Invasive Neuromodulation Research Articles

A Novel Wireless Minimally Invasive Neuromodulation Device for the Treatment of Chronic Intractable Occipital Neuralgia: Case Illustrations

A Novel Wireless Minimally Invasive Neuromodulation Device for the Treatment of Chronic Intractable Occipital Neuralgia: Case Illustrations

Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia.

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia's neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.

An update on migraine: current understanding and future directions

Migraine is a common brain disorder with high disability rates which involves a series of abnormal neuronal networks, interacting at different levels of the central and peripheral nervous system. An increase in the interest around migraine pathophysiology has allowed researchers to unravel certain neurophysiological mechanisms and neurotransmitter involvement culminating in the recent development of novel therapies, which might substantially change the clinical approach to migraine patients. The present review will highlight the current aspects of migraine pathophysiology, covering an understanding of the complex workings of the migraine state and the brain regions responsible for them. We will further discuss the therapeutic agents which have appeared in the most recent years for migraine care, from calcitonin gene-related peptide (CGRP) receptor antagonists, gepants; through serotonin 5-HT1F receptor agonists, ditans, and CGRP or CGRP receptor monoclonal antibodies to invasive and non-invasive neuromodulation techniques.

Long-Term Results of a Simultaneous Trial of Deep Brain and Motor Cortex Stimulation in Refractory Neuropathic Pain

Objective Although deep brain stimulation (DBS) and motor cortex stimulation (MCS) are effective in patients with refractory neuropathic pain, their application is still empirical; there is no consensus on which technique is better. Methods To enhance the success rate of trial stimulation of invasive neuromodulation techniques and identify approapriate stimulation targets in individual patients, we performed a simultaneous trial of thalamic ventralis caudalis (Vc) DBS and MCS in 11 patients with chronic neuropathic pain and assessed the results of the trial stimulation and long-term analgesia. Results Of the 11 patients implanted with both DBS and MCS electrodes, nine (81.8%) had successful trials. Seven of these nine patients (77.8%) responded to MCS, and two (18.2%) responded to Vc DBS. With long-term follow-up (56 ± 27.5 months), the mean numerical rating scale decreased significantly (P < 0.05). The degree of percentage pain relief in the chronic MCS (n = 7) and chronic DBS (n = 2) groups were 34.1% ± 18.2% and 37.5%, respectively, and there was no significant difference (P = 0.807). Five out of the seven MCS patients (71%) and both DBS patients had long-term success with the treatments, defined as >30% pain relief compared with baseline. Conclusions With simultaneous trial of DBS and MCS, we could enhance the success rate of invasive trials. Considering the initial success rate and the less invasive nature of epidural MCS over DBS, we suggest that MCS may be a better, initial means of treatment in chronic intractable neuropathic pain. Further investigations including other subcortical target-associated medial pain pathways are warranted.

P258 Combining tDCS with prismatic adaptation for non invasive neuromodulation of the motor cortex

Introduction Prismatic adaptation (PA) shifts visual field laterally and induces lateralized deviations of spatial attention. Recently, it has been suggested that prismatic goggles are also able to modulate brain excitability ( Magnani, 2014 ), with cognitive after-effects documented even in tasks not necessarily spatial in nature ( Oliveri, 2013 ). Objectives The aim of the present study was to test whether prisms can modulate motor cortical excitability similarly as anodal transcranial direct current stimulation (tDCS) does; to test whether neuromodulatory effects obtained from tDCS and prismatic goggles could interact and induce homeostatic changes in brain excitability. Materials and methods Twenty-four subjects were submitted to single-pulse transcranial magnetic stimulation (TMS) over the right M1 to measure their Input–Output (IO) curve as a measure of cortical excitability ( Carroll, 2011 ). Assessment was made in three experimental groups: before and after rightward PA; before and after atDCS of the right M1; before and after rightward PA and atDCS of the right M1. Results A significant increase of the steepness of the IO curve slope on the right motor cortex was found following either rightward PA or atDCS; on the other hand, a decrease of the steepness of the IO curve slope was found after the combination of rightward PA and atDCS. Conclusion These findings suggest that PA could be an additional tool to modulate cortical plasticity in motor cortices and that an increase or a decrease in corticospinal excitability depends on the functional state of the M1 before or at the time of conditioning ( Lang, 2004 ).

Surgical Neurostimulation for Spinal Cord Injury.

