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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 28944

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Prof. Dr. Felipe Fregni

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1. Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
2. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Interests: neuromodulation; pain perception modulation; neurophysiology; neuroplasticity
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Dr. Kevin Pacheco-Barrios

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Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Interests: neuromodulation; pain perception modulation; neurophysiology; neuroplasticity
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Dr. Aurore Thibaut

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Guest Editor

1. Coma Science Group, GIGA-Consciousness, GIGA Research Center, University of Liège, Liège, Belgium
2. Centre du Cerveau, University Hospital of Liège, Liège, Belgium
Interests: brain injury; disorders of consciousness; neuromodulation; rehabilitation; neurophysiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent evidence reveals how the nervous system is involved in almost all physiological activities of the human body, from cardiorespiratory rhythm and inflammation to perception and consciousness. Consequently, the nervous system's role is fundamental to keeping the “health–disease” balance, resilience across life, and overall well-being. Neuromodulation includes a myriad of non-pharmacological therapeutic approaches that aim to modulate nervous system activity to restore maladaptive neuroplasticity associated with multiple conditions, such as chronic pain, neurodegenerative diseases, brain injury, mental health conditions, and inflammatory diseases. The main intervention types include transcranial electrical stimulation (tES), transcranial magnetic stimulation (TMS), spinal cord stimulation, nerve stimulation, and behavioral therapies such as meditation, mindfulness, mental imagery, and hypnosis. These techniques have shown positive effects on several medical conditions; however, their clinical validation, regulatory approval, and systematic use are still incipient, mainly due to unpowered studies, inappropriate parameter selection, and lack of evidence integration. To accelerate the knowledge translation of neuromodulation, we must build a bridge between theoretical/technological development, clinical trial findings, meta-synthesis methods, and implementation strategies, including cost-effectiveness studies. A coherent and organized integration among these disciplines will foster neuromodulation translation to the clinic and unlock these therapies' real potential.

This Special Issue aims to create a space for “cross-talk” between disciplines about the clinical translation of neuromodulatory techniques, from theoretical and basic neuromodulation models to clinical findings. We welcome original research papers, theoretical and methodology papers, and review papers describing the generation, use, and knowledge translation of neuromodulation, especially those exploring new technologies, precision medicine, transdiagnosis approach, and biomarkers.

Dr. Felipe Fregni
Dr. Kevin Pacheco-Barrios
Dr. Aurore Thibaut
Guest Editors

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Keywords

neuromodulation
non-pharmacological interventions
neuropsychiatric conditions
chronic pain
brain injury
computational models

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Related Special Issues

Neuromodulation from Theory to Therapy Volume II in Biomedicines (3 articles)
Feature Papers in Neuromodulation and Brain Stimulation in Biomedicines (2 articles)

Published Papers (10 papers)

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Research

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15 pages, 724 KiB

Open AccessArticle

Motor Cortex Inhibition and Facilitation Correlates with Fibromyalgia Compensatory Mechanisms and Pain: A Cross-Sectional Study

by Kevin Pacheco-Barrios, Danielle Carolina Pimenta, Anne Victorio Pessotto and Felipe Fregni

Biomedicines 2023, 11(6), 1543; https://doi.org/10.3390/biomedicines11061543 - 26 May 2023

Cited by 1 | Viewed by 1631

Abstract

The role of transcranial magnetic stimulation (TMS) measures as biomarkers of fibromyalgia syndrome (FMS) phenotypes is still unclear. We aimed to determine the clinical correlates of TMS measures in FMS patients. We conducted a cross-sectional analysis that included 58 patients. We performed standardized TMS assessments, including resting motor threshold (MT), motor-evoked potential (MEP), short intracortical inhibition (SICI), and intracortical facilitation (ICF). Sociodemographic, clinical questionnaires, and quantitative sensory testing were collected from all of the patients. Univariate and multivariate linear regression models were built to explore TMS-associated factors. We found that SICI did not significantly correlate with pain levels but was associated with sleepiness, comorbidities, disease duration, and anxiety. On the other hand, ICF showed a positive correlation with pain levels and a negative correlation with body mass index (BMI). BMI was a negative effect modifier of the ICF and pain association. The clinical correlates of MT and MEP were scarce. Our results suggest that SICI and ICF metrics are potential phenotyping biomarkers in FMS related to disease compensation and levels of pain perception, respectively. The clinical translation of TMS paired-pulse protocols represents an opportunity for a mechanistic understanding of FMS and the future development of precision treatments. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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16 pages, 653 KiB

