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AIMS: There is limited evidence to support the efficacy of sacral neuromodulation (SNM) for older adults with overactive bladder (OAB). This study aims to report outcomes following SNM among nursing home (NH) residents, a vulnerable population with high rates of frailty and comorbidity. METHODS: This is a retrospective cohort study of long-stay NH residents who underwent a trial of percutaneous nerve evaluation (PNE) or Stage 1 permanent lead placement (Stage 1) between 2014 and 2016. Residents were identified using the Minimum Data Set linked to Medicare claims. The primary outcome of this study was successful progression from trial to implant. Rates of 1-year device explant/revisions were also investigated. RESULTS: Trial of SNM was observed in 1089 residents (mean age: 77.9 years). PNE was performed in 66.9% of residents and 33.2% underwent Stage 1. Of Stage 1 procedures, 23.8% were performed with simultaneous device implant (single-stage). Overall, 53.1% of PNEs and 72.4% of Stage 1 progressed to device implant, which was associated with Stage 1 procedure versus PNE (adjusted relative risk [aRR]: 1.34; 95% confidence interval [95% CI]: 1.21-1.49) and female versus male sex (aRR: 1.26; 95% CI: 1.09-1.46). One-year explant/revision was observed in 9.3% of residents (6.3% for PNE, 10.5% for Stage 1, 20.3% single-stage). Single stage procedure versus PNE was significantly associated with device explant/revision (aRR: 3.4; 95% CI: 1.9-6.2). CONCLUSIONS: In this large cohort of NH residents, outcomes following SNM were similar to previous reports of younger healthier cohorts. Surgeons managing older patients with OAB should use caution when selecting patients for single stage SNM procedures.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p

Deep brain stimulation (DBS) holds promise for neuropsychiatric conditions where imbalance in network activity contributes to symptoms. Treatment-resistant Combat post-traumatic stress disorder (TR-PTSD) is a highly morbid condition and 50% of PTSD sufferers fail to recover despite psychotherapy or pharmacotherapy. Reminder-triggered symptoms may arise from inadequate top-down ventromedial prefrontal cortex (vmPFC) control of amygdala reactivity. Here, we report long-term data on two TR-PTSD participants from an investigation utilizing high-frequency amygdala DBS. The two combat veterans were implanted bilaterally with quadripolar electrodes targeting the basolateral amygdala. Following a randomized staggered onset, patients received stimulation with adjustments based on PTSD symptom severity for four years while psychiatric and neuropsychiatric symptoms, neuropsychological performance, and electroencephalography were systematically monitored. Evaluation of vmPFC-Amygdala network engagement was assessed with 18FDG positron emission tomography (PET). CAPS-IV scores varied over time, but improved 55% from 119 at baseline to 53 at 4-year study endpoint in participant 1; and 44%, from 68 to 38 in participant 2. Thereafter, during 5 and 1.5 years of subsequent clinical care respectively, long-term bilateral amygdala DBS was associated with additional, clinically significant symptomatic and functional improvement. There were no serious stimulation-related adverse psychiatric, neuropsychiatric, neuropsychological, neurological, or neurosurgical effects. In one subject, symptomatic improvement was associated with an intensity-dependent reduction in amygdala theta frequency power. In out two participants, FDG-PET findings were inconclusive regarding the hypothesized mechanism of suppression of amygdala hyperactivity. Our findings encourage further research to confirm and extend our preliminary observations.

Neuropathic pain is a chronic condition representing a significant burden for society. It is estimated 1 out of 10 people over the age of 30 that in the US have been diagnosed with neuropathic pain. Most of the available treatments for neuropathic pain have moderate efficacy over time which limit their use; therefore, other therapeutic approaches are needed for patients. Spinal cord stimulation is an established and cost-effective modality for treating severe chronic pain. In this article we will review the current approved indications for the use of spinal cord stimulation in the US and the novel therapeutic options which are now available using this therapy.