Traumatic spinal cord injury (SCI) is a devastating neurological condition characterized by a constellation of symptoms including paralysis, paraesthesia, pain, cardiovascular, bladder, bowel and sexual dysfunction. Current treatment for SCI involves acute resuscitation, aggressive rehabilitation and symptomatic treatment for complications. Despite the progress in scientific understanding, regenerative therapies are lacking. In this review, we outline the current state and future potential of invasive and non-invasive neuromodulation strategies including deep brain stimulation (DBS), spinal cord stimulation (SCS), motor cortex stimulation (MCS), transcutaneous direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) in the context of SCI. We consider the ability of these therapies to address pain, sensorimotor symptoms and autonomic dysregulation associated with SCI. In addition to the potential to make important contributions to SCI treatment, neuromodulation has the added ability to contribute to our understanding of spinal cord neurobiology and the pathophysiology of SCI.

Deep Brain Stimulation for Alzheimer's Disease: Ethical Challenges for Clinical Research.

Deep brain stimulation (DBS) is an invasive neuromodulation modality that has shown early promise as a novel treatment of Alzheimer's disease (AD). Further clinical research is warranted on the basis of positive results from animal and human studies, as well as the inadequacy of existing treatments in reducing the enormous medical and financial costs of untreated AD. Nevertheless, unique ethical challenges require particular attention to elements of subject enrollment and informed consent. Study protocols should specify robust assessment and regular monitoring of subject decision-making capacity to consent to trial participation. Investigators should also assess for and mitigate therapeutic misconception (the phenomenon whereby a research participant conflates the goals of research with those of clinical treatment) and ensure that all prospective trial participants have adequate post-trial access to treatment and DBS device maintenance. In the following discussion, each issue is summarized and followed by recommendations for proper ethical procedure. We conclude by assimilating relevant ethical considerations into a decision-making algorithm designed to aid future clinical investigators of DBS for AD with the task of ethical subject enrollment.

Flexible Neural Electrode Array Based-on Porous Graphene for Cortical Microstimulation and Sensing.

Neural sensing and stimulation have been the backbone of neuroscience research, brain-machine interfaces and clinical neuromodulation therapies for decades. To-date, most of the neural stimulation systems have relied on sharp metal microelectrodes with poor electrochemical properties that induce extensive damage to the tissue and significantly degrade the long-term stability of implantable systems. Here, we demonstrate a flexible cortical microelectrode array based on porous graphene, which is capable of efficient electrophysiological sensing and stimulation from the brain surface, without penetrating into the tissue. Porous graphene electrodes show superior impedance and charge injection characteristics making them ideal for high efficiency cortical sensing and stimulation. They exhibit no physical delamination or degradation even after 1 million biphasic stimulation cycles, confirming high endurance. In in vivo experiments with rodents, same array is used to sense brain activity patterns with high spatio-temporal resolution and to control leg muscles with high-precision electrical stimulation from the cortical surface. Flexible porous graphene array offers a minimally invasive but high efficiency neuromodulation scheme with potential applications in cortical mapping, brain-computer interfaces, treatment of neurological disorders, where high resolution and simultaneous recording and stimulation of neural activity are crucial.

Clinical Significance of Invasive Motor Cortex Stimulation for Trigeminal Facial Neuropathic Pain Syndromes

Invasive neuromodulation of the cortical surface for various chronic pain syndromes has been performed for >20 years. The significance of motor cortex stimulation (MCS) in chronic trigeminal neuropathic pain (TNP) syndromes remains unclear. Different techniques are performed worldwide in regard to operative procedure, stimulation parameters, test trials, and implanted materials. To present the clinical experiences of a single center with MCS, surgical approach, complications, and follow-up as a prospective, noncontrolled clinical trial. The implantation of epidural leads over the motor cortex was performed via a burr hole technique with neuronavigation and intraoperative neurostimulation. Special focus was placed on a standardized test trial with an external stimulation device and the implementation of a double-blinded or placebo test phase to identify false-positive responders. A total of 36 patients with TNP were operated on, and MCS was performed. In 26 of the 36 patients (72%), a significant pain reduction from a mean of 8.11 to 4.58 (on the visual analog scale) during the test trial was achieved (P < .05). Six patients were identified as false-positive responders (17%). At the last available follow-up of 26 patients (mean, 5.6 years), active MCS led to a significant pain reduction compared with the preoperative pain ratings (mean visual analog scale score, 5.01; P < .05). MCS is an additional therapeutic option for patients with refractory chronic TNP, and significant long-term pain suppression can be achieved. Placebo or double-blinded testing is mandatory. MCS, motor cortex stimulationNRS, numeric pain rating scaleTNP, trigeminal neuropathic or deafferentation painVAS, visual analog scale.

