Neuromodulatory Approaches Research Articles

Neuromodulation for treatment-resistant depression: Functional network targets contributing to antidepressive outcomes.

Non-invasive brain stimulation is designed to target accessible brain regions that underlie many psychiatric disorders. One such method, transcranial magnetic stimulation (TMS), is commonly used in patients with treatment-resistant depression (TRD). However, for non-responders, the choice of an alternative therapy is unclear and often decided empirically without detailed knowledge of precise circuit dysfunction. This is also true of invasive therapies, such as deep brain stimulation (DBS), in which responses in TRD patients are linked to circuit activity that varies in each individual. If the functional networks affected by these approaches were better understood, a theoretical basis for selection of interventions could be developed to guide psychiatric treatment pathways. The mechanistic understanding of TMS is that it promotes long-term potentiation of cortical targets, such as dorsolateral prefrontal cortex (DLPFC), which are attenuated in depression. DLPFC is highly interconnected with other networks related to mood and cognition, thus TMS likely alters activity remote from DLPFC, such as in the central executive, salience and default mode networks. When deeper structures such as subcallosal cingulate cortex (SCC) are targeted using DBS for TRD, response efficacy has depended on proximity to white matter pathways that similarly engage emotion regulation and reward. Many have begun to question whether these networks, targeted by different modalities, overlap or are, in fact, the same. A major goal of current functional and structural imaging in patients with TRD is to elucidate neuromodulatory effects on the aforementioned networks so that treatment of intractable psychiatric conditions may become more predictable and targeted using the optimal technique with fewer iterations. Here, we describe several therapeutic approaches to TRD and review clinical studies of functional imaging and tractography that identify the diverse loci of modulation. We discuss differentiating factors associated with responders and non-responders to these stimulation modalities, with a focus on mechanisms of action for non-invasive and intracranial stimulation modalities. We advance the hypothesis that non-invasive and invasive neuromodulation approaches for TRD are likely impacting shared networks and critical nodes important for alleviating symptoms associated with this disorder. We close by describing a therapeutic framework that leverages personalized connectome-guided target identification for a stepwise neuromodulation paradigm.

Ultrasound modulation of neurons by sonogenetics

Focused ultrasound (FUS) can noninvasively deliver ultrasound energy to target any area in the whole brain with combined depth penetration and spatial focusing that cannot be achieved with other external stimulations. Sonogenetics, integrating focused ultrasound with genetic engineering, can achieve noninvasive control of neurons genetically modified with ultrasound-sensitive ion channels. Crucial to the development of sonogenetics has been the identification of ultrasound-sensitive probes to control neurons. FUS propagation through the tissue can generate mechanical and thermal effects within its focal region. This talk will present recent progress in the development of mechanosensitive and thermosensitive ion channels as sonogenetic probes. Recent success in using sonogenetics for noninvasive and cell-type-specific behavior control of freely moving mice will also be presented. This noninvasive and cell-type-specific neuromodulation approach has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders.

Dynamic flexibility and controllability of network communities in juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is the most common syndrome within the idiopathic generalized epilepsy spectrum, manifested by myoclonic and generalized tonic-clonic seizures and spike-and-wave discharges (SWDs) on electroencephalography (EEG). Currently, the pathophysiological concepts addressing SWD generation in JME are still incomplete. In this work, we characterize the temporal and spatial organization of functional networks and their dynamic properties as derived from high-density EEG (hdEEG) recordings and MRI in 40 JME patients (25.4 ± 7.6 years, 25 females). The adopted approach allows for the construction of a precise dynamic model of ictal transformation in JME at the cortical and deep brain nuclei source levels. We implement Louvain algorithm to attribute brain regions with similar topological properties to modules during separate time windows before and during SWD generation. Afterwards, we quantify how modular assignments evolve and steer through different states towards the ictal state by measuring characteristics of flexibility and controllability. We find antagonistic dynamics of flexibility and controllability within network modules as they evolve towards and undergo ictal transformation. Prior to SWD generation, we observe concomitantly increasing flexibility (F(1,39) = 25.3, corrected p < 0.001) and decreasing controllability (F(1,39) = 55.3, p < 0.001) within the fronto-parietal module in γ-band. On a step further, during interictal SWDs as compared to preceding time windows, we notice decreasing flexibility (F(1,39) = 11.9, p < 0.001) and increasing controllability (F(1,39) = 10.1, p < 0.001) within the fronto-temporal module in γ-band. During ictal SWDs as compared to prior time windows, we demonstrate significantly decreasing flexibility (F(1,14) = 31.6; p < 0.001) and increasing controllability (F(1,14) = 44.7, p < 0.001) within the basal ganglia module. Furthermore, we show that flexibility and controllability within the fronto-temporal module of the interictal SWDs relate to seizure frequency and cognitive performance in JME patients. Our results demonstrate that detection of network modules and quantification of their dynamic properties is relevant to track the generation of SWDs. The observed flexibility and controllability dynamics reflect the reorganization of de−/synchronized connections and the ability of evolving network modules to reach a seizure-free state, respectively. These findings may advance the elaboration of network-based biomarkers and more targeted therapeutic neuromodulatory approaches in JME.