Neuromodulation via Responsive Neurostimulation (RNS) or Deep Brain Stimulation (DBS) is an emerging treatment strategy for pediatric drug-resistant epilepsy (DRE). Knowledge gaps exist in patient selection, surgical technique, and perioperative care. Here, we use an expert survey to clarify practices. Thirty-two members of the Pediatric Epilepsy Research Consortium were surveyed using REDCap. Respondents were from 17 pediatric epilepsy centers (missing data in one): Four centers implant RNS only while 13 implant both RNS and DBS. Thirteen RNS programs commenced in or before 2020, and 10 of 12 DBS programs began thereafter. The busiest six centers implant 6-10 new RNS devices per year; all DBS programs implant 50%) was reported by 81% (13/16) of centers. RNS and DBS are rapidly evolving treatment modalities for safe and effective treatment of pediatric DRE. There is increasing interest in multicenter collaboration to gain knowledge and facilitate dialogue. PLAIN LANGUAGE SUMMARY: We surveyed 32 pediatric epilepsy centers in USA to highlight current practices of intracranial neuromodulation. Of the 17 that replied, we found that most centers are implanting thalamic targets in pediatric drug-resistant epilepsy using the RNS device. DBS device is starting to be used in pediatric epilepsy, especially after 2020. Different strategies for target identification are enumerated. This study serves as a starting point for future collaborative research.

In medication-resistant epilepsy, the goal of epilepsy surgery is to make a patient seizure free with a resection/ablation that is as small as possible to minimize morbidity. The standard of care in planning the margins of epilepsy surgery involves electroclinical delineation of the seizure-onset zone and incorporation of neuroimaging findings from MRI, PET, single-photon emission CT and magnetoencephalography modalities. Resecting cortical tissue generating high-frequency oscillations has been investigated as a more efficacious alternative to targeting the seizure-onset zone. In this study, we used a support vector machine (SVM), with four distinct fast ripple (FR: 350-600 Hz on oscillations, 200-600 Hz on spikes) metrics as factors. These metrics included the FR resection ratio, a spatial FR network measure and two temporal FR network measures. The SVM was trained by the value of these four factors with respect to the actual resection boundaries and actual seizure-free labels of 18 patients with medically refractory focal epilepsy. Leave-one-out cross-validation of the trained SVM in this training set had an accuracy of 0.78. We next used a simulated iterative virtual resection targeting the FR sites that were of highest rate and showed most temporal autonomy. The trained SVM utilized the four virtual FR metrics to predict virtual seizure freedom. In all but one of the nine patients who were seizure free after surgery, we found that the virtual resections sufficient for virtual seizure freedom were larger in volume (P < 0.05). In nine patients who were not seizure free, a larger virtual resection made five virtually seizure free. We also examined 10 medically refractory focal epilepsy patients implanted with the responsive neurostimulator system and virtually targeted the responsive neurostimulator system stimulation contacts proximal to sites generating FR at highest rates to determine if the simulated value of the stimulated seizure-onset zone and stimulated FR metrics would trend towards those patients with a better seizure outcome. Our results suggest the following: (i) FR measures can accurately predict whether a resection, defined by the standard of care, will result in seizure freedom; (ii) utilizing FR alone for planning an efficacious surgery can be associated with larger resections; (iii) when FR metrics predict the standard-of-care resection will fail, amending the boundaries of the planned resection with certain FR-generating sites may improve outcome and (iv) more work is required to determine whether targeting responsive neurostimulator system stimulation contact proximal to FR generating sites will improve seizure outcome.

Aminergic nuclei in mammals are generally composed of relatively small numbers of cells with broad projection patterns. Despite the gross similarity of many individual neurons, recent transcriptomic, anatomic and behavioral studies suggest previously unsuspected diversity. Smaller clusters of aminergic neurons in the model organism Drosophila melanogaster provide an opportunity to explore the ramifications of neuronal diversity at the level of individual cells. A group of approximately 10 tyraminergic/octopaminergic neurons innervates the female reproductive tract in flies and has been proposed to regulate multiple activities required for fertility. The projection patterns of individual neurons within the cluster are not known and it remains unclear whether they are functionally heterogenous. Using a single cell labeling technique, we show that each region of the reproductive tract is innervated by a distinct subset of tyraminergic/octopaminergic cells. Optogenetic activation of one subset stimulates oviduct contractions, indicating that the cluster as a whole is not required for this activity, and underscoring the potential for functional diversity across individual cells. Using whole cell patch clamp, we show that two adjacent and morphologically similar cells are tonically inhibited, but each responds differently to injection of current or activation of the inhibitory GluCl receptor. GluCl appears to be expressed at relatively low levels in tyraminergic/octopaminergic neurons within the cluster, suggesting that it may regulate their excitability via indirect pathways. Together, our data indicate that specific tyraminergic/octopaminergic cells within a relatively homogenous cluster have heterogenous properties and provide a platform for further studies to determine the function of each cell.

Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation of the nervous system by precise delivery of electrical current for the treatment of clinical conditions, such as post-stroke movement recovery or drug-resistant disorders. The unquestionable clinical impact of Bioelectronic Medicine is underscored by the successful translation to humans in the last decades, and the long list of preclinical studies. Given the emergency of accelerating the progress in new neuromodulation treatments (i.e., drug-resistant hypertension, autoimmune and degenerative diseases), collaboration between multiple fields is imperative. This work intends to foster multidisciplinary work and bring together different fields to provide the fundamental basis underlying Bioelectronic Medicine. In this review we will go from the biophysics of the cell membrane, which we consider the inner core of neuromodulation, to patient care. We will discuss the recently discovered mechanism of neurotransmission switching and how it will impact neuromodulation design, and we will provide an update on neuronal and glial basis in health and disease. The advances in biomedical technology have facilitated the collection of large amounts of data, thereby introducing new challenges in data analysis. We will discuss the current approaches and challenges in high throughput data analysis, encompassing big data, networks, artificial intelligence, and internet of things. Emphasis will be placed on understanding the electrochemical properties of neural interfaces, along with the integration of biocompatible and reliable materials and compliance with biomedical regulations for translational applications. Preclinical validation is foundational to the translational process, and we will discuss the critical aspects of such animal studies. Finally, we will focus on the patient point-of-care and challenges in neuromodulation as the ultimate goal of bioelectronic medicine. This review is a call to scientists from different fields to work together with a common endeavor: accelerate the decoding and modulation of the nervous system in a new era of therapeutic possibilities.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating avatars (herein defined as an extension of digital twins) of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

The relationship between heart failure and diabetes is intricate and bidirectional. Individuals with diabetes face an elevated risk of developing heart failure due to factors like insulin resistance, chronic inflammation, and metabolic irregularities. Elevated blood sugar levels can harm blood vessels and nerves, culminating in the buildup of fatty deposits in arteries, atherosclerosis, and hypertension, which significantly contribute to heart failure. Furthermore, diabetes can adversely impact the structure and function of the heart muscle, impairing its pumping capacity. Conversely, heart failure can also contribute to the onset of diabetes by disrupting the bodys metabolic processes and amplifying insulin resistance. The complex interaction between these conditions mandates a comprehensive approach to managing individuals with both diabetes and heart failure, underscoring the importance of addressing both aspects for enhanced patient outcomes. Although existing pharmacological treatments are limited and frequently associated with undesirable side effects, acupuncture has established itself as a traditional practice with a legacy. It remains a supplementary option for treating cardiovascular diseases. Heart failure and diabetes are both heavily associated with chronic upregulation of the sympathetic nervous system, which has been identified as a pivotal factor in the progression of disease. Mechanistic interplays such as the attenuation of central nitric oxide signaling may interfere with the production or availability of nitric oxide in key areas of the central nervous system, including the brainstem and hypothalamus. This review will delve into the current understanding of acupuncture on the autonomic nervous system and offer insights into its potential role in the future treatment landscape for diabetes and heart failure.

The aim of the present study was to determine if anodal transcutaneous spinal direct current stimulation (tsDCS) affects corticospinal excitability (CSE) and voluntary activation (VA) of the quadriceps femoris muscle (QM). This was a double‐blind, randomized study in which spine‐shoulder anodal tsDCS (active electrode centered over T11–12, 2.5 mA, 20 min) was applied in a seated position. Transcranial magnetic stimulation (TMS) was used to measure motor evoked potentials (MEP) and construct stimulus–response curves in healthy participants (eight females and five males, Experiment 1). VA was measured via the interpolated twitch technique, whereby muscle twitches were evoked using electrical femoral nerve stimulation and TMS (seven females and six males, Experiment 2). Measurements were carried out before, directly, and 30 min after sham and anodal tsDCS (with ≥4 days between sessions). There was no interaction between stimulation × time on stimulus–response curve expressed by slope, stimulus intensity corresponding to 50% of the maximal MEP, and peak‐to‐peak amplitude of the maximal MEP. Maximal voluntary isometric contraction (MVIC) torque did not change and VA was not affected regardless of the QM torque level (25, 50, or 100% of MVIC). A single, twenty‐minute session of spine‐shoulder anodal tsDCS did not increase CSE and VA of QM during submaximal and maximal contraction. This suggests that neither excitability to a known input nor responsiveness of motoneurons to submaximal and maximal cortical drive were affected by anodal tsDCS. [ABSTRACT FROM AUTHOR]