Open AccessArticle

Development of a Clinical Prediction Rule for Treatment Success with Transcranial Direct Current Stimulation for Knee Osteoarthritis Pain: A Secondary Analysis of a Double-Blind Randomized Controlled Trial

by Paulo E. P. Teixeira, Daniela R. B. Tavares, Kevin Pacheco-Barrios, Luis Castelo Branco, Eric Slawka, Julie Keysor, Virginia F. M. Trevisani, Doug K Gross and Felipe Fregni

Biomedicines 2023, 11(1), 4; https://doi.org/10.3390/biomedicines11010004 - 20 Dec 2022

Cited by 3 | Viewed by 2232

Abstract

The study’s objective was to develop a clinical prediction rule that predicts a clinically significant analgesic effect on chronic knee osteoarthritis pain after transcranial direct current stimulation treatment. This is a secondary analysis from a double-blind randomized controlled trial. Data from 51 individuals with chronic knee osteoarthritis pain and an impaired descending pain inhibitory system were used. The intervention comprised a 15-session protocol of anodal primary motor cortex transcranial direct current stimulation. Treatment success was defined by the Western Ontario and McMaster Universities’ Osteoarthritis Index pain subscale. Accuracy statistics were calculated for each potential predictor and for the final model. The final logistic regression model was statistically significant (p < 0.01) and comprised five physical and psychosocial predictor variables that together yielded a positive likelihood ratio of 14.40 (95% CI: 3.66–56.69) and an 85% (95%CI: 60–96%) post-test probability of success. This is the first clinical prediction rule proposed for transcranial direct current stimulation in patients with chronic pain. The model underscores the importance of both physical and psychosocial factors as predictors of the analgesic response to transcranial direct current stimulation treatment. Validation of the proposed clinical prediction rule should be performed in other datasets. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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11 pages, 958 KiB

Open AccessArticle

Brain Perfusion Alterations Induced by Standalone and Combined Non-Invasive Brain Stimulation over the Dorsolateral Prefrontal Cortex

by Lais Boralli Razza, Pedro Henrique Rodrigues da Silva, Geraldo F. Busatto, Fábio Luis de Souza Duran, Juliana Pereira, Stefanie De Smet, Izio Klein, Tamires A. Zanão, Matthias S. Luethi, Chris Baeken, Marie-Anne Vanderhasselt, Carlos Alberto Buchpiguel and André Russowsky Brunoni

Biomedicines 2022, 10(10), 2410; https://doi.org/10.3390/biomedicines10102410 - 27 Sep 2022

Cited by 5 | Viewed by 2346

Abstract

Non-invasive brain stimulation (NIBS) interventions are promising for the treatment of psychiatric disorders. Notwithstanding, the NIBS mechanisms of action over the dorsolateral prefrontal cortex (DLPFC), a hub that modulates affective and cognitive processes, have not been completely mapped. We aimed to investigate regional cerebral blood flow (rCBF) changes over the DLPFC and the subgenual anterior cingulate cortex (sgACC) of different NIBS protocols using Single-Photon Emission Computed Tomography (SPECT). A factorial, within-subjects, double-blinded study was performed. Twenty-three healthy subjects randomly underwent four sessions of NIBS applied once a week: transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), combined tDCS + iTBS and placebo. The radiotracer 99m-Technetium-ethylene-cysteine-dimer was injected intravenously during the NIBS session, and SPECT neuroimages were acquired after the session. Results revealed that the combination of tDCS + iTBS increased right sgACC rCBF. Cathodal and anodal tDCS increased and decreased DLPFC rCBF, respectively, while iTBS showed no significant changes compared to the placebo. Our findings suggest that the combined protocol might optimize the activity in the right sgACC and encourage future trials with neuropsychiatric populations. Moreover, mechanistic studies to investigate the effects of tDCS and iTBS over the DLPFC are required. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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11 pages, 933 KiB

