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Updates on Neurostimulation: From Mechanistic Principles to Clinical Applications
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Updates on Neurostimulation: From Mechanistic Principles to Clinical Applications

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 11226

Special Issue Editors

Dr. Jose Gomez Tames

E-Mail Website
Guest Editor
Department of Medical Engineering, Graduate School of Science and Engineering, Chiba University, Chiba 263-8522, Japan
Interests: neural engineering; brain stimulation; electromagnetics; neuroscience
Dr. Mariano Fernández-Corazza

E-Mail Website
Guest Editor
LEICI Institute, National University of La Plata, CONICET, La Plata 1900, Argentina
Interests: electromagnetic modeling; brain stimulation; electroencephalography; electrical impedance tomography

Special Issue Information

Dear Colleagues,

Neurostimulation techniques offer a therapeutic alternative to pharmacological treatments in neurological disorders, including those disorders that are resistant to current treatments. These techniques include non-invasive brain stimulation, such as transcranial electrical stimulation (tES) and transcranial magnetic stimulation (TMS); invasive brain stimulation, such as deep brain stimulation (DBS); or peripheral stimulation, such as vagus nerve stimulation (VNS) and spinal cord stimulation (SCS). Neurostimulation can also serve as a diagnostic tool, such as in-depth electrical stimulation mapping (DESM) for drug-resistant epilepsy patients. Neuromodulation research has experienced significant growth in the last 20 years, and better treatments and new clinical applications are expected in the following years. Optimizing neuromodulation to favor clinical responses is an ongoing work.

However, the physiological mechanisms underlying neurostimulation are not yet fully understood. Measuring neurophysiological responses to stimulation (magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), or electroencephalography (EEG), electromyography (EMG), among others) can help us to better understand the neurological mechanism and main factors contributing to better clinical outcomes. Computational physics has also permitted quantifying and determining the interaction of physical quantity (i.e., induced electric field) on the target neural elements as the basis of the neuromodulation process, while optimizing the simulation parameters.

This Special Issue welcomes advances in understanding the mechanistic foundations of neurostimulation, proposals of novel or enhanced methodologies, and clinical applications through in vivo, in vitro, ex vivo, in silico and simulation studies. Original research articles and systematic reviews/meta-analyses are welcomed.

Dr. Jose Gomez Tames
Dr. Mariano Fernández-Corazza
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • brain stimulation
  • non-invasive brain stimulation
  • deep brain stimulation
  • neuroimaging
  • computational modelling
  • therapy

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Published Papers (5 papers)