Inhibition and Excitation of Bladder Function by Tibial Nerve Stimulation Using a Wirelessly Powered Implant: An Acute Study in Anesthetized Cats

Tibial nerve stimulation is a minimally invasive neuromodulation treatment of overactive bladder. However, in addition to our limited understanding of the underlying mechanisms, there are also questions regarding the long-term delivery of tibial nerve stimulation therapy in patients. We aimed to characterize the effects of stimulation frequency using a wirelessly powered implantable stimulation device. Six α-chloralose anesthetized adult male cats were used in this study. A multicontact lead was surgically implanted subcutaneously in the hind limb and used to stimulate the tibial nerve. Using an isovolumetric bladder a short duration of electrical pulses was applied at amplitudes 3 times the motor threshold and at frequencies from 2 to 20 Hz. Implant driven stimulation of the tibial nerve resulted in frequency dependent activation of bladder reflexes. Low frequency tibial nerve stimulation (2 Hz) consistently evoked excitatory responses (mean ± SE 32.9% ± 3.8%). In contrast, higher frequency tibial nerve stimulation (6 to 20 Hz) inhibited bladder function (overall mean 14.9% ± 2.4%). Although low foot motor thresholds were achieved at initial implantation (mean 0.83 ± 0.05 mA), a notable elevation in threshold amplitude was observed 5 hours after implantation. To our knowledge this study provides the first evidence of frequency dependent modulation of bladder function in anesthetized cats. The inhibitory influence of tibial nerve stimulation at frequencies above 6 Hz transitioned to an excitatory effect at 2 Hz. Taken together these preclinical data support the feasibility of using a wirelessly powered implantable device to potentially modulate bladder function in patients.

Potential Mechanisms Supporting the Value of Motor Cortex Stimulation to Treat Chronic Pain Syndromes.

Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary MCS to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1) modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g., glutamate, GABA, and serotonin) as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of MCS to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g., tDCS and TMS), which are analyzed comparatively.

Spinal cord stimulation improves forelimb use in an alpha-synuclein animal model of Parkinson's disease

Neuromodulation by spinal cord stimulation has been proposed as a symptomatic treatment for Parkinson's disease. We tested the chronic effects of spinal cord stimulation in a progressive model of Parkinson's based on overexpression of alpha-synuclein in the substantia nigra. Adult Sprague Dawley rats received unilateral injections of adeno-associated virus serotype 6 (AAV6) in the substantia nigra to express alpha-synuclein. Locomotion and forepaw use of the rats were evaluated during the next 10 weeks. Starting on week 6, a group of AAV6-injected rats received spinal cord stimulation once a week. At the end of the experiment, tyrosine hydroxylase and alpha-synuclein immunostaining were performed. Rats with unilateral alpha-synuclein expression showed a significant decrease in the use of the contralateral forepaw, which was mildly but significantly reverted by spinal cord stimulation applied once a week from the 6th to the 10th week after the AAV6 injection. Long-term spinal cord stimulation proved to be effective to suppress or delay motor symptoms in a sustained and progressive model of Parkinson's and might become an alternative, less invasive neuromodulation option to treat this disease.

Cortical neurostimulation for neuropathic pain

The treatment of neuropathic pain by neuromodulation is an objective for more than 40 years in modern clinical practice. With respect to spinal cord and deep brain structures, the cerebral cortex is the most recently evaluated target of invasive neuromodulation therapy for pain. In the early 90s, the first successes of invasive epidural motor cortex stimulation (EMCS) were published. A few years later was developed repetitive transcranial magnetic stimulation (rTMS), a noninvasive stimulation technique. Then, electrical transcranial stimulation returned valid and is currently in full development, with transcranial direct current stimulation (tDCS). Regarding transcranial approaches, the main studied and validated target was still the motor cortex, but other cortical targets are under investigation. The mechanisms of action of these techniques share similarities, especially between EMCS and rTMS, but they also have differences that could justify specific indications and applications. It is therefore important to know the principles and to assess the merit of these techniques on the basis of a rigorous assessment of the results, to avoid fad. Various types of chronic neuropathic pain syndromes can be significantly relieved by EMCS or repeated daily sessions of high-frequency (5-20 Hz) rTMS or anodal tDCS over weeks, at least when pain is lateralized and stimulation is applied to the motor cortex contralateral to pain side. However, cortical stimulation therapy remains to be optimized, especially by improving EMCS electrode design, rTMS targeting, or tDCS montage, to reduce the rate of nonresponders, who do not experience clinically relevant effects of these techniques.

