Acoustic deep brain modulation: Enhancing neuronal activation and neurogenesis.

BACKGROUND: Non-invasive deep brain modulation (DBM) stands as a promising therapeutic avenue to treat brain diseases. Acoustic DBM represents an innovative and targeted approach to modulate the deep brain, employing techniques such as focused ultrasound and shock waves. Despite its potential, the optimal mechanistic parameters, the effect in the brain and behavioral outcomes of acoustic DBM remains poorly understood. OBJECTIVE: To establish a robust protocol for the shock wave DBM by optimizing its mechanistic profile of external stimulation, and to assess its efficacy in preclinical settings. METHODS: We used shockwaves due to their capacity to leverage a broader spectrum of peak intensity (10-127 W/mm2) in contrast to ultrasound (0.1-5.0 W/mm2), thereby enabling a more extensive range of neuromodulation effects. We established various types of shockwave pressure profiles of DBM and compared neural and behavioral responses. To ascertain the anticipated cause of the heightened neural activity response, numerical analysis was employed to examine the mechanical dynamics within the brain. RESULTS: An optimized profile led to an enhancement in neuronal activity within the hypothalamus of mouse models. The optimized profile in the hippocampus elicited a marked increase in neurogenesis without neuronal damage. Behavioral analyses uncovered a noteworthy reduction in locomotion without significant effects on spatial memory function. CONCLUSIONS: The present study provides an optimized shock wave stimulation protocol for non-invasive DBM. Our optimized stimulation profile selectively triggers neural functions in the deep brain. Our protocol paves the way for new non-invasive DBM devices to treat brain diseases.

Evolution of Bioelectric Membrane Potentials: Implications in Cancer Pathogenesis and Therapeutic Strategies.

Electrophysiology typically deals with the electrical properties of excitable cells like neurons and muscles. However, all other cells (non-excitable) also possess bioelectric membrane potentials for intracellular and extracellular communications. These membrane potentials are generated by different ions present in fluids available in and outside the cell, playing a vital role in communication and coordination between the cell and its organelles. Bioelectric membrane potential variations disturb cellular ionic homeostasis and are characteristic of many diseases, including cancers. A rapidly increasing interest has emerged in sorting out the electrophysiology of cancer cells. Compared to healthy cells, the distinct electrical properties exhibited by cancer cells offer a unique way of understanding cancer development, migration, and progression. Decoding the altered bioelectric signals influenced by fluctuating electric fields benefits understanding cancer more closely. While cancer research has predominantly focussed on genetic and molecular traits, the delicate area of electrophysiological characteristics has increasingly gained prominence. This review explores the historical exploration of electrophysiology in the context of cancer cells, shedding light on how alterations in bioelectric membrane potentials, mediated by ion channels and gap junctions, contribute to the pathophysiology of cancer.

Engineering 3D Scaffold-Free Nanoparticle-Laden Stem Cell Constructs for Piezoelectric Enhancement of Human Neural Tissue Formation and Function.

Electrical stimulation (ES) of cellular systems can be utilized for biotechnological applications and electroceuticals (bioelectric medicine). Neural cell stimulation especially has a long history in neuroscience research and is increasingly applied for clinical therapies. Application of ES via conventional electrodes requires external connectors and power sources, hindering scientific and therapeutic applications. Here engineering novel 3D scaffold-free human neural stem cell constructs with integrated piezoelectric nanoparticles for enhanced neural tissue induction and function is described. Tetragonal barium titanate (BaTi03) nanoparticles are employed as piezoelectric stimulators prepared as cytocompatible dispersions, incorporated into 3D self-organizing neural spheroids, and activated wirelessly by ultrasound. Ultrasound delivery (low frequency; 40 kHz) is optimized for cell survival, and nanoparticle activation enabled ES throughout the spheroids during differentiation, tissue formation, and maturation. The resultant human neural tissues represent the first example of direct tissue loading with piezoelectric particles for ensuing 3D ultrasound-mediated piezoelectric enhancement of human neuronal induction from stem cells, including augmented neuritogenesis and synaptogenesis. It is anticipated that the platform described will facilitate advanced tissue engineering and in vitro modeling of human neural (and potentially non-neural) tissues, with modeling including tissue development and pathology, and applicable to preclinical testing and prototyping of both electroceuticals and pharmaceuticals.