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Research

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12 pages, 879 KiB  
Article
Comparison of the Acute Effects of Auricular Vagus Nerve Stimulation and Deep Breathing Exercise on the Autonomic Nervous System Activity and Biomechanical Properties of the Muscle in Healthy People
by Çağıl Ertürk and Ali Veysel Özden
J. Clin. Med. 2025, 14(4), 1046; https://doi.org/10.3390/jcm14041046 - 7 Feb 2025
Viewed by 1857
Abstract
Background/Objectives: We aimed to examine the acute effects of deep breathing exercise and transcutaneous auricular vagus nerve stimulation (taVNS) on autonomic nervous system activation and the characteristics of certain muscle groups and to compare these two methods. Methods: 60 healthy adults between the [...] Read more.
Background/Objectives: We aimed to examine the acute effects of deep breathing exercise and transcutaneous auricular vagus nerve stimulation (taVNS) on autonomic nervous system activation and the characteristics of certain muscle groups and to compare these two methods. Methods: 60 healthy adults between the ages of 18 and 45 were randomly divided into two groups to receive a single session of taVNS and deep breathing exercises. Acute measurements of pulse, blood pressure, perceived stress scale, autonomic activity, and muscle properties were performed before and after the application. Results: A significant decrease was detected in the findings regarding the perceived stress scale, pulse, and blood pressure values as a result of a single session application in both groups (p < 0.05). In addition, it was determined that the findings regarding autonomic measurement values increased in favor of the parasympathetic nervous system in both groups (p < 0.05). In measurements of the structural properties of the muscle, the stiffness values of the muscles examined in both groups decreased (p < 0.05), while the findings regarding relaxation increased (p < 0.05), except for the masseter in the deep breathing (DB) group. As a result of the comparative statistical evaluation between the groups, the increase in parasympathetic activity was found to be greater in the DB group according to root mean square of differences in successive RR intervals (RMSSD), the percent of differences in adjacent RR intervals > 50 ms (pNN50), and stress index parameters (p < 0.05). In the measurements made with the Myoton®PRO device, the increase in the relaxation value was higher in the gastrocnemius muscle of the VNS group (p < 0.05). Conclusions: It has been observed that both methods can increase parasympathetic activity and muscle relaxation in healthy people in a single session. However, DB appears to be slightly superior in increasing parasympathetic activity, and VNS appears to be slightly superior in increasing relaxation. Full article
(This article belongs to the Special Issue Updates on Neurostimulation: From Mechanistic Principles to Clinical Applications)
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12 pages, 1762 KiB  
Article
The Effect of In-Ear and Behind-Ear Transcutaneous Auricular Vagus Nerve Stimulation on Autonomic Function: A Randomized, Single-Blind, Sham-Controlled Study
by Alper Percin, Ali Veysel Ozden, Semiha Yenisehir, Berkay Eren Pehlivanoglu and Ramazan Cihad Yılmaz
J. Clin. Med. 2024, 13(15), 4385; https://doi.org/10.3390/jcm13154385 - 26 Jul 2024
Viewed by 2012
Abstract
Background/Objectives: Transcutaneous auricular vagus nerve stimulation (TaVNS) is a non-invasive method of electrical stimulation used to autonomic neuromodulation. Position and form of the electrodes are important for the effectiveness of autonomic modulation. This study was aimed to investigate the effect of TaVNS in-ear [...] Read more.
Background/Objectives: Transcutaneous auricular vagus nerve stimulation (TaVNS) is a non-invasive method of electrical stimulation used to autonomic neuromodulation. Position and form of the electrodes are important for the effectiveness of autonomic modulation. This study was aimed to investigate the effect of TaVNS in-ear and behind-ear on autonomic variables. Methods: A total of 76 healthy participants (male: 40, female: 36) were randomized into four groups as in-ear TaVNS, behind-ear TaVNS, in-ear sham, and behind-ear sham. The TaVNS protocol included bilateral auricular stimulation for 20 min, 25 hertz frequency, a pulse width of 250 μs, and a suprathreshold current (0.13–50 mA). Heart rate (HR), systolic and diastolic blood pressure (SBP and DBP), and heart rate variability (HRV) were measured baseline and after stimulation. The parameters RMSSD (root mean square of consecutive differences between normal heartbeats), LF power (low-frequency), and HF power (high-frequency) were assessed in the HRV analysis. Results: HR decreased in the in-ear TaVNS after intervention (p < 0.05), but did not change in behind-ear TaVNS and sham groups compared to baseline (p > 0.05). SBP and DBP decreased and RMSSD increased in the in-ear and behind-ear TaVNS groups (p < 0.05), but did not change in sham groups compared to baseline (p > 0.05). There was no significant difference in LF and HF power after TaVNS compared to baseline in all groups (p > 0.05). SBP was lower and RMSSD was higher in-ear TaVNS than behind-ear TaVNS after intervention (p < 0.05). Conclusions: In-ear TaVNS appears to be more effective than behind-ear TaVNS in modulating SBP and RMSSD, but this needs to be studied in larger populations. Full article
(This article belongs to the Special Issue Updates on Neurostimulation: From Mechanistic Principles to Clinical Applications)
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21 pages, 4224 KiB  
Article
Comparative Analysis of High-Frequency and Low-Frequency Transcutaneous Electrical Stimulation of the Right Median Nerve in the Regression of Clinical and Neurophysiological Manifestations of Generalized Anxiety Disorder
by Mustafa Al-Zamil, Natalia G. Kulikova, Inessa A. Minenko, Irina P. Shurygina, Marina M. Petrova, Numman Mansur, Rufat R. Kuliev, Vasilissa V. Blinova, Olga V. Khripunova and Natalia A. Shnayder
J. Clin. Med. 2024, 13(11), 3026; https://doi.org/10.3390/jcm13113026 - 21 May 2024
Cited by 6 | Viewed by 2117
Abstract
Background/Objectives: The anxiolytic effect of transcutaneous electrical nerve stimulation (TENS) is associated with the activation of endogenous inhibitory mechanisms in the central nervous system. Both low-frequency, high-amplitude TENS (LF-TENS) and high-frequency, low-amplitude TENS (HF-TENS) are capable of activating opioid, GABA, serotonin, muscarinic, [...] Read more.
Background/Objectives: The anxiolytic effect of transcutaneous electrical nerve stimulation (TENS) is associated with the activation of endogenous inhibitory mechanisms in the central nervous system. Both low-frequency, high-amplitude TENS (LF-TENS) and high-frequency, low-amplitude TENS (HF-TENS) are capable of activating opioid, GABA, serotonin, muscarinic, and cannabinoid receptors. However, there has been no comparative analysis of the effectiveness of HF-TENS and LF-TENS in the treatment of GAD. The purpose of our research was to study the effectiveness of direct HF-TENS and LF-TENS of the right median nerve in the treatment of patients with GAD compared with sham TENS. Methods: The effectiveness of direct HF-TENS and LF-TENS of the right median nerve in the treatment of GAD was studied using Generalized Anxiety Disorder 7-item scale (GAD-7) and the Hamilton Anxiety Rating Scale (HAM-A). 40 patients underwent sham TENS, 40 patients passed HF-TENS (50 Hz—50 μs—sensory response) and 41 patients completed LF –TENS (1 Hz—200 μs—motor response) for 30 days daily. After completion of treatment, half of the patients received weekly maintenance therapy for 6 months. Electroencephalography was performed before and after treatment. Results: Our study showed that a significant reduction in the clinical symptoms of GAD as assessed by GAD-7 and HAM-A was observed after HF-TENS and LF-TENS by an average of 42.4%, and after sham stimulation only by 13.5% for at least 2 months after the end of treatment. However, LF-TENS turned out to be superior in effectiveness to HF-TENS by 51% and only on electroencephalography leads to an increase in PSD for the alpha rhythm in the occipital regions by 24% and a decrease in PSD for the beta I rhythm in the temporal and frontal regions by 28%. The prolonged effect of HF-TENS and LF-TENS was maintained without negative dynamics when TENS treatment was continued weekly throughout the entire six-month observation period. Conclusions: A prolonged anxiolytic effect of direct TENS of the right median nerve has been proven with greater regression of clinical and neurophysiological manifestations of GAD after LF-TENS compared to HF-TENS. Minimal side effects, low cost, safety, and simplicity of TENS procedures are appropriate as a home treatment modality. Full article
(This article belongs to the Special Issue Updates on Neurostimulation: From Mechanistic Principles to Clinical Applications)
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19 pages, 4396 KiB  
Article
Efficacy of Non-Invasive Brain Stimulation for Treating Depression in Patients with Traumatic Brain Injury: A Meta-Analysis and Meta-Regression of Randomized Controlled Trials
by Chun-Hung Chang, Po-Han Chou, Hao-Yu Chuang, Chi-Yu Yao, Wei-Jen Chen and Hsin-Chi Tsai
J. Clin. Med. 2023, 12(18), 6030; https://doi.org/10.3390/jcm12186030 - 18 Sep 2023
Cited by 4 | Viewed by 2257
Abstract
Objective: This meta-analysis aimed to ascertain the efficacy of non-invasive brain stimulation (NIBS)—comprising repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)—for depression in traumatic brain injury (TBI) patients. Methods: Comprehensive searches were conducted in PubMed, Cochrane Database of Systematic Reviews, [...] Read more.
Objective: This meta-analysis aimed to ascertain the efficacy of non-invasive brain stimulation (NIBS)—comprising repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)—for depression in traumatic brain injury (TBI) patients. Methods: Comprehensive searches were conducted in PubMed, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials up to 28 January 2023. Random-effects models assessed the treatment effects, and heterogeneity was evaluated through I2 statistics and funnel plot inspection. Results: From 10 trials (234 participants; 8 rTMS, 2 tDCS), NIBS was found significantly more effective than sham in alleviating depressive symptoms (SMD: 0.588, 95% CI: 0.264–0.912; p < 0.001). rTMS, specifically, showed higher efficacy (SMD: 0.707, 95% CI: 0.306–1.108; p = 0.001) compared to sham, whereas tDCS outcomes were inconclusive (SMD: 0.271, 95% CI: −0.230 to 0.771; p = 0.289). Meta-regression found no correlation with the number of sessions, treatment intensity, or total dose. Notably, while post-treatment effects were significant, they diminished 1–2 months post intervention. Adverse events associated with NIBS were minimal, with no severe outcomes like seizures and suicide reported. Conclusions: rTMS emerged as a potent short-term intervention for depression in TBI patients, while tDCS findings remained equivocal. The long-term efficacy of NIBS is yet to be established, warranting further studies. The low adverse event rate reaffirms NIBS’s potential safety. Full article
(This article belongs to the Special Issue Updates on Neurostimulation: From Mechanistic Principles to Clinical Applications)
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Review