An increase in the auditory steady-state response amplitudes after a period of listening to binaural beat stimuli in tinnitus patients: a pilot study

BackgroundTinnitus impact on persons’ lifestyle, function, and emotion is of significant importance that has been the leader for conducting an increasing amount of research in the field of tinnitus pathophysiology, assessment, and management. Binaural beats (BB) are one of acoustic neuromodulation approaches used in psychological disorders, such as distress and anxiety. Thus, we hypothesized that binaural beat could be helpful in the relief of tinnitus distress and annoyance.MethodsSeventeen chronic tinnitus subjects participated in this quasi-experimental (quantitative research) study. In this study, the effect of binaural beat stimuli was evaluated subjectively using the tinnitus handicap inventory (THI) scores, the visual analog scale for loudness and annoyance (VAS_L, VAS_A), and objectively by the 40-Hz ASSR after 1 month of listening to binaural beats, and the correlation between these two assessments was evaluated.ResultsAfter 1 month of binaural beat stimuli listening, all of the subjective findings were significantly improved, and the amplitude of 40-Hz ASSR was increased in the right auditory and anterior frontal regions at 2000-Hz carrier frequency. Besides, there was a high correlation between the decreasing of the subjective scores with the rising of the amplitude of 40-Hz ASSR.ConclusionThe use of binaural beat as an acoustic neuromodulation method for tinnitus management may be recommended according to the current study findings. However, more investigations on the effectiveness supported by data from controlled clinical trials and more correlations with ASSR alteration are highly suggested.

Engineered Sensory Nerve Guides Self-Adaptive Bone Healing via NGF-TrkA Signaling Pathway.

The upstream role of sensory innervation during bone homeostasis is widely underestimated in bone repairing strategies. Herein, a neuromodulation approach is proposed to orchestrate bone defect healing by constructing engineered sensory nerves (eSN) in situ to leverage the adaptation feature of SN during tissue formation. NGF liberated from ECM-constructed eSN effectively promotes sensory neuron differentiation and enhances CGRP secretion, which lead to improved RAOECs mobility and osteogenic differentiation of BMSC. In turn, such eSN effectively drives ossification in vivo via NGF-TrkA signaling pathway, which substantially accelerates critical size bone defect healing. More importantly, eSN also adaptively suppresses excessive bone formation and promotes bone remodeling by activating osteoclasts via CGRP-dependent mechanism when combined with BMP-2 delivery, which ingeniously alleviates side effects of BMP-2. In sum, this eSN approach offers a valuable avenue to harness the adaptive role of neural system to optimize bone homeostasis under various clinical scenario.

The Interictal Suppression Hypothesis in focal epilepsy: network-level supporting evidence.

