Active Neurostimulation Research Articles

Characterization of neural networks involved in transdiagnostic emotion dysregulation from a pilot randomized controlled trial of a neurostimulation-enhanced behavioral intervention

BackgroundEmotional dysregulation is a serious and impairing mental health problem. We examined functional activity and connectivity of neural networks involved in emotional dysregulation at baseline and following a pilot neurostimulation-enhanced cognitive restructuring intervention in a transdiagnostic clinical adult sample. MethodsNeuroimaging data were analyzed from adults who scored 89 or higher on the Difficulties with Emotion Regulation (DERS) scale and had at least one DSM-5 diagnosis. These participants were part of a pilot randomized, double-blind, placebo-controlled trial combining a single therapeutic session of cognitive restructuring with active or sham transcranial magnetic stimulation over the dorsolateral prefrontal cortex. During the study, participants engaged in an emotional regulation task using personalized autobiographical stressors while undergoing functional magnetic resonance imaging (fMRI) before and after the pilot intervention. The fMRI task required participants to either experience the emotions associated with the memories or apply cognitive restructuring strategies to reduce their distress. ResultsWhole-brain fMRI results during regulation at baseline revealed increased activation in the dorsal frontoparietal network but decreased activation in the supplementary motor area, cingulate cortex, insula, and ventrolateral prefrontal cortex (vlPFC). Emotion dysregulation was associated with greater vmPFC and amygdala activation and functional connectivity between these regions. The strength of functional connectivity between the dlPFC and other frontal regions was also a marker of emotional dysregulation. Preliminary findings from a subset of participants who completed the follow-up fMRI scan showed that active neurostimulation improved behavioral indices of emotion regulation more than sham stimulation. A whole-brain generalized psychophysiological interaction analysis indicated that active neurostimulation selectively increased occipital cortex connectivity with both the insula and the dlPFC. Region-of-interest functional connectivity analyses showed that active neurostimulation selectively increased dlPFC connectivity with the insula and orbitofrontal cortex (OFC). ConclusionInsufficient neural specificity during the emotion regulation process and over-involvement of frontal regions may be a marker of emotional dysregulation across disorders. OFC, vlPFC, insula activity, and connectivity are associated with improved emotion regulation in transdiagnostic adults. In this pilot study, active neurostimulation led to neural changes in the emotion regulation network after a single session; however, the intervention findings are preliminary, given the small sample size. These functional network properties can inform future neuroscience-driven interventions and larger-scale studies.

O153 The use of non-invasive brain stimulation techniques to reduce body weight and food cravings: a systematic review and meta-analysis

Abstract Introduction Non-invasive brain stimulation (NIBS) techniques such as transcranial Direct Current Stimulation (tDCS) and transcranial Magnetic Stimulation (TMS) are safe and simple techniques that have been used to reduce body weight, food cravings and food consumption in patients with obesity. Such strategy, if effective can be used as an adjunct, prior to bariatric surgery. We therefore aim to systematically evaluate current evidence on the efficacy of active NIBS versus sham stimulation in reducing body weight and food cravings. Methods We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) between January 1990 and February 2022. Mean differences (MDs) for continuous outcome variables with 95% confidence intervals (95% CIs) were used to examine the effects of NIBS on body weight and BMI, while the hedges's g test was used to measure the effects on food craving. Results Nineteen RCTs involving 571 participants were included in this study. Active neurostimulation (TMS and tDCS) was significantly more likely than sham stimulation to reduce body weight (TMS: -3.29 kg, P<0.001; tDCS: -0.82 kg, P=0.00) and BMI (TMS: - 0.74, P = 0.00; tDCS: MD= - 0.55, P = 0.54) as well as food cravings (TMS: g= -0.91, P = 0.00; tDCS: g= -0.32, P = 0.04). Conclusion Compared to sham stimulation, our findings indicate that active NIBS can significantly induce a reduction of body weight and food cravings. Hence, these novel techniques may be used as primary or adjunct tools in treating patients with obesity prior to bariatric surgery.

Neurostimulation artifact removal for implantable sensors improves signal clarity and decoding of motor volition.