Disruption of somatosensorimotor integration (SMI) after stroke is a significant obstacle to achieving precise motor restoration. Integrating somatosensory input into motor relearning to reconstruct SMI is critical during stroke rehabilitation. However, current robotic approaches focus primarily on precise control of repetitive movements and rarely effectively engage and modulate somatosensory responses, which impedes motor rehabilitation that relies on SMI. This article discusses how to effectively regulate somatosensory feedback from target muscles through peripheral and central neuromodulatory stimulations based on quantitatively measured somatosensory responses in real time during robot-assisted rehabilitation after stroke. Further development of standardized recording protocols and diagnostic databases of quantitative neuroimaging features in response to post-stroke somatosensory stimulations for real-time precise detection, and optimized combinations of peripheral somatosensory stimulations with robot assistance and central nervous neuromodulation are needed to enhance the recruitment of targeted ascending neuromuscular pathways in robot-assisted training, aiming to achieve precise muscle control and integrated somatosensorimotor functions, thereby improving long-term neurorehabilitation after stroke. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second‐fastest growing neurodegenerative disease in the world. The major clinical symptoms rigor, tremor, and bradykinesia derive from the degeneration of the nigrostriatal pathway. However, PD is a multi‐system disease, and neurodegeneration extends beyond the degradation of the dopaminergic pathway. Symptoms such as postural instability, freezing of gait, falls, and cognitive decline are predominantly caused by alterations of transmitter systems outside the classical dopaminergic axis. While levodopa and deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus internus effectively address PD primary motor symptoms, they often fall short in mitigating axial symptoms and cognitive impairment. Along these lines, the cholinergic system is increasingly recognized to play a crucial role in governing locomotion, postural stability, and cognitive function. Thus, there is a growing interest in bolstering the cholinergic tone by DBS of cholinergic targets such as the pedunculopontine nucleus (PPN) and nucleus basalis of Meynert (NBM), aiming to alleviate these debilitating symptoms resistant to traditional treatment strategies targeting the dopaminergic network. This review offers a comprehensive overview of the role of cholinergic dysfunction in PD. We discuss the impact of PPN and NBM DBS on the management of symptoms not readily accessible to established DBS targets and pharmacotherapy in PD and seek to provide guidance on patient selection, surgical approach, and stimulation paradigms. [ABSTRACT FROM AUTHOR]

Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier frequency is thought to be less painful than conventional pulsed currents by reducing the sensitivity of pain receptors. However, no purported benefit has been shown unequivocally. We compared the effects of carrier‐frequency stimulation and conventional stimulation on pain tolerance and the thresholds for sensory and motor axons in twelve participants. The ulnar nerve was stimulated transcutaneously with a conventional single pulse and 5 and 10 kHz carrier‐frequency waveforms that had 5 and 10 pulses, respectively, when delivered in bursts of ∼1 ms duration. Phase durations were adjusted across waveform types to match the total charge for a given current amplitude. Single bursts of stimulation were delivered from 1 mA up until no longer tolerable. This was repeated with repetitive bursts of stimulation at 20 Hz for 1 s. Participants tolerated higher current amplitudes with both carrier‐frequency waveforms than conventional stimulation, with repetitive bursts more painful than single bursts. However, compared to conventional stimulation, carrier‐frequency waveforms required more current to produce sensory and motor‐threshold responses and to obtain a maximal motor response (Mmax). When the current at pain tolerance was normalised to the current at Mmax, participants tolerated lower stimulus intensities with carrier‐frequency waveforms than conventional stimulation. These findings indicate that there is little to no benefit in using carrier‐frequency waveforms to minimise the discomfort from electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in the activation of sensory and motor axons. Key points: Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier‐frequency waveform is thought to be less painful than conventional pulsed currents.For ulnar nerve stimulation, when stimulus waveforms were matched for total phase charge, participants tolerated higher current amplitudes with carrier‐frequency stimulation than conventional stimulation.However, compared to conventional stimulation, carrier‐frequency waveforms required more current to produce a threshold response in both sensory and motor axons and to produce a maximal motor response (Mmax).When current at pain tolerance was normalised to current at Mmax, participants tolerated lower stimulus intensities with carrier‐frequency waveforms than conventional stimulation.Carrier‐frequency waveforms provide little to no benefit in minimising the discomfort from transcutaneous electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in activating sensory and motor axons. [ABSTRACT FROM AUTHOR]