Why are people with focal epilepsy not continuously having seizures? Previous neuronal signalling work has implicated gamma-aminobutyric acid balance as integral to seizure generation and termination, but is a high-level distributed brain network involved in suppressing seizures? Recent intracranial electrographic evidence has suggested that seizure-onset zones have increased inward connectivity that could be associated with interictal suppression of seizure activity. Accordingly, we hypothesize that seizure-onset zones are actively suppressed by the rest of the brain network during interictal states. Full testing of this hypothesis would require collaboration across multiple domains of neuroscience. We focused on partially testing this hypothesis at the electrographic network level within 81 individuals with drug-resistant focal epilepsy undergoing presurgical evaluation. We used intracranial electrographic resting-state and neurostimulation recordings to evaluate the network connectivity of seizure onset, early propagation and non-involved zones. We then used diffusion imaging to acquire estimates of white-matter connectivity to evaluate structure-function coupling effects on connectivity findings. Finally, we generated a resting-state classification model to assist clinicians in detecting seizure-onset and propagation zones without the need for multiple ictal recordings. Our findings indicate that seizure onset and early propagation zones demonstrate markedly increased inwards connectivity and decreased outwards connectivity using both resting-state (one-way ANOVA, P-value = 3.13 × 10-13) and neurostimulation analyses to evaluate evoked responses (one-way ANOVA, P-value = 2.5 × 10-3). When controlling for the distance between regions, the difference between inwards and outwards connectivity remained stable up to 80 mm between brain connections (two-way repeated measures ANOVA, group effect P-value of 2.6 × 10-12). Structure-function coupling analyses revealed that seizure-onset zones exhibit abnormally enhanced coupling (hypercoupling) of surrounding regions compared to presumably healthy tissue (two-way repeated measures ANOVA, interaction effect P-value of 9.76 × 10-21). Using these observations, our support vector classification models achieved a maximum held-out testing set accuracy of 92.0 ± 2.2% to classify early propagation and seizure-onset zones. These results suggest that seizure-onset zones are actively segregated and suppressed by a widespread brain network. Furthermore, this electrographically observed functional suppression is disproportionate to any observed structural connectivity alterations of the seizure-onset zones. These findings have implications for the identification of seizure-onset zones using only brief electrographic recordings to reduce patient morbidity and augment the presurgical evaluation of drug-resistant epilepsy. Further testing of the interictal suppression hypothesis can provide insight into potential new resective, ablative and neuromodulation approaches to improve surgical success rates in those suffering from drug-resistant focal epilepsy.

Time since onset might be of essence: A recommendation to assess the effects of combination of non-pharmacological neuromodulatory approaches at early stage since symptoms onset.

In the past decade researchers began to assess the potential beneficial effects of non-invasive brain stimulation (NIBS) combined with a behavioral task as a treatment approach for various medical conditions. Transcranial direct current stimulation (tDCS) applied to the motor cortex combined with another treatment approach has been assessed as analgesic treatment in neuropathic and non-neuropathic pain conditions, and was found to exert only modest pain relief. Our group results show that combined tDCS and mirror therapy dramatically reduced acute phantom limb pain intensity with long-lasting effects, potentially preventing pain chronification. A review of the scientific literature indicates that our approach differs from that of others: We applied the intervention at the acute stage of the disease, whereas other studies applied the intervention in patients whose disease had already been established. We suggest that the timing of administration of the combined intervention is critical. Unlike in patients with chronic painful condition, in which the maladaptive plasticity associated with pain chronification and chronicity is well-consolidated, early treatment at the acute pain stage may be more successful in counterbalancing the not-yet consolidated maladaptive plasticity. We encourage the research community to test our hypothesis, both in the treatment of pain, and beyond.

Effects of electrostatic therapy on nighttime sleep and daytime symptoms in patients with chronic insomnia: Evidences from an open label study.