As the demand for prosthetic limbs with reliable and multi-functional control increases, recent advances in myoelectric pattern recognition and implanted sensors have proven considerably advantageous. Additionally, sensory feedback from the prosthesis can be achieved via stimulation of the residual nerves, enabling closed-loop control over the prosthesis. However, this stimulation can cause interfering artifacts in the electromyographic (EMG) signals which deteriorate the reliability and function of the prosthesis. Here, we implement two real-time stimulation artifact removal algorithms, Template Subtraction (TS) and ε-Normalized Least Mean Squares (ε-NLMS), and investigate their performance in offline and real-time myoelectric pattern recognition in two transhumeral amputees implanted with nerve cuff and EMG electrodes. We show that both algorithms are capable of significantly improving signal-to-noise ratio (SNR) and offline pattern recognition accuracy of artifact-corrupted EMG signals. Furthermore, both algorithms improved real-time decoding of motor intention during active neurostimulation. Although these outcomes are dependent on the user-specific sensor locations and neurostimulation settings, they nonetheless represent progress toward bi-directional neuromusculoskeletal prostheses capable of multifunction control and simultaneous sensory feedback.

0794 Reduction in Restless Legs Syndrome Symptoms with Non-Invasive Peripheral Nerve Stimulation

Abstract Introduction Restless Legs Syndrome (RLS) is a sensorimotor neurological condition characterized by an uncontrollable urge to move the legs that interferes with falling and staying asleep. For the over 5 million Americans with clinically significant RLS, these symptoms occur multiple nights per week, significantly impair quality of life, increase the prevalence of depression and anxiety, and increase suicide risk. FDA-approved medications for RLS are associated with progressively worsening RLS symptoms and numerous adverse events, whereas existing medical device treatments have limited efficacy. Methods We evaluated a novel neurostimulation intervention for RLS developed by Noctrix Health; electrical stimulation was applied non-invasively and bilaterally to the peroneal nerve of patients with moderate-to-severe primary RLS. Stimulation parameters were engineered to maximize therapeutic efficacy while minimizing interference with sleep. To assess the therapeutic efficacy of this technique, we conducted a multi-site randomized patient-blinded crossover trial comparing active neurostimulation treatment to a sham device. Following a lab visit for calibration, optimization, and training, each patient was instructed to self-administer each treatment - active and sham - for 14 consecutive nights at home. Results Active neurostimulation treatment resulted in a clinically significant reduction in RLS severity of 4.2 points on the International RLS Rating Scale (IRLS) relative to sham (P<0.01), comparable to FDA-approved medications. Moreover, 79% of patients demonstrated a clinically significant improvement on the Clinical Global Impressions-Improvement scale (CGI-I) compared to 7% for sham (P<0.01). Conclusion To our knowledge, this is the first sham-controlled study demonstrating a clinically significant reduction in RLS severity resulting from a non-pharmacological intervention. This therapeutic effect was sustained over 2-weeks of in-home patient-administered usage, indicating consistent efficacy. A medical device based on this technology could be a promising alternative or complement to medications. Support Funding was provided by Noctrix Health, Inc.

Enhancing neural efficiency of cognitive processing speed via training and neurostimulation: An fNIRS and TMS study

Speed of Processing (SoP) represents a fundamental limiting step in cognitive performance which may underlie General Intelligence. The measure of SoP is particularly sensitive to aging, neurological or cognitive diseases, and has become a benchmark for diagnosis, cognitive remediation, and enhancement. Neural efficiency of the Dorsolateral Prefrontal Cortex (DLPFC) is proposed to account for individual differences in SoP. However, the mechanisms by which DLPFC efficiency is shaped by training and whether it can be enhanced remain elusive. To address this, we monitored the brain activity of sixteen healthy participants using functional Near Infrared Spectroscopy (fNIRS) while practicing a common SoP task (Symbol Digit Substitution Task) across 4 sessions. Furthermore, in each session, participants received counterbalanced excitatory repetitive transcranial magnetic stimulation (rTMS) during mid-session breaks. Results indicate a significant involvement of the left-DLPFC in SoP, whose neural efficiency is consistently increased through task practice. Active neurostimulation, but not Sham, significantly enhanced the neural efficiency. These findings suggest a common mechanism by which neurostimulation may aid to accelerate learning.