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32 pages, 2270 KiB  
Review
Perspectives on Optimized Transcranial Electrical Stimulation Based on Spatial Electric Field Modeling in Humans
by Jose Gomez-Tames and Mariano Fernández-Corazza
J. Clin. Med. 2024, 13(11), 3084; https://doi.org/10.3390/jcm13113084 - 24 May 2024
Cited by 1 | Viewed by 1649
Abstract
Background: Transcranial electrical stimulation (tES) generates an electric field (or current density) in the brain through surface electrodes attached to the scalp. Clinical significance has been demonstrated, although with moderate and heterogeneous results partly due to a lack of control of the [...] Read more.
Background: Transcranial electrical stimulation (tES) generates an electric field (or current density) in the brain through surface electrodes attached to the scalp. Clinical significance has been demonstrated, although with moderate and heterogeneous results partly due to a lack of control of the delivered electric currents. In the last decade, computational electric field analysis has allowed the estimation and optimization of the electric field using accurate anatomical head models. This review examines recent tES computational studies, providing a comprehensive background on the technical aspects of adopting computational electric field analysis as a standardized procedure in medical applications. Methods: Specific search strategies were designed to retrieve papers from the Web of Science database. The papers were initially screened based on the soundness of the title and abstract and then on their full contents, resulting in a total of 57 studies. Results: Recent trends were identified in individual- and population-level analysis of the electric field, including head models from non-neurotypical individuals. Advanced optimization techniques that allow a high degree of control with the required focality and direction of the electric field were also summarized. There is also growing evidence of a correlation between the computationally estimated electric field and the observed responses in real experiments. Conclusions: Computational pipelines and optimization algorithms have reached a degree of maturity that provides a rationale to improve tES experimental design and a posteriori analysis of the responses for supporting clinical studies. Full article
(This article belongs to the Special Issue Updates on Neurostimulation: From Mechanistic Principles to Clinical Applications)
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