Invasive neuromodulation in the treatment of drug-resistant epilepsies

Neuromodulation is one of the most developing new disciplines of medical science, which examines how electrical, chemical and mechanical interventions can modulate or change the functioning of the central and peripheral nervous system. Neuromodulation is a reversible form of therapy which uses electrical or mechanical stimulation or centrally-delivered drugs to modulate the abnormal function of the central nervous system in pain, spasticity, epilepsy, movement and psychiatric disorders, and certain cardiac, incontinency, visual and auditory diseases. Neuromodulation therapy has two major branches. Non-invasive neuromodulation includes transcranial magnetic simulation, direct current stimulation and transcutaneous electric nerve stimulation. Invasive neuromodulation includes deep brain stimulation, cortical stimulation, spinal cord stimulation, peripheral nerve stimulation, sacral nerve simulation, and subcutan stimulation. In this article the authors overview the apparently available neural interface technologies in epilepsy surgery.

High Rates of Undiagnosed Psychological Distress Exist in a Referral Population for Spinal Cord Stimulation in the Management of Chronic Pain.

Neuropathic pain affects various dimensions of patient health including physical, psychological, and socioeconomic. The spectrum of psychological dysfunction that accompanies this pain phenotype is unknown, as well as differences based on the etiology of the pain among patients referred for spinal cord stimulation (SCS). We prospectively assessed SCS referral patients with neuropathic pain for features of psychological distress, either mood or anxiety. Demographic data included age, gender, diagnosis, marital status, and educational level. Screening tools were applied for neuropathic pain (Douleur Neuropathic Quatre and Leeds Assessment of Neuropathic Symptoms and Signs) and psychological distress (Beck Depression Inventory [BDI] and Beck Anxiety Inventory [BAI]). Descriptive statistics defined disease prevalence, compared by gender and diagnosis. Logistic regression correlated pain intensity with severity of psychopathology. Among 150 patients with suitable neuropathic pain diagnoses and no treatable structural pathology, 57% were women, median age was 54 years, and 35% and 42% admitted to routine smoking and alcohol use, respectively. The most common diagnoses were complex regional pain syndrome (46%) and failed back surgery syndrome (38%). Depression symptoms were screened positive by BDI in 63% of patients, and anxiety symptoms were screened positive by BAI in 23% of patients. Pain intensity correlated with BDI scores (p < 0.02) but not BAI scores (p = 0.43). The high frequency of depressive and anxiety symptoms screened by the Beck scores in this cohort is an order of magnitude higher than seen in the general population. That many of these cases are undiagnosed should motivate clinicians from primary care providers, comprehensive pain specialists, and surgeons to screen SCS patients for such psychopathology. This represents an opportunity to enhance overall pain management as well as success with invasive neuromodulation strategies.

Dissecting neural circuits for multisensory integration and crossmodal processing.

We rely on rich and complex sensory information to perceive and understand our environment. Our multisensory experience of the world depends on the brain's remarkable ability to combine signals across sensory systems. Behavioural, neurophysiological and neuroimaging experiments have established principles of multisensory integration and candidate neural mechanisms. Here we review how targeted manipulation of neural activity using invasive and non-invasive neuromodulation techniques have advanced our understanding of multisensory processing. Neuromodulation studies have provided detailed characterizations of brain networks causally involved in multisensory integration. Despite substantial progress, important questions regarding multisensory networks remain unanswered. Critically, experimental approaches will need to be combined with theory in order to understand how distributed activity across multisensory networks collectively supports perception.