Transcranial electric stimulation (TES) is a neuromodulation approach that applies low-intensity electrical current to the brain and has been proposed as a treatment for insomnia. Electrostatic therapy is a kind of TES and people do not have a feeling of electrical stimuli when the voltage of static electricity is lower than 2,000 volts. However, no studies have examined the effects of electrostatic therapy on objective sleep and daytime symptoms in patients with insomnia. Thirty chronic insomnia patients were included. All patients received a 6 week electrostatic therapy and three comprehensive assessments including two consecutive polysomnography (PSG) and daytime symptoms assessments, at pre-treatment, 3 week and 6 week of treatment. Insomnia Severity Index (ISI) was used to assess the severity of insomnia. Multiple sleep latency test (MSLT), Epworth Sleepiness Scale (ESS), and Flinders Fatigue Scale (FFS) were used to assess objective and self-reported daytime sleepiness and fatigue, respectively. Attention network test (ANT) was used to assess attention levels. Total ISI scores decreased significantly at 3 weeks (p < 0.001) and 6 weeks (p < 0.001) after initiation of treatment. Furthermore, objective total sleep time (TST, p = 0.020) and sleep efficiency (SE, p = 0.009) increased and wake time after sleep onset (p = 0.012) decreased significantly after 6 weeks electrostatic therapy. Regarding daytime symptoms, ESS and FFS scores decreased significantly at 3 weeks (ESS, p = 0.047; FFS, p = 0.017) and 6 weeks (ESS, p = 0.008; FFS, p = 0.003) after initiation of treatment. Moreover, executive control improved significantly from pre-treatment to 3 weeks (p = 0.006) and 6 weeks (p = 0.013) and altering network improved significantly at 6 weeks (p = 0.003) after initiation of treatment. Secondary analyses showed that TST and SE improved significantly after electrostatic therapy in insomnia patients who slept < 390 min (all p-value < 0.05). However, no significant changes regarding TST and SE were observed in insomnia patients who slept ≥ 390 min. Electrostatic therapy improves both nighttime sleep and daytime symptoms in patients with chronic insomnia. The effect on objective sleep appears to be stronger in patient with objective short sleep duration. Electrostatic therapy might be a therapeutic choice for insomnia patients with difficulty maintaining sleep and not responding to behavioral treatments. [www.clinicaltrials.gov], identifier [ChiCTR2100051590].

Bibliometric and Visual Analysis of the Scientific Literature on Percutaneous Electrical Nerve Stimulation (PENS) for Pain Treatment

Background: Percutaneous electrical nerve stimulation (PENS) is a minimally invasive peripheral neuromodulation approach implemented against chronic neuropathic and mixed pain. This bibliometric study aims to quantitatively evaluate the output of PENS for pain treatment in the scientific literature. The main purpose is to stimulate research in the field and bridge potential scientific gaps. Methods: Articles were retrieved from the Web of Science (WOS) database. The search key term was “percutaneous electrical nerve stimulation (All Fields) and pain (All Fields)”. Year of publication, journal metrics (impact factor and quartile, Q), title, document type, topic, and citations were extracted. The join-point regression was implemented to assess differences in time points for the publication output. The software tool VOSviewer (version 1.6.17) was used for the visual analysis. Results: One thousand three hundred and eighteen articles were included in the knowledge visualization process. A linear upward trend for annual new publications was found. Almost two-thirds of the documents were published in top-ranked journals (Q1 and Q2). The topic “efficacy” was prevalent (12.81%). Concerning article type, the search strategy yielded 307 clinical investigations (23.3%). Articles were cited 36,610 times with a mean of 42.4 citations per article. Approximately one-half of the articles were cited less than 23 times in a range of 21 years. The semantic network analysis for keywords found eight clusters. The analysis of collaborative efforts among researchers showed five thematic clusters including 102 authors with a minimum of five documents produced in collaborations. Most partnerships involved the United States, England, and Germany. Conclusions: despite the upward trend in the number of publications on the subject and the publication of articles in top-ranked journals, there is a need to increase scientific collaborations between researchers and institutions from different countries.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Das soziale Gehirn – 2. Bedeutung von erworbenen Hirnschädigungen für das Sozialverhalten: Klinik, Diagnostik und Therapie

Nach erworbenen Hirnschädigungen führen Störungen der sozialen Kognition und der sozialen Kompetenz häufig zu erheblichen Einschränkungen in der sozialen Teilhabe, zu sozialem Rückzug und Isolation. Infolge erhöhter Morbidität und Mortalität sind diese Störungen auch sozialmedizinisch relevant. Allerdings besteht ein Mangel sowohl an Diagnostik als auch an Angeboten therapeutischer oder rehabilitativer Interventionen. Die vorliegende Literaturübersicht plädiert nach einem Überblick über die Studienlage für eine systematischeren Erfassung von Störungen der sozialen Kognition und Kompetenz nach erworbener Hirnschädigung sowie für die Entwicklung und Überprüfung weiterer therapeutische Interventionen zu ihrer Behandlung. Schlüsselwörter: soziale Kognition, soziale Kompetenz, erworbene Hirnschädigung, Schädel-Hirn-Trauma, Schlaganfall, Teilhabe, Rehabilitation

Low-Intensity Focused Ultrasound Neuromodulation for Stroke Recovery: A Novel Deep Brain Stimulation Approach for Neurorehabilitation?