A Wearable Self-Charging Electroceutical Device for Bacteria-Infected Wound Healing.

The prolonged wound-healing process caused by pathogen infection remains a major public health challenge. The developed electrical antibiotic administration typically requires metal electrodes wired to a continuous power supply, restricting their use beyond clinical environments. To obviate the necessity for antibiotics and an external power source, we have developed a wearable synergistic electroceutical device composed of an air self-charging Zn battery. This battery integrates sustained tissue regeneration and antibacterial modalities while maintaining more than half of the initial capacity after ten cycles of chemical charging. In vitro bacterial/cell coculture with the self-charging battery demonstrates inhibited bacterial activity and enhanced cell function by simulating the endogenous electric field and dynamically engineering the microenvironment with released chemicals. This electroceutical device provides accelerated healing of a bacteria-infected wound by stimulating angiogenesis and modulating inflammation, while effectively inhibiting bacterial growth at the wound site. Considering the simple structure and easy operation for long-term treatment, this self-charging electroceutical device offers great potential for personalized wound care.

Electroceuticals: emerging applications beyond the nervous system and excitable tissues.

Electroceuticals have evolved beyond devices manipulating neuronal signaling for symptomatic treatment, becoming more precise and disease modulating and expanding beyond the nervous system. These advancements promise transformative applications in arthritis, cancer treatment, tissue regeneration, and more. Here, we discuss these recent advances and offer insights for future research.

Transcranial Electrical Neurostimulation as a Potential Addiction Treatment.

Addiction remains difficult to treat, but non-invasive transcranial electrical and magnetic neurostimulation methods may provide promising and cost-effective treatment approaches. We provide a narrative review of recent developments and evidence of effectiveness and consider newer technology that may yield improved treatment approaches. In particular, we review temporal interference electrical neurostimulation, which allows non-invasive and focal stimulation of deep brain regions. This provides a promising new potential approach to treat addiction, because many of the brain regions that seem most important for addiction are deeper in the brain, out of reach of existing technologies such as transcranial direct current stimulation.

Antibacterial coatings for electroceutical devices based on PEDOT decorated with gold and silver particles.

The continuous progression in the field of electrotherapies implies the development of multifunctional materials exhibiting excellent electrochemical performance and biocompatibility, promoting cell adhesion, and possessing antibacterial properties. Since the conditions favouring the adhesion of mammalian cells are similar to conditions favouring the adhesion of bacterial cells, it is necessary to engineer the surface to exhibit selective toxicity, i.e., to kill or inhibit the growth of bacteria without damaging mammalian tissues. The aim of this paper is to introduce a surface modification approach based on a subsequent deposition of silver and gold particles on the surface of a conducting polymer, poly(3,4-ethylenedioxythiophene) (PEDOT). The resulting PEDOT-Au/Ag surface is found to possess optimal wettability, roughness, and surface features making it an excellent platform for cell adhesion. By depositing Ag particles on PEDOT surface decorated with Au particles, it is possible to reduce toxic effects of Ag particles, while maintaining their antibacterial activity. Besides, electroactive and capacitive properties of PEDOT-Au/Ag account for its applicability in various electroceutical therapies.

Peripheral nerve stimulation enables somatosensory feedback while suppressing phantom limb pain in transradial amputees.