Sacral roots stimulation in chronic pelvic pain

IntroductionChronic pelvic pain is a syndrome of chronic non-malignant pain of multifactorial pathophysiology. Perineal, anal and coccygeal pain can be a form of failed-back surgery syndrome or complex regional pain syndrome. Apart from conservative treatment interventional methods are useful in this condition as neurolytic blocks or non-destructive neuromodulation procedures. Peripheral nerve, spinal cord stimulation or sacral stimulation can be applied. AimWe describe a minimally invasive method of sacral roots stimulation with percutaneous electrodes implanted through the sacral hiatus in the treatment of chronic pelvic pain. Materials and methodsWe evaluated a series of nine female patients with pelvic pain treated with sacral roots stimulation in regard of efficacy and complications of this method. ResultsShort-term results in all patients were satisfactory with statistically significant improvement (median VAS=9 before surgery) (median VAS=2 after implantation, p=0.001), (median VAS=3 after 6 months, p=0.043). The long-term follow-up revealed less satisfactory result (median VAS=6 after 12 months). High incidence of complications was noted: mainly infection in 3/9 patients. ConclusionSacral roots stimulation is a non-destructive and minimally invasive neuromodulation method in the treatment of chronic pelvic pain. It can be effective even in the long-term observation but special care is advised to secure aseptic conditions in the implantation and to prevent the infection which leads to removal of the stimulating system.

Noninvasive neuromodulation in cluster headache.

Neuromodulation is an alternative in the management of medically intractable cluster headache patients. Most of the techniques are invasive, but in the last 2 years, some studies using a noninvasive device have been presented. The objective of this article is to review the data using this approach. Techniques as occipital nerve stimulation or sphenopalatine ganglion stimulation are recommended as first-line therapy in refractory cluster patients, but they are invasive and maybe associated with complications. Noninvasive vagal nerve stimulation with an external device has been tried in cluster patients. Results from clinical practice and a single randomized clinical trial have been presented showing a reduction of the number of cluster attacks/week in the patients treated with the device. The rate of adverse events was low and most of them were mild. In the last decade, invasive neuromodulation treatments have demonstrated good efficacy in cluster refractory patients. Noninvasive approaches such as the noninvasive vagal nerve stimulation have shown efficacy in one trial and could be an easier alternative in the management of this debilitating headache. We need to replicate these results with further controlled studies and conduct basic research in order to clarify the mechanism of action.

Minimally invasive motor cortex stimulation for Parkinson's disease.

Extra/intradural strip electrode implantation on motor cortex may be possible minimally invasive neurosurgical method for therapeutic neuromodulation in Parkinson's disease (PD). The aim of this review is to assess motor cortex stimulation (MCS) efficacy and safety in advanced PD. Sixteen published articles were included with a total of 130 PD patients treated. In almost all results are from prospective observational open labeled study, only in two studies blinded assessment was carried out. Negative results are reported in three studies. Significant improvement in motor symptoms with remarkable effect on axial symptoms, L-dopa-induced dyskinesia and quality of life are outlined in thirteen studies. Surgical technique involved implant of four-contact strip electrode over M1 in epidural space with exception of few cases in which implant was carried out in subdural space. Surgical procedure was performed contralateral to most affected side with exception of five patients in which it was carried at dominant hemisphere; in four patients electrode implant was bilateral but stimulation was carried out simultaneously on both sides only in two cases. Complications and adverse events occurred very rarely for extradural MCS whereas with higher rate for subdural MCS. Based on review of current literature extra/intradural MCS represents an alternative to deep brain stimulation (DBS) to surgically treat PD patients who are not candidate for DBS. MCS is a minimally invasive neuromodulation procedure with low morbidity-mortality that can relieve all three major symptoms of PD on both sides simultaneously and bilaterally; it has significant effectiveness on axial symptoms, gait disturbances and therapy complications.

Neuromodulation - new techniques

Neuromodulative procedures have become an inherent component in the therapy of functional urinary bladder and pelvic floor function disorders. Sacral neuromodulation has been used in Germany for more than 20 years and reresents the standard neuromodulative therapy. Technical improvements in the field of test stimulation and the phasing out of the large pulse generator models represent current changes with the resulting advantages and disadvantages. Pudendal neuromodulation (PNM) has been known for many years as a procedure for treatment of chronic diseases of the urinary bladder and the lesser pelvis and is predominantly used as second-line neuromodulative therapy; however, for pelvic pain syndromes and in particular for pudendal neuralgia, it represents a promising minimally invasive first-line therapy. Due to the technically demanding puncture procedure, PNM has so far only been used in Germany in specialized centers. Through the development of new operation techniques, the prerequisites for a wider multicentric use, with the future aim of approval of the procedure, have been achieved. External transdermal pudendal neuromodulation is a promising therapeutic approach and after further testing in randomized studies could find an application as a conservative step before minimally invasive pudendal neuromodulation. Although the technique of laparoscopic electrode placement on neural structures of the lesser pelvis is technically attractive, it predominantly finds a monocentric use and must in due course be critically compared with established minimally invasive procedures.