Focal status epilepticus, particularly the motor variant of epilepsia partialis continua (EPC), is a rare condition characterized by near‐continuous, chronic focal motor seizures, and associated with poor outcomes. Medications, including anesthetics, are often unsuccessful. Surgical resection can result in motor deficits. We report a medically complex pediatric case of super‐refractory EPC that was successfully managed with combined focal resection and responsive neuromodulation. This case introduces neuromodulation as a treatment modality for this challenging condition. [ABSTRACT FROM AUTHOR]

Introduction: In primary auditory cortex (A1), nicotinic acetylcholine receptors (nAChRs) containing α2 subunits are expressed in layer 5 Martinotti cells (MCs)—inhibitory interneurons that send a main axon to superficial layers to inhibit distal apical dendrites of pyramidal cells (PCs). MCs also contact interneurons in supragranular layers that, in turn, inhibit PCs. Thus, MCs may regulate PCs via inhibition and disinhibition, respectively, of distal and proximal apical dendrites. Auditory inputs to PCs include thalamocortical inputs to middle layers relaying information about characteristic frequency (CF) and near-CF stimuli, and intracortical long-distance ("horizontal") projections to multiple layers carrying information about spectrally distant ("nonCF") stimuli. CF and nonCF inputs integrate to create broad frequency receptive fields (RFs). Systemic administration of nicotine activates nAChRs to "sharpen" RFs—to increase gain within a narrowed RF—resulting in enhanced responses to CF stimuli and reduced responses to nonCF stimuli. While nicotinic mechanisms to increase gain have been identified, the mechanism underlying RF narrowing is unknown. Methods: Here, we examine the role of α2 nAChRs in mice with α2 nAChR-expressing neurons labeled fluorescently, and in mice with α2 nAChRs genetically deleted. Results: The distribution of fluorescent neurons in auditory cortex was consistent with previous studies demonstrating α2 nAChRs in layer 5 MCs, including nonpyramidal somata in layer 5 and dense processes in layer 1. We also observed label in subcortical auditory regions, including processes, but no somata, in the medial geniculate body, and both fibers and somata in the inferior colliculus. Using electrophysiological (current-source density) recordings in α2 nAChR knock-out mice, we found that systemic nicotine failed to enhance CF-evoked inputs to layer 4, suggesting a role for subcortical α2 nAChRs, and failed to reduce nonCF-evoked responses, suggesting that α2 nAChRs regulate horizontal projections to produce RF narrowing. Discussion: The results support the hypothesis that α2 nAChRs function to simultaneously enhance RF gain and narrow RF breadth in A1. Notably, a similar neural circuit may recur throughout cortex and hippocampus, suggesting widespread conserved functions regulated by α2 nAChRs. [ABSTRACT FROM AUTHOR]

Various preclinical and clinical studies have demonstrated the neuromodulatory and ablative effects of focused ultrasound (FUS). However, the safety and efficacy of FUS in clinical settings for treating epilepsy have not been well established. This study aims to provide a systematic review of all preclinical and clinical studies that have used FUS for the treatment of epilepsy. A systematic search was conducted using Scopus, Web of Science, PubMed, and Embase databases. All preclinical and clinical studies reporting outcomes of FUS in the treatment of epilepsy were included in the systematic review. Random-effect meta-analysis was performed to determine safety in clinical studies and seizure activity reduction in preclinical studies. A total of 24 articles were included in the study. Meta-analysis demonstrated that adverse events occurred in 13% (95% CI = 2–57%) of patients with epilepsy who underwent FUS. The frequency of adverse events was higher with the use of FUS for lesioning (36%, 95% CI = 4–88%) in comparison to neuromodulation (5%, 95% CI = 0–71%), although this difference was not significant (P = 0.31). Three-level meta-analysis in preclinical studies demonstrated a reduced spike rate in neuromodulating FUS compared to the control group (P = 0.02). According to this systematic review and meta-analysis, FUS can be considered a safe and feasible approach for treating epileptic seizures, especially in drug-resistant patients. While the efficacy of FUS has been demonstrated in several preclinical studies, further research is necessary to confirm its effectiveness in clinical practice and to determine the adverse events. [ABSTRACT FROM AUTHOR]