To simultaneously treat phantom limb pain (PLP) and restore somatic sensations using peripheral nerve stimulation (PNS), two bilateral transradial amputees were implanted with stimulating electrodes in the proximity of the medial, ulnar and radial nerves. Application of PNS evoked tactile and proprioceptive sensations in the phantom hand. Both patients learned to determine the shape of invisible objects by scanning a computer tablet with a stylus while receiving feedback based on PNS or transcutaneous electrical nerve stimulation (TENS). Оne patient learned to use PNS as feedback from the prosthetic hand that grasped objects of different sizes. PNS abolished PLP completely in one patient and reduced it by 40-70% in the other. We suggest incorporating PNS and/or TENS in active tasks to reduce PLP and restore sensations in amputees.

Spatial response of jejunal pacing defined by a novel high-resolution multielectrode array.

Gastric pacing has shown preclinical success in modulating bioelectrical slow-wave activity and has potential as a novel therapy for functional motility disorders. However, the translation of pacing techniques to the small intestine remains preliminary. This paper presents the first high-resolution framework for simultaneous pacing and response mapping of the small intestine. A novel surface-contact electrode array, capable of simultaneous pacing and high-resolution mapping of the pacing response, was developed and applied in vivo on the proximal jejunum of pigs. Pacing parameters including the input energy and pacing electrode orientation were systematically evaluated, and the efficacy of pacing was determined by analyzing spatiotemporal characteristics of entrained slow waves. Histological analysis was conducted to determine if the pacing resulted in tissue damage. A total of 54 studies were conducted on 11 pigs, and pacemaker propagation patterns were successfully achieved at both low (2 mA, 50 ms) and high (4 mA, 100 ms) energy levels with the pacing electrodes oriented in the antegrade, retrograde, and circumferential directions. The high energy level performed significantly better (P = 0.014) in achieving spatial entrainment. Comparable success (greater than 70%) was achieved when pacing in the circumferential and antegrade pacing directions, and no tissue damage was observed at the pacing sites. This study defined the spatial response of small intestine pacing in vivo revealing effective pacing parameters for slow-wave entrainment in the jejunum. Intestinal pacing now awaits translation to restore disordered slow-wave activity associated with motility disorders.NEW & NOTEWORTHY A novel surface-contact electrode array customized for the small intestine anatomy enabled simultaneous pacing and high-resolution response mapping. The spatial response of small intestine bioelectrical activity to pacing was mapped for the first time in vivo. Antegrade and circumferential pacing achieved spatial entrainment over 70% of the time and their induced pattern was held for 4-6 cycles postpacing at high energy (4 mA, 100 ms, at ∼2.7 s which corresponds to 1.1 × intrinsic frequency).

Electroceutical approach ameliorates intracellular PMP22 aggregation and promotes pro-myelinating pathways in a CMT1A in vitro model.

Charcot-Marie-Tooth disease subtype 1A (CMT1A) is one of the most prevalent demyelinating peripheral neuropathies worldwide, caused by duplication of the peripheral myelin protein 22 (PMP22) gene, which is expressed primarily in Schwann cells (SCs). PMP22 overexpression in SCs leads to intracellular aggregation of the protein, which eventually results in demyelination. Unfortunately, previous biochemical approaches have not resulted in an approved treatment for CMT1A disease, compelling the pursuit for a biophysical approach such as electrical stimulation (ES). However, the effects of ES on CMT1A SCs have remained unexplored. In this study, we established PMP22-overexpressed Schwannoma cells as a CMT1A in vitro model, and investigated the biomolecular changes upon applying ES via a custom-made high-throughput ES platform, screening for the condition that delivers optimal therapeutic effects. While PMP22-overexpressed Schwannoma exhibited intracellular PMP22 aggregation, ES at 20 Hz for 1 h improved this phenomenon, bringing PMP22 distribution closer to healthy condition. ES at this condition also enhanced the expression of the genes encoding myelin basic protein (MBP) and myelin-associated glycoprotein (MAG), which are essential for assembling myelin sheath. Furthermore, ES altered the gene expression for myelination-regulating transcription factors Krox-20, Oct-6, c-Jun and Sox10, inducing pro-myelinating effects in PMP22-overexpressed Schwannoma. While electroceuticals has previously been applied in the peripheral nervous system towards acquired peripheral neuropathies such as pain and nerve injury, this study demonstrates its effectiveness towards ameliorating biomolecular abnormalities in an in vitro model of CMT1A, an inherited peripheral neuropathy. These findings will facilitate the clinical translation of an electroceutical treatment for CMT1A.