Stroke as the leading cause of adult long-term disability and has a significant impact on patients, society and socio-economics. Non-invasive brain stimulation (NIBS) approaches such as transcranial magnetic stimulation (TMS) or transcranial electrical stimulation (tES) are considered as potential therapeutic options to enhance functional reorganization and augment the effects of neurorehabilitation. However, non-invasive electrical and magnetic stimulation paradigms are limited by their depth focality trade-off function that does not allow to target deep key brain structures critically important for recovery processes. Transcranial ultrasound stimulation (TUS) is an emerging approach for non-invasive deep brain neuromodulation. Using non-ionizing, ultrasonic waves with millimeter-accuracy spatial resolution, excellent steering capacity and long penetration depth, TUS has the potential to serve as a novel non-invasive deep brain stimulation method to establish unprecedented neuromodulation and novel neurorehabilitation protocols. The purpose of the present review is to provide an overview on the current knowledge about the neuromodulatory effects of TUS while discussing the potential of TUS in the field of stroke recovery, with respect to existing NIBS methods. We will address and discuss critically crucial open questions and remaining challenges that need to be addressed before establishing TUS as a new clinical neurorehabilitation approach for motor stroke recovery.

Combined Approaches Leading to Synergistic Therapeutic Effects in Spinal Cord Injury: State of the Art.

Cell-based regenerative medicine approaches and motor rehabilitation are currently being used to overcome the consequences of spinal cord injury (SCI). However, their success in preclinical studies does not always translate into successful implementation in clinical practice. Recent work suggests that modern neuromodulation approaches hold great therapeutic promise. Despite these advances, the complete resolution of functional deficits caused by SCI is impossible, especially in cases of severe injury. Therefore, combined approaches based on cell transplantation and neuromodulation are needed to enhance the neuroregenerative effect. The additional inclusion of a dosed locomotor load in the overall therapeutic plan and against a background of combined approaches can have a significant supportive effect. The aim of this review is to evaluate studies that use combinations of different approaches, thereby advancing our current understanding of the mechanisms that underlie their therapeutic effect. This review will consider mostly the effects and limitations of regenerative approaches, as well as the effects of locomotor load and neuromodulation on molecular and cellular changes in the spinal cord.

Deep Brain Stimulation and Responsive Neurostimulation Implantation for Medically Refractory Epilepsy: A Case Report Study of a Single-Center's Experience

BACKGROUND AND IMPORTANCE: Nearly 25% of all epilepsy is drug-resistant epilepsy. Responsive neurostimulation (RNS) and deep brain stimulation (DBS) offer viable options when resection or ablation is not feasible. Neuromodulation leads to improved seizure control. However, in patients with highly complex epileptogenic networks, a multimodality approach using simultaneous RNS and DBS may provide a summative benefit. CLINICAL PRESENTATION: We present 2 cases of drug-resistant epilepsy who received simultaneous anterior nucleus of the thalamus DBS and RNS neuromodulation. To our knowledge, this is the first report of simultaneous DBS and RNS neurostimulation for the treatment of epilepsy. Given the complexity of their seizure networks, a combined neuromodulatory approach was deemed best to achieve seizure control. Both experienced multiple seizure semiology patterns consistent with multifocal onsets which were confirmed on phase I monitoring, nuclear medicine, and magnetoencephalography studies. Case 1 had a seizure reduction of 75% to 89% at 12 months which has remained stable at last follow-up (26 months) and case 2 achieved near seizure freedom and remained seizure-free at last follow-up (16 months). CONCLUSION: Neuromodulation has proven efficacious and safe in randomized controlled trials for the treatment of epilepsy. This is particularly important in multifocal epilepsy or if resective surgery is not an option. The optimal stimulation pathways and multimodal neuromodulation technique remains under investigation. We are the first to report that RNS and DBS implantation in the same patient is feasible, without major adverse effects and potentially effective.

Device-based neuromodulation for cardiovascular diseases and patient' s age.