Transcutaneous supraorbital neurostimulation for the prevention of chronic migraine: a prospective, open-label preliminary trial.

Since chronic migraine is difficult to treat and often associated with medication overuse, non-invasive neurostimulation approaches are worth investigating. Transcutaneous supraorbital neurostimulation using the Cefaly® device is promising as a non-invasive preventive treatment for episodic migraine, but no data are available for chronic migraine. Our aim was to perform a preliminary evaluation of the efficacy of the Cefaly® device for the prophylaxis of chronic migraine with or without medication overuse. Primary endpoints were 50% reduction in monthly migraine days and 50% reduction in monthly medication use over 4months. In an open-label study, twenty-three consecutive headache center patients with chronic migraine, diagnosed according to International Headache Society criteria, were recruited prospectively. After informed consent, patients were trained to use Cefaly® and instructed to use it for 20min daily over 4months. All patients received active neurostimulation. Thirty-five percent of the patients enrolled in the study achieved the study endpoints. Over half the patients had a greater than 50% reduction in acute medication consumption.

Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.

Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.

IntroductionThe inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model.MethodsRats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed.ResultsCompared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01).ConclusionsThe severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.

Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial

Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment. In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18-75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 μs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889. Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0 to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. Medtronic.

Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial

Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial. In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259). An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to -20·8 points (SD 17·1; -47·9%; n=40) at 6 months; -26·5 points (19·7; -61·1%; n=31) at 3 years; and -25·1 points (21·3; -57·8%; n=32). The improvement from 6 months to 3 years (-5·7 points [SD 8·4]; -34%) was significant and sustained at the 5-year follow-up (-4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae. 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia. Medtronic.

Use of Noninvasive Interactive Neurostimulation to Improve Short-Term Recovery in Patients with Surgically Repaired Bimalleolar Ankle Fractures: A Prospective, Randomized Clinical Trial

We undertook a trial with 60 patients who had undergone operative reduction and internal fixation of bimalleolar, AO type B2 ankle fractures with comminution. Patients were randomized into 2 groups, one of which received postoperative treatment using a noninvasive interactive neurostimulation device (InterX ®) and the other with a sham device. The trial was designed to test the hypothesis that incorporation of noninvasive interactive neurostimulation into the rehabilitation protocol would result in reduced pain, increased range of motion, reduced edema, and reduced consumption of pain medication, in comparison with the sham therapy group. Outcome measurements included the patient's subjective assessment of level of pain, range of motion, and the extent of edema in the involved ankle, and the use of ketorolac for postoperative control of pain. The results showed significantly better results in the patients receiving treatment with active neurostimulation (repeated measures analysis of variance, P < .001).

OC-066 A preliminary study of neurostimulation based interventions in the treatment of chronic dysphagia post-stroke