Open AccessArticle

A Single Session of Bifrontal tDCS Can Improve Facial Emotion Recognition in Major Depressive Disorder: An Exploratory Pilot Study

by Laetitia Imbert, Rémi Moirand, Benoit Bediou, Olivier Koenig, Gabrielle Chesnoy, Eric Fakra and Jérôme Brunelin

Biomedicines 2022, 10(10), 2397; https://doi.org/10.3390/biomedicines10102397 - 26 Sep 2022

Cited by 4 | Viewed by 1886

Abstract

Emotional processing deficits are key features in major depressive disorder (MDD). Neuroimaging studies indicate that the dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in both depressive symptoms and emotional processing. Recently, transcranial Direct Current Stimulations (tDCS) applied over the DLPFCs have held the promise to alleviate the symptoms in patients with MDD, but the effect on emotional processing in the patients is unclear. Here, we investigated the effect of a single session of tDCS over the DLPFCs on the emotional processing in patients with treatment-resistant MDD. In a randomized sham-controlled study, 35 patients received a single 30 min session of either active (2 mA, n = 18) or sham tDCS (n = 17). The anode was placed over the left and the cathode over the right DLPFC. Emotional processing accuracy was measured by a facial emotion recognition (FER) task. We observed an overall improvement in FER performance after the active tDCS, but not the sham tDCS. These exploratory results suggest that a single session of tDCS over the DLPFCs may improve FER in MDD, a crucial function of social cognition. Further studies are needed to investigate whether this acute improvement of FER in response to a single tDCS session could translate into clinical benefits or predict remission following repeated sessions of stimulation. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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11 pages, 1059 KiB

Open AccessArticle

Simultaneous Bilateral Frontal and Bilateral Cerebellar Transcranial Direct Current Stimulation in Treatment-Resistant Depression—Clinical Effects and Electrical Field Modelling of a Novel Electrodes Montage

by Giordano D’Urso, Michelangelo Dini, Marta Bonato, Silvia Gallucci, Marta Parazzini, Natale Maiorana, Marco Bortolomasi, Alberto Priori and Roberta Ferrucci

Biomedicines 2022, 10(7), 1681; https://doi.org/10.3390/biomedicines10071681 - 12 Jul 2022

Cited by 7 | Viewed by 2642

Abstract

Depressive disorders are one of the leading causes of disability worldwide. Transcranial direct current stimulation (tDCS) is a safe, simple, non-invasive brain stimulation technique showing considerable effectiveness in improving depressive symptoms. Most studies to date have applied anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC), in line with the hypothesis that depressed patients exhibit relative hypoactivity in the left DLPFC compared to the right. Considering the emerging role of the cerebellum in emotional processes, we aimed to study the effect of combining bilateral cerebellar tDCS with the commonly used bifrontal stimulation in patients with severe depression. This open-label pilot study entailed the simultaneous administration of bilateral cerebellar (anode over the left cerebellum, cathode over the right cerebellum) and bilateral frontal (anode over the left DLPFC, cathode over the right DLPFC) tDCS to patients (N = 12) with treatment-resistant depression. The 21-item Hamilton Depression Rating Scale (HDRS) and Beck’s Depression Inventory-II (BDI-II) were selected as outcome measures. Electric fields distribution originating from this novel electrode montage was obtained by a computational method applied to a realistic human head model. We observed a 30% reduction of both clinician-rated and self-reported severity of depressive symptoms after only five days (10 sessions) of treatment. Younger age was associated with greater clinical improvement. Adverse events were similar to those of the conventional electrodes montage. The modelling studies demonstrated that the electric fields generated by each pair of electrodes are primarily distributed in the cortical areas under the electrodes. In conclusion, the cerebellum could represent a promising adjunctive target for tDCS interventions in patients with TRD, particularly for younger patients. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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Review

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21 pages, 3016 KiB

Open AccessReview

Modeling Electric Fields in Transcutaneous Spinal Direct Current Stimulation: A Clinical Perspective

by Matteo Guidetti, Stefano Giannoni-Luza, Tommaso Bocci, Kevin Pacheco-Barrios, Anna Maria Bianchi, Marta Parazzini, Silvio Ionta, Roberta Ferrucci, Natale Vincenzo Maiorana, Federico Verde, Nicola Ticozzi, Vincenzo Silani and Alberto Priori