The autonomic nervous system plays an important role in the pathogenesis of cardiovascular diseases. With aging, autonomic activity changes, and this impacts the physiological reactions to internal and external signals. Both sympathetic and parasympathetic responses seem to decline, reflecting functional and structural changes in nervous regulation. Although some investigators suggested that both the sympathetic and parasympathetic activities were suppressed, others found that only the parasympathetic activity was suppressed while the sympathetic activity increased. In addition, cardiac innervation progressively diminishes with aging. Therefore, one may suggest that neuromodulation interventions may have different effects, and older age groups can express an attenuated response. This article aims to discuss the effect of device-based neuromodulation in different cardiovascular diseases, depending on the patient's age. Thus, we cover renal denervation, pulmonary artery denervation, baroreceptor activation therapy, vagus nerve stimulation, spinal cord stimulation, ganglionated plexi ablation for the management of arterial and pulmonary hypertension, heart failure, angina and arrhythmias. The results of many clinical studies appeared to be unconvincing. In view of the low rate of positive findings in clinical studies incorporating neuromodulation approaches, we suggest the underestimation of advanced age as a potential contributing factor to poorer response. Analysis of outcomes between different age groups in clinical trials may shed more light on the true effects of neuromodulation when neutral/ambiguous results are obtained.

The efficacy of neurofeedback for alcohol use disorders - a systematic review

Background Alcoholism is a serious social, economic, and public health problem. Alcoholism can affect the gastrointestinal, neurological, cardiovascular, and respiratory systems, and it can be fatal, costing the healthcare system huge amounts of money. Despite the availability of cognitive-behavioral and psychosocial therapies, alcoholism has a high recurrence rate and a dismal prognosis, with a wide inter-individual variation. As a result, better or adjuvant therapies that improve or facilitate alcoholism therapy are required. We conducted a systematic review to look into the published studies that reported the effectiveness of non-pharmacological neurofeedback interventions in patients with alcohol use disorders. Methods PubMed, Google Scholar, The Cochrane Library, Science Direct, and Clinicaltrial.gov were searched until April 04, 2022. Original articles of any design reporting on the use of neurofeedback approaches in the treatment of alcohol use disorders were included. Information related to study design, participants, control group, neuromodulation therapy, number of sessions, and key findings of the study were extracted. The Joanna Briggs Institute’s (JBI) Critical Appraisal Checklist for Studies was used to assess the quality of studies. Results 20 research articles (including 618 participants) were retrieved and included for qualitative analysis. The sample size ranged from one (case report) to eighty, with years of publication ranging from 1977 to 2022. Nine of the 20 articles included in the study were conducted in the United States, followed by Germany, the United Kingdom, India, the Netherlands, and South Korea. Out of the 20 studies included, 8 (40%) had a moderate risk of bias, while the other i.e., 60% had a low risk of bias. The effectiveness of various neurological treatments in the treatment of alcohol use disorders was established in these 20 studies. There have been 11 studies on EEG neurofeedback training, three studies on real-time FMRI neurofeedback, two studies each on transcranial direct current stimulation and transcranial magnetic stimulation, and one study each on deep brain stimulation and theta burst stimulation. These alternative neurological therapies have been demonstrated to lower alcohol cravings and consumption temporarily, reduce anxiety and depression scores, reduce relapse rates, and increase control of brain activity. Conclusion: The use of various neuromodulation approaches to the treatment of alcohol use disorder shows promise. However, more research with larger sample size is required.

Invasive neuromodulation for epilepsy: Comparison of multiple approaches from a single center