<h3>Introduction</h3> Oropharyngeal dysphagia after stroke has an incidence up to 45% and when chronic, leads to increased risk of institutionalisation and death in the long term. Pharyngeal electrical stimulation (PES),1 repetitive transcranial magnetic stimulation (rTMS)2 and paired associative stimulation (PAS)3 are three neurostimulation techniques developed to increase cortical excitability of pharyngeal motor cortex, with therapeutic potential. However the effects of these techniques on chronic but stable swallowing problems in stroke patients remain unknown. We therefore investigated the effects of these interventions in stroke patients with dysphagia persisting for &gt;6 weeks. <h3>Methods</h3> In 12 dysphagic stroke patients (69±9 years (mean±SD), 79±25 weeks post-stroke (mean±SD), 6 left, 5 right hemispheric, 1 undetermined) pharyngeal electromyographic responses were recorded using an intraluminal catheter after the application of single TMS pulses over pharyngeal motor cortex, in order to measure cortico-bulbar excitability before, immediately and 30 minutes after real and sham applications of either: a) PES (10 mins of 5 Hz), b) rTMS (250 repeated TMS pulses at 5 Hz), or c) PAS (10 mins of repeated pairs of pharyngeal and TMS pulse every 20 s). In nine subjects, swallowing performance and safety (aspiration-penetration scores, APs) were assessed with videofluoroscopy before and after both real and sham neurostimulation techniques. <h3>Results</h3> Compared to sham, the application of all neurostimulation interventions showed a significant increase in cortical excitability in the unaffected hemisphere by 54%±17% (mean±SEM) immediately post (repeated measures ANOVA p&lt;0.001, Time*Intervention p=0.005), not observed in the affected hemisphere (p=0.12). In addition, after active neurostimulation, APs were reduced by −14%±6% (mean±SEM) compared to sham (Wilcoxon9s test, p=0.05). Moreover, the delay between the oral and pharyngeal phases of swallowing, important for swallowing safety, was shortened by −56%±13% (mean±SEM) after real neurostimulation (Wilcoxon9s test, p=0.01) compared to sham. There was no consistent difference in cortical or swallowing response between the interventions. <h3>Conclusion</h3> These preliminary results show that neurostimulation interventions have beneficial neurophysiological and behavioural effects in chronic stroke patients with dysphagia, increasing cortical excitability and improving swallowing safety. These findings provide support for neurostimulation being a useful adjunct in swallowing rehabilitation, even in chronic neurologic illness, and lay the foundation for further clinical trials of these forms of intervention.

Impact of electrical neurostimulation on persistent ST elevation after successful reperfusion by primary percutaneous coronary intervention

Aims To study the effect of electrical neurostimulation on the ST segment shift in patients with ST elevation myocardial infarction (STEMI) with residual ST elevation after primary percutaneous coronary intervention (PCI). Methods After primary PCI, 38 patients with STEMI were divided into 2 groups. Group 1 received 15 minutes of active neurostimulation after the baseline electrocardiogram (ECG); group 2 received 15 minutes of active neurostimulation after 15 minutes of nonactive neurostimulation. Results In group 1, ST elevation decreased with neurostimulation from 0.65 ± 0.56 to 0.55 ± 0.51 ( P = .02) and to 0.50 ± 0.52 ( P = .01) without electrical neurostimulation. In group 2, ST elevation changed without neurostimulation from 0.37 ± 0.32 to 0.33 ± 0.30 ( P = NS) and to 0.28 ± 0.27 ( P = .01) with electrical neurostimulation. In a posthoc analysis, 17 responders had higher ST elevation at the ECG before active electrical neurostimulation than 21 nonresponders ( P = .001). Conclusion Electrical neurostimulation may result in significant additional reduction of ST elevation in STEMI after reperfusion treatment, in particular in patients with marked ST elevation on the first ECG after successful primary PCI.

The effect of electrical neurostimulation on collateral perfusion during acute coronary occlusion

BackgroundElectrical neurostimulation can be used to treat patients with refractory angina, it reduces angina and ischemia. Previous data have suggested that electrical neurostimulation may alleviate myocardial ischaemia through increased collateral perfusion. We investigated the effect of electrical neurostimulation on functional collateral perfusion, assessed by distal coronary pressure measurement during acute coronary occlusion. We sought to study the effect of electrical neurostimulation on collateral perfusion.MethodsSixty patients with stable angina and significant coronary artery disease planned for elective percutaneous coronary intervention were split in two groups. In all patients two balloon inflations of 60 seconds were performed, the first for balloon dilatation of the lesion (first episode), the second for stent delivery (second episode). The Pw/Pa ratio (wedge pressure/aortic pressure) was measured during both ischaemic episodes. Group 1 received 5 minutes of active neurostimulation before plus 1 minute during the first episode, group 2 received 5 minutes of active neurostimulation before plus 1 minute during the second episode.ResultsIn group 1 the Pw/Pa ratio decreased by 10 ± 22% from 0.20 ± 0.09 to 0.19 ± 0.09 (p = 0.004) when electrical neurostimulation was deactivated. In group 2 the Pw/Pa ratio increased by 9 ± 15% from 0.22 ± 0.09 to 0.24 ± 0.10 (p = 0.001) when electrical neurostimulation was activated.ConclusionElectrical neurostimulation induces a significant improvement in the Pw/Pa ratio during acute coronary occlusion.