Biomedicines 2023, 11(5), 1283; https://doi.org/10.3390/biomedicines11051283 - 26 Apr 2023

Cited by 4 | Viewed by 2233

Abstract

Clinical findings suggest that transcutaneous spinal direct current stimulation (tsDCS) can modulate ascending sensitive, descending corticospinal, and segmental pathways in the spinal cord (SC). However, several aspects of the stimulation have not been completely understood, and realistic computational models based on MRI are the gold standard to predict the interaction between tsDCS-induced electric fields and anatomy. Here, we review the electric fields distribution in the SC during tsDCS as predicted by MRI-based realistic models, compare such knowledge with clinical findings, and define the role of computational knowledge in optimizing tsDCS protocols. tsDCS-induced electric fields are predicted to be safe and induce both transient and neuroplastic changes. This could support the possibility to explore new clinical applications, such as spinal cord injury. For the most applied protocol (2–3 mA for 20–30 min, active electrode over T10–T12 and the reference on the right shoulder), similar electric field intensities are generated in both ventral and dorsal horns of the SC at the same height. This was confirmed by human studies, in which both motor and sensitive effects were found. Lastly, electric fields are strongly dependent on anatomy and electrodes’ placement. Regardless of the montage, inter-individual hotspots of higher values of electric fields were predicted, which could change when the subjects move from a position to another (e.g., from the supine to the lateral position). These characteristics underlines the need for individualized and patient-tailored MRI-based computational models to optimize the stimulation protocol. A detailed modeling approach of the electric field distribution might contribute to optimizing stimulation protocols, tailoring electrodes’ configuration, intensities, and duration to the clinical outcome. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

Other

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15 pages, 2103 KiB

Open AccessSystematic Review

The Effects of Transcranial Direct Current Stimulation in Obsessive–Compulsive Disorder Symptoms: A Meta-Analysis and Integrated Electric Fields Modeling Analysis

by Bianca Silva Pinto, Beatriz Araújo Cavendish, Pedro Henrique Rodrigues da Silva, Paulo Jeng Chian Suen, Kalian Almeida Pereira Marinho, Leandro da Costa Lane Valiengo, Marie-Anne Vanderhasselt, André Russowsky Brunoni and Laís Boralli Razza

Biomedicines 2023, 11(1), 80; https://doi.org/10.3390/biomedicines11010080 - 29 Dec 2022

Cited by 10 | Viewed by 4173

Abstract

Transcranial direct current stimulation (tDCS) has been showing promising effects for the treatment of obsessive–compulsive disorder (OCD), but there is still no conclusion on its efficacy for this disorder. We performed a systematic review and meta-analysis of trials using tDCS for OCD and a computer modeling analysis to evaluate the electric field (EF) strengths of different electrode assemblies in brain regions of interest (ROIs) (PROSPERO-42021262465). PubMed/MEDLINE, Embase, Cochrane Library and Web of Science databases were searched from inception to 25 September 2022. Randomized controlled trials (RCTs) and open-label studies were included. The primary aim was the effect size (Hedges’ g) of continuous outcomes and potential moderators of response. For EF modeling, SimNIBS software was used. Four RCTs and four open-label trials were included (n = 241). Results revealed a large effect of tDCS in the endpoint, but no significant effect between active and sham protocols. No predictor of response was found. EF analysis revealed that montages using the main electrode over the (pre)supplementary motor area with an extracephalic reference electrode might lead to stronger EFs in the predefined ROIs. Our results revealed that tDCS might be a promising intervention to treat OCD; however, larger studies are warranted. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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Graphical abstract

8 pages, 794 KiB

Open AccessCase Report

High-Frequency Transcranial Random Noise Stimulation for Auditory Hallucinations of Schizophrenia: A Case Series

by Marine Mondino, Delphine Janin, Filipe Galvao and Jérôme Brunelin

Biomedicines 2022, 10(11), 2698; https://doi.org/10.3390/biomedicines10112698 - 25 Oct 2022