BackgroundDrug-resistant epilepsy (DRE) patients not amenable to epilepsy surgery can benefit from neurostimulation. Few data compare different neuromodulation strategies. ObjectiveCompare five invasive neuromodulation strategies for the treatment of DRE: anterior thalamic nuclei deep brain stimulation (ANT-DBS), centromedian thalamic nuclei DBS (CM-DBS), responsive neurostimulation (RNS), chronic subthreshold stimulation (CSS), and vagus nerve stimulation (VNS). MethodsSingle center retrospective review and phone survey for patients implanted with invasive neuromodulation for 2004–2021. ResultsN = 159 (ANT-DBS = 38, CM-DBS = 19, RNS = 30, CSS = 32, VNS = 40). Total median seizure reduction (MSR) was 61 % for the entire cohort (IQR 5–90) and in descending order: CSS (85 %), CM-DBS (63 %), ANT-DBS (52 %), RNS (50 %), and VNS (50 %); p = 0.07. The responder rate was 60 % after a median follow-up time of 26 months. Seizure severity, life satisfaction, and quality of sleep were improved. Cortical stimulation (RNS and CSS) was associated with improved seizure reduction compared to subcortical stimulation (ANT-DBS, CM-DBS, and VNS) (67 % vs. 52 %). Effectiveness was similar for focal epilepsy vs. generalized epilepsy, closed-loop vs. open-loop stimulation, pediatric vs. adult cases, and high frequency (>100 Hz) vs. low frequency (<100 Hz) stimulation settings. Delivered charge per hour varied widely across approaches but was not correlated with improved seizure reduction. ConclusionsMultiple invasive neuromodulation approaches are available to treat DRE, but little evidence compares the approaches. This study used a uniform approach for single-center results and represents an effort to compare neuromodulation approaches.

Spatially controlled, bipolar, cortical stimulation with high-capacitance, mechanically flexible subdural surface microelectrode arrays.

Most neuromodulation approaches rely on extracellular electrical stimulation with penetrating electrodes at the cost of cortical damage. Surface electrodes, in contrast, are much less invasive but are challenged by the lack of proximity to axonal processes, leading to poor resolution. Here, we demonstrate that high-density (40-μm pitch), high-capacitance (>1 nF), single neuronal resolution PEDOT:PSS electrodes can be programmed to shape the charge injection front selectively at depths approaching 300 micrometers with a lateral resolution better than 100 micrometers. These electrodes, patterned on thin-film parylene substrate, can be subdurally implanted and adhere to the pial surface in chronic settings. By leveraging surface arrays that are optically transparent with PEDOT:PSS local interconnects and integrated with depth electrodes, we are able to combine surface stimulation and recording with calcium imaging and depth recording to demonstrate these spatial limits of bidirectional communication with pyramidal neurons in mouse visual cortex both laterally and at depth from the surface.

Effects of Cerebellar Transcranial Alternating Current Stimulation on Gait and Balance in Healthy Subjects

Transcranial Alternating Current Stimulation (tACS) is a non-invasive brain stimulation technique [1] able to modulate neural oscillatory activities, including those linked to the cortico-cerebello-thalamo- cortical network [2,3]. In this double-blind sham-controlled study, we aimed to investigate the effects of cerebellar tACS delivered at theta and gamma frequencies on gait and balance in healthy subjects, as assessed by kinematic techniques. In a group of young healthy subjects, we applied tACS over the dominant cerebellar hemisphere during the execution of three different motor tasks: 1) standing (both with eyes open and closed); 2) gait initiation (assessed both for the dominant and non-dominant lower limb); 3) 5-meter walk test (5MWT) (Fig. 1). tACS was delivered in a random order at the theta (5 Hz, theta-tACS) and gamma (50 Hz, gamma-tACS) frequencies, and sham-tACS was used as a control condition. The stimulation intensity was set at 1,5 mA and the stimulation duration lasted as long as the motor task was accomplished. Kinematic data were obtained using a force platform and an optoelectronic system. The data analysis was conducted using a dedicated software. Theta-tACS induced a significant reduction of the Centre Of Pressure (COP) displacement during standing with eyes closed compared to sham- and gamma-tACS (mean radius displacement: theta- tACS 4.65±0.74 mm, gamma-tACS 5.58±1.26 mm, sham-tACS 5.99±2.12 mm). A similar, though weaker, trend was present in the eyes open condition. Furthermore, stride width during 5MWT resulted tighter during theta-tACS compared to sham- and gamma tACS. Boosting theta oscillations in the cerebellum through tACS improves balance during standing and gait in healthy subjects. This effect may rely on the modulation of the activity of cerebellar neurons resonant to the theta rhythm. This non-invasive neuromodulation approach could be applied in neurological conditions characterized by ataxia to possibly ameliorate the imbalance and reduce the risk of falling.

Ten sessions of transcranial direct current stimulation for chronic chikungunya arthralgia: study protocol for a randomised clinical trial

IntroductionThe chikungunya virus infection is still an epidemic in Brazil with an incidence of 59.4 cases per 100 000 in the Northeast region. More than 60% of the patients present...