vagotomy, it was no longer evident following transection of C6 dorsal columns or atropinization. Beta-adrenoceptor blockade eliminated ischemia induced SCD, while alpha-receptor blockade doubled its incidence. During SCS, myocardial ischemia induced SCD was eliminated following vagotomy while remaining unaffected by atropinization. These data indicate that, in contrast to thoracic spinal neurons, i) cranial cervical spinal neurons affect both adrenergic and cholinergic motor outflows to the heart such that ii) their activation modifies ventricular infarct size and lethal arrhythmogenesis.

Peripheral neuromodulation for migraine headache.

Extremely high prevalence among general population along with the high percentage of treatment-refractory cases makes migraine headaches one of the potentially largest indications for neuromodulation. Cranial peripheral nerve stimulation targeting the occipital nerve(s) alone or in combination with others appears to be both safe and efficacious for the treatment of medically intractable migraine headaches. Although initial reports of occipital nerve stimulation for migraine headaches were very encouraging, this clinical benefit was not clearly confirmed in larger-scale prospective randomized trials. Moreover, the exact mechanism of neuromodulation effect in migraine treatment remains unclear. Significant further investigation needs to be performed to optimize our knowledge concerning patient selection, stimulation targets and parameters and device programming, and further improve clinical results. At present, neurostimulation for migraine headache pain is performed in the United States on an 'off-label' basis, but based upon our experience and the increasing evidence in the medical literature, we look forward to its approval by the FDA in the near future so that patients suffering from severe, medically intractable headache pain may gain access to these potentially important therapies.

[Bilateral occipital nerve stimulation for the treatment of chronic cluster headache: case series and initiation of a prospective study]. / Beidseitige Nervus-occipitalis-Stimulation zur Behandlung des therapierefraktären chronischen Cluster-Kopfschmerzes: eigene Fallserie und Initiierung einer prospektiven Studie.

BACKGROUND: The chronic cluster headache (CCH) is a disabling disorder for every patient. Treatment is a challenging situation for the physician. Some patients will not experience adequate resolution of their cluster attacks by medication and the prophylaxis does not reduce the attacks sufficiently. Therefore, other treatment options have to be found. METHODS: Since December 2008 seven patients with CCH have been treated by bilateral occipital nerve stimulation (ONS) at the University Hospital Essen. Implantation of the electrodes and stimulation paradigms were standardised. The maximum follow-up to date is 12 months. RESULTS: ONS was successfully employed in all patients. The intensity of the attacks decreased by 50 %. The consumption of attack medication was reduced by 77 % on average. Some patients could reduce their medication prophylaxis. A tendency towards improved quality of life was seen in all patients by means of a standardised questionnaire (SF-36). One generator had to be exchanged due to infection. Scar formations required reoperation and adhesiolysis of the thoracic connector in another patient. 6 out of 7 patients would fully recommend the operation. CONCLUSION: Bilateral ONS is a promising treatment for CCH, with a low risk profile in our experience. Further studies have to be conducted to clarify the mechanism of the stimulation and optimal parameters of ONS. For this particular reason, patients with CCH have been included in a prospective study since October 2009.

Occipital nerve stimulator placement under general anesthesia: initial experience with 5 cases and review of the literature.

Anesthesiologists support nerve stimulator insertion procedures, including occipital nerve stimulator placement for refractory headache disorders. Sedation during these cases can be challenging on account of variable surgical stimuli and surgery positioning that contribute to neck flexion, potentially compromising the airway. Greater patient comfort and safety may be found in performing permanent occipital stimulator placement procedures entirely under general anesthesia, assuming that appropriate stimulation patterns can be achieved in patients who are unable to provide intraoperative feedback. The purpose of this study is to describe our initial experience with occipital nerve stimulator placement performed entirely under general anesthesia and the resulting stimulation patterns, and to review the medical literature regarding the anesthetic techniques used during these novel neurosurgical procedures. After institutional review board approval, we reviewed the records of 5 patients who underwent permanent occipital nerve stimulator placement under general anesthesia. Appropriateness of the postoperative stimulation patterns was noted in addition to complications. The medical literature was searched for occipital stimulation surgery studies that also described the anesthetic technique. We found that all 5 patients underwent uncomplicated general anesthetics. Postoperative occipital stimulation was nonpainful and symmetrical for all. The literature search provided little information on the anesthetic technique; most procedures were performed at least in part under local anesthesia with sedation. On the basis of this small case series, we conclude that the occipital nerve stimulator systems can be successfully placed under general anesthesia while still achieving the desired occipital region stimulation. Further studies are needed to correlate occipital nerve stimulator placement under general anesthesia and long-term headache control.

Implant for augmentation of cerebral blood flow trial 1: a pilot study evaluating the safety and effectiveness of the Ischaemic Stroke System for treatment of acute ischaemic stroke.