Views about neuromodulation interventions for depression by stakeholder group, treatment modality, and depression severity.

BACKGROUND: The past few decades have seen the emergence both of new neuromodulation treatment protocols and novel applications of standard neuromodulation interventions in psychiatry. Yet little is known about different stakeholders' views about these interventions. METHODS: We administered an online survey with an embedded video vignette experiment to four national samples: the general public (N = 1022), caregivers for people with depression (N = 1026), patients living with depression (N = 1050), and board-certified psychiatrists (N = 505). We randomly assigned subjects to one of eight conditions in our full factorial design: four neuromodulation interventions [electroconvulsive therapy, repetitive transcranial magnetic stimulation, deep brain stimulation, or adaptive brain implants] by two depression severity levels [moderate or severe]. In this paper we present results from ANOVA and linear regression models explaining how views about these four neuromodulation interventions-as measured in five attitudinal scales (general affect, perceived influence on self, perceived benefit, perceived risk, and perceived invasiveness)-vary by (1) intervention, (2) depression severity, and/or (3) stakeholder group. RESULTS: Our results provide evidence that psychiatrists views differ significantly in important ways from other stakeholder groups. Type of intervention also shaped participants' attitudes, including perceptions of invasiveness, effectiveness, and safety. CONCLUSIONS: Given the differing affective valence among stakeholders and the differences found by modality and stakeholder groups across the different scales, future targeted educational initiatives could be developed to help address key misunderstandings and misinformed perceptions.

Looking through the lens of stigma: Understanding and anticipating concerns about the responsible development and use of psychiatric electroceutical interventions (PEIs).

Psychiatric electroceutical interventions (PEIs) show promise for treating depression, but few studies have examined stakeholders' views on them. Using interview data and survey data that analyzed the views of psychiatrists, patients, caregivers, and the general public, a conceptual map was created to represent stakeholders' views on four PEIs: electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and adaptive brain implants (ABIs). Stigma emerged as a key theme connecting diverse views, revealing that it is a significant factor in the acceptance and usage of PEIs. Stigma not only discourages seeking mental health services for depression but also inhibits the acceptance of PEIs. Addressing the pervasive and complex effects of stigma highlights the need to change societal attitudes toward mental illnesses and their treatments and to provide support to patients who may benefit from these interventions. The map also demonstrates the value of conceptual mapping for anticipating and mitigating ethical considerations in the development and use of PEIs.

Neuromorphic-Based Neuroprostheses for Brain Rewiring: State-of-the-Art and Perspectives in Neuroengineering.

Neuroprostheses are neuroengineering devices that have an interface with the nervous system and supplement or substitute functionality in people with disabilities. In the collective imagination, neuroprostheses are mostly used to restore sensory or motor capabilities, but in recent years, new devices directly acting at the brain level have been proposed. In order to design the next-generation of neuroprosthetic devices for brain repair, we foresee the increasing exploitation of closed-loop systems enabled with neuromorphic elements due to their intrinsic energy efficiency, their capability to perform real-time data processing, and of mimicking neurobiological computation for an improved synergy between the technological and biological counterparts. In this manuscript, after providing definitions of key concepts, we reviewed the first exploitation of a real-time hardware neuromorphic prosthesis to restore the bidirectional communication between two neuronal populations in vitro. Starting from that 'case-study', we provide perspectives on the technological improvements for real-time interfacing and processing of neural signals and their potential usage for novel in vitro and in vivo experimental designs. The development of innovative neuroprosthetics for translational purposes is also presented and discussed. In our understanding, the pursuit of neuromorphic-based closed-loop neuroprostheses may spur the development of novel powerful technologies, such as 'brain-prostheses', capable of rewiring and/or substituting the injured nervous system.