Cited by 1 | Viewed by 2193

Abstract

Transcranial electrical stimulation has been proposed as a noninvasive therapeutic approach for reducing treatment-resistant symptoms of schizophrenia—in particular, auditory hallucinations. However, the high variability observed in the clinical response leaves much room to optimize the stimulation parameters and strengthen its benefits. We proposed to investigate the effects of high-frequency transcranial random noise stimulation (hf-tRNS), which is supposed to induce larger effects than conventional direct current stimulation. Here, we present an initial case series of ten patients with schizophrenia who underwent 10 sessions of 20 min hf-tRNS (2 mA, 100–500 Hz, 1 mA offset), with the anode placed over the left dorsolateral prefrontal cortex and the cathode over the left temporoparietal junction. Patients showed a significant reduction in auditory hallucinations after the hf-tRNS sessions (−36.1 +/− 21.8%, p = 0.0059). In this preliminary, open-label study conducted in ten patients with treatment-resistant symptoms of schizophrenia, frontotemporal hf-tRNS was shown to induce a substantial improvement in auditory hallucinations. Additional sham-controlled studies are needed to further evaluate hf-tRNS as a treatment for schizophrenia. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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16 pages, 2144 KiB

Open AccessHypothesis

Therapeutic Neuromodulation toward a Critical State May Serve as a General Treatment Strategy

by Simon Arvin, Keisuke Yonehara and Andreas Nørgaard Glud

Biomedicines 2022, 10(9), 2317; https://doi.org/10.3390/biomedicines10092317 - 18 Sep 2022

Viewed by 3465

Abstract

Brain disease has become one of this century’s biggest health challenges, urging the development of novel, more effective treatments. To this end, neuromodulation represents an excellent method to modulate the activity of distinct neuronal regions to alleviate disease. Recently, the medical indications for neuromodulation therapy have expanded through the adoption of the idea that neurological disorders emerge from deficits in systems-level structures, such as brain waves and neural topology. Connections between neuronal regions are thought to fluidly form and dissolve again based on the patterns by which neuronal populations synchronize. Akin to a fire that may spread or die out, the brain’s activity may similarly hyper-synchronize and ignite, such as seizures, or dwindle out and go stale, as in a state of coma. Remarkably, however, the healthy brain remains hedged in between these extremes in a critical state around which neuronal activity maneuvers local and global operational modes. While it has been suggested that perturbations of this criticality could underlie neuropathologies, such as vegetative states, epilepsy, and schizophrenia, a major translational impact is yet to be made. In this hypothesis article, we dissect recent computational findings demonstrating that a neural network’s short- and long-range connections have distinct and tractable roles in sustaining the critical regime. While short-range connections shape the dynamics of neuronal activity, long-range connections determine the scope of the neuronal processes. Thus, to facilitate translational progress, we introduce topological and dynamical system concepts within the framework of criticality and discuss the implications and possibilities for therapeutic neuromodulation guided by topological decompositions. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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23 pages, 993 KiB

Open AccessSystematic Review

Electroencephalographic Patterns in taVNS: A Systematic Review

by Anna Carolyna L. Gianlorenco, Paulo S. de Melo, Anna Marduy, Angela Yun Kim, Chi Kyung Kim, Hyuk Choi, Jae-Jun Song and Felipe Fregni

Biomedicines 2022, 10(9), 2208; https://doi.org/10.3390/biomedicines10092208 - 6 Sep 2022

Cited by 16 | Viewed by 4466

Abstract

Transcutaneous auricular vagus nerve stimulation (taVNS) is a newer delivery system using a non-invasive stimulation device placed at the ear. taVNS research is focused on clinical trials showing potential therapeutic benefits, however the neurophysiological effects of this stimulation on brain activity are still unclear. We propose a systematic review that aims to describe the effects of taVNS on EEG measures and identify taVNS parameters that can potentially lead to consistent EEG-mediated biomarkers for this therapy. A systematic literature review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) and the Cochrane handbook for systematic reviews. Clinical trials examining EEG parameters were considered, including absolute and relative power, coherence, degree of symmetry, evoked potentials, and peak frequency of all bands. According to our criteria, 18 studies (from 122 articles) were included. Our findings show a general trend towards increased EEG power spectrum activity in lower frequencies, and changes on early components of the ERP related to inhibitory tasks. This review suggests that quantitative electroencephalography can be used to assess the effects of taVNS on brain activity, however more studies are needed to systematically establish the specific effects and metrics that would reflect the non-invasive stimulation through the auricular branch of the vagus nerve. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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