INTRODUCTION: In rat stroke models, sphenopalatine ganglion stimulation up to 24 h after stroke onset augments cerebral blood flow, reduces infarct volume and improves neurological deficits. The ischaemic stroke system 500 has been designed to stimulate the sphenopalatine ganglion in humans. OBJECTIVES: (1) To determine the safety and tolerability of the ischaemic stroke system 500 in acute ischaemic stroke within 24 h of stroke onset. (2) To determine the effectiveness of ischaemic stroke system 500 in acute ischaemic stroke treatment. DESIGN/METHODS: Implant for augmentation of cerebral blood flow trial-1 is a multi-national open-label study in patients of acute ischaemic stroke in the anterior circulation with National Institutes of Health Stroke Scales 7-20. The treatment initiation will be within 24 h of stroke onset. The ischaemic stroke system is implanted adjacent to the sphenopalatine ganglion via the greater palatine canal using local anaesthesia and a minimally invasive approach. The treatment protocol is constituted as 3-4 h of daily stimulation over 5-7 days. CONCLUSIONS: The implant for augmentation of cerebral blood flow trial-1 will determine the safety and tolerability of the ischaemic stroke system 500 in acute ischaemic stroke as reflected by the incidence of adverse events.

Occipital nerve stimulation for headache: mechanisms and efficacy.

Headache disorders are common problems in medicine and it is this commonness that often provides an air of the simple or obvious. Patients expect doctors understand headache; indeed doctors expect they may understand headache, and in turn since simple treatments exist and can be purchased from a supermarket, the very concept of the difficult headache problem has a pejorative connotation. A decade ago none of the authors were using device-based therapies to any substantial extent, and now hardly a week goes by when we will not see a patient who has considerable potential to benefit from such approaches. Here we cover the most promising of the device-based approaches, neurostimulation therapy using occipital nerve stimulation. Far from proven and with much work to be done, this is an exciting potential development for patients and doctors. Other device-based therapies, such as deep brain stimulation for cluster headache and patent foramen ovale closure, are covered elsewhere.

C2 area neurostimulation: a surgical treatment for fibromyalgia.

BACKGROUND: Fibromyalgia (FM), a disorder characterized by diffuse pain, fatigue, and a variety of other symptoms, is thought to derive from dysfunction of the central nervous system. Neuromodulation is a technique to treat pain from a variety of causes, including disorders of the central nervous system (CNS). Occipital nerve stimulation is a neuromodulation technique currently under study to treat various migraine headache disorders. This study examines a technique of neurostimulation that appears to affect the pain and symptoms of FM. OBJECTIVE: To evaluate the effect of a new technique of peripheral neurostimulation of the C2 scalp area on pain, fatigue, depression, and quality of life in FM patients. METHODS: In total, 12 patients (nine females and three males; mean age 48 years) who met criteria for FM, and with comorbid headache disorder, were trialed and implanted with this C2 area stimulation technique. Outcome was prospectively studied with standard evaluation tools at baseline, 3 and 6 months post implant. RESULTS: Visual Analog Scale (VAS) pain levels for FM-related pain decreased significantly at 6 months, and pain-drawing total area and number of areas colored in also decreased dramatically. Chronic fatigue and depression as assessed by the Beck Depression Inventory and Fatigue Impact Scale were markedly improved. Overall quality of life as assessed by the Health Survey Short Form 36 (SF-36) was markedly improved. There were no infectious or technical complications. CONCLUSION: C2 area scalp stimulation may diminish pain and related symptoms in patients with FM.

Chronic cluster headache: new and emerging treatment options.

Cluster headache (CH) is a primary headache syndrome characterized by short-lasting unilateral head pain attacks accompanied by ipsilateral oculofacial autonomic phenomena. Approximately 20% of CH patients have the chronic form and need continuous medical care. In the chronic form, attacks continue unabated for years, often on a daily basis, resulting in severe debilitation. It is a common experience that drug treatments are able to control or prevent the attacks in approximately 80% of chronic CH patients. In the remaining 20% of chronic cases, drugs are ineffective. Until recently, the etiology of CH was poorly understood and this hampered the development of new therapies. However, we have now gained a much improved understanding of the peripheral and central mechanisms giving rise to the pain in CH and this has inspired the development of new treatment approaches, which, although still in the initial phases of validation, appear to be very promising. Among these, the novel approach based on hypothalamic deep brain stimulation is one of the most promising.

Tratamiento nutricional del niño con patología neurológica / Nutritional treatment in child with neurologycal patology

El riesgo de padecer malnutrición es muy alto en niños y adolescentes que padecen determinado tipo de patología neurológica (PN) por una diversidad de factores que en ellos concurren: trastornos de coordinación motora de la deglución en sus distintas fases, reflujo gastroesofágico, esofagitis, gastritis, alteración del reflejo gastrocólico, estreñimiento, anorexia, etc. Estos trastornos alteran la proporcionalidad deseable entre la cantidad de alimento aportado al paciente y las ingestas netas del mismo. Debido a ello se hace necesaria 1) la valoración periódica y sistemática del estado nutricional, adaptada a este tipo de pacientes, y a partir de los datos recabados 2) la toma de decisiones oportunas referidas a su alimentación: requerimientos, opciones para el soporte nutricional, vía de administración y 3) tratamiento de las complicaciones digestivas si las hubiere. Con ello se contribuirá a mejorar su calidad de vida y a disminuir el nivel de estrés que viven las personas encargadas de su cuidado y alimentación. Importa mucho abordar con acierto las particularidades en su comportamiento alimentario. Estas acciones, complejas en su abordaje, requieren un enfoque interdisciplinar. La intencionalidad de este trabajo es contribuir a estos objetivos (AU)