Bipolar Electrochemical Stimulation Using Conducting Polymers for Wireless Electroceuticals and Future Directions.

Electrochemistry has become a powerful strategy to modulate cellular behavior and biological activity by manipulating electrical signals. Subsequent electrical stimulus-responsive conducting polymers (CPs) have advanced traditional wired electrochemical stimulation (ES) systems and developed wireless cell stimulation systems due to their electroconductivity, biocompatibility, stability, and flexibility. Bipolar electrochemistry (BPE), i.e., wireless electrochemistry, offers an effective pathway to modify wired ES systems into a desirable contactless mode, turning out a potential technique to offer fundamental insights into neural cell stimulation and neural network formation. This review commences with a brief discussion of the BPE technique and also the advantages of a bipolar electrochemical stimulation (BPES) system compared to traditional wired ES systems and other wireless ES systems. Then, the BPES system is elucidated through four aspects: the benefits of BPES, the key factors to establish BPES platforms for cell stimulation, the limits/barriers to overcome for current rigid materials in particular metals-based systems, and a brief overview of the concept proved by CPs-based systems. Furthermore, how to refine the existing BPES system from materials/devices modification that combine CP compositions with 3D fabrication/bioprinting technologies is elaborately discussed as well. Finally, the review ends together with future research directions, picturing the potential of BPES system in biomedical applications.

Microfluidic Electroceuticals Platform for Therapeutic Strategies of Intervertebral Disc Degeneration: Effects of Electrical Stimulation on Human Nucleus Pulposus Cells under Inflammatory Conditions.

The degeneration of an intervertebral disc (IVD) is a major cause of lower back pain. IVD degeneration is characterized by the abnormal expression of inflammatory cytokines and matrix degradation enzymes secreted by IVD cells. In addition, macrophage-mediated inflammation is strongly associated with IVD degeneration. However, the precise pathomechanisms of macrophage-mediated inflammation in IVD are still unknown. In this study, we developed a microfluidic platform integrated with an electrical stimulation (ES) array to investigate macrophage-mediated inflammation in human nucleus pulposus (NP). This platform provides multiple cocultures of different cell types with ES. We observed macrophage-mediated inflammation and considerable migration properties via upregulated expression of interleukin (IL)-6 (p < 0.001), IL-8 (p < 0.05), matrix metalloproteinase (MMP)-1 (p < 0.05), and MMP-3 (p < 0.05) in human NP cells cocultured with macrophages. We also confirmed the inhibitory effects of ES at 10 µA due to the production of IL-6 (p < 0.05) and IL-8 (p < 0.01) under these conditions. Our findings indicate that ES positively affects degenerative inflammation in diverse diseases. Accordingly, the microfluidic electroceutical platform can serve as a degenerative IVD inflammation in vitro model and provide a therapeutic strategy for electroceuticals.

Electroceuticals for peripheral nerve regeneration.

Electroceuticals provide promising opportunities for peripheral nerve regeneration, in terms of modulating the extensive endogenous tissue repair mechanisms between neural cell body, axons and target muscles. However, great challenges remain to deliver effective and controllable electroceuticals via bioelectronic implantable device. In this review, the modern fabrication methods of bioelectronic conduit for bridging critical nerve gaps after nerve injury are summarized, with regard to conductive materials and core manufacturing process. In addition, to deliver versatile electrical stimulation, the integration of implantable bioelectronic device is discussed, including wireless energy harvesters, actuators and sensors. Moreover, a comprehensive insight of beneficial mechanisms is presented, including up-to-datein vitro, in vivoand clinical evidence. By integrating conductive biomaterials, 3D engineering manufacturing process and bioelectronic platform to deliver versatile electroceuticals, the modern biofabrication enables comprehensive biomimetic therapies for neural tissue engineering and regeneration in the new era.

Implantable Electroceutical Approach Improves Myelination by Restoring Membrane Integrity in a Mouse Model of Peripheral Demyelinating Neuropathy.

Although many efforts are undertaken to treat peripheral demyelinating neuropathies based on biochemical interventions, unfortunately, there is no approved treatment yet. Furthermore, previous studies have not shown improvement of the myelin membrane at the biomolecular level. Here, an electroceutical treatment is introduced as a biophysical intervention to treat Charcot-Marie-Tooth (CMT) disease-the most prevalent peripheral demyelinating neuropathy worldwide-using a mouse model. The specific electrical stimulation (ES) condition (50 mV mm-1 , 20 Hz, 1 h) for optimal myelination is found via an in vitro ES screening system, and its promyelinating effect is validated with ex vivo dorsal root ganglion model. Biomolecular investigation via time-of-flight secondary ion mass spectrometry shows that ES ameliorates distribution abnormalities of peripheral myelin protein 22 and cholesterol in the myelin membrane, revealing the restoration of myelin membrane integrity. ES intervention in vivo via flexible implantable electrodes shows not only gradual rehabilitation of mouse behavioral phenotypes (balance and endurance), but also restored myelin thickness, compactness, and membrane integrity. This study demonstrates, for the first time, that an electroceutical approach with the optimal ES condition has the potential to treat CMT disease and restore impaired myelin membrane integrity, shifting the paradigm toward practical interventions for peripheral demyelinating neuropathies.

The multibranched nerve: vagal function beyond heart rate variability.

This paper reviews the many functions of the vagus nerve, to understand how they interact in daily life and what might be accomplished by therapeutical electrical stimulation. A short historical introduction on the discovery and name-giving of the cranial nerves numbers 9-12 is followed by an overview of the functions that are under lower brain stem control: heart (rate, contractility), intestine (swallowing, peristalsis and glands secretions, feeling of satiety), lungs (bronchoconstriction, lung-irritant and stretch receptor signaling), blood pressure (by vascular wall stress sensing) and blood gases by specialized receptors. Key in the review is the physiology behind beat-by-beat heart rate variations, how everyday life is reflected in its variability, from exciting moments to quiet sleep, with the 'common faint' or vasovagal collapse as extreme example. Next, the recently proposed role of the vagus nerve in limiting inflammation is discussed. This has led to adoption of an earlier developed technique for epilepsy treatment, i.e., electrical stimulation of one vagus nerve bundle in the neck, but now for immune diseases like rheumatoid arthritis and the scope is even widening to depression and cluster headache. However, the problem in application of whole vagus nerve stimulation is the lack of specificity: there is no way to titrate the stimulation to an observable effect variable. All nerves in the bundle, incoming and outgoing, can be 'hit', leading to side-effects which limit the intended application.

New Era of Electroceuticals: Clinically Driven Smart Implantable Electronic Devices Moving towards Precision Therapy.

In the name of electroceuticals, bioelectronic devices have transformed and become essential for dealing with all physiological responses. This significant advancement is attributable to its interdisciplinary nature from engineering and sciences and also the progress in micro and nanotechnologies. Undoubtedly, in the future, bioelectronics would lead in such a way that diagnosing and treating patients' diseases is more efficient. In this context, we have reviewed the current advancement of implantable medical electronics (electroceuticals) with their immense potential advantages. Specifically, the article discusses pacemakers, neural stimulation, artificial retinae, and vagus nerve stimulation, their micro/nanoscale features, and material aspects as value addition. Over the past years, most researchers have only focused on the electroceuticals metamorphically transforming from a concept to a device stage to positively impact the therapeutic outcomes. Herein, the article discusses the smart implants' development challenges and opportunities, electromagnetic field effects, and their potential consequences, which will be useful for developing a reliable and qualified smart electroceutical implant for targeted clinical use. Finally, this review article highlights the importance of wirelessly supplying the necessary power and wirelessly triggering functional electronic circuits with ultra-low power consumption and multi-functional advantages such as monitoring and treating the disease in real-time.