Key points Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exist. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry and ultrastructure of these neurons across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections and had high synaptic efficacy constituting an obligatory synapse. At pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold EPSPs like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant vasoactive intestinal polypeptide observed in human but not pig or mouse ganglia, and little substance P or calcitonin gene‐related peptide in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after‐hyperpolarizations. Intrinsic excitability differed; 95% of human neurons were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs and humans identifies similarities and differences in the evolution of ICNs. Intrinsic cardiac neurons (ICNs) are essential to the regulation of cardiac function. We investigated the neurochemistry, morphology, ultrastructure, membrane physiology and synaptic transmission of ICNs from donated human hearts in parallel with identical studies of ICNs from mice and pigs to create a publicly accessible cellular atlas detailing the structure and function of these neurons across species. In addition to presenting foundational data on human ICNs, this comparative study identifies both conserved and derived attributes of these neurons within mammals. The findings have significant implications for understanding the regulation of cardiac autonomic function in humans and may greatly influence strategies for neuromodulation in conditions such as atrial fibrillation and heart failure. [ABSTRACT FROM AUTHOR]

Purpose: Simulator Adaptation Syndrome arises from a perceptual discordance between expected and actual motion, giving rise to symptoms such as nausea and disorientation. This research focused on determining the benefit of Transcutaneous Vagal Nerve Stimulation (tVNS) and Galvanic Cutaneous Stimulation (GCS), where both were applied in conjunction, as compared to their administration in isolation, to decrease Simulator Adaptation Syndrome (SAS). Method: A driving simulation study was proposed where SAS, body balance, and driving performance were measured. These measurements were taken during seven different stimulation scenarios with a baseline condition without stimulation compared against tVNS and GCS conditions. Results: The main result showed that the combination of tVNS and GCS reduced SAS and improved body balance and driving performance more successfully than their administration in isolation. Conclusion: Similar neuromodulation in the temporoparietal junction is proposed to mitigate SAS for GCS and tVNS (although additional explanations are discussed). Applying both techniques simultaneously is encouraged to decrease SAS in future interventions. [ABSTRACT FROM AUTHOR]

The editorial titled "How does brain stimulation work? Neuroversion and other putative mechanisms of action" explores the evolving field of brain stimulation techniques in psychiatry and neurology. It discusses various methods such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS) that trigger neurochemical and electrophysiological changes in the brain to produce therapeutic effects. The research topic includes 10 articles authored by 76 individuals covering a range of brain stimulation techniques and their applications in neuropsychiatric disorders, aiming to enhance understanding and influence further research and clinical practice. The findings presented in the editorial highlight the diverse applications of brain stimulation techniques and their potential benefits, contributing to the advancement of clinical practice and stimulating further investigation into the mechanisms underlying these therapies. [Extracted from the article]

There are limited treatment options for individuals with drug‐resistant idiopathic generalized epilepsy (IGE). Small, limited case series suggest that centromedian thalamus deep brain stimulation (CM‐DBS) may be an effective treatment option. The optimal CM‐DBS target for IGE is underexamined. Here, we present a retrospective analysis of CM‐DBS targeting and efficacy for five patients with drug‐resistant IGE. Volume of tissue activated (VTA) overlap with CM nucleus was performed using an open‐source toolbox. Median follow‐up time was 13 months. Median convulsive seizure frequency reduction was 66%. One patient had only absence seizures, with >99% reduction in absence seizure frequency. Four patients had electrode contacts positioned within the CM nucleus target, all of whom had >50% reduction in primary semiology seizure, with 85% median seizure reduction (p =.004, paired‐sample t test). Volumetric "sweet‐spot" mapping revealed that best outcomes were correlated with stimulation of the middle ventral CM nucleus. Connectivity strength between the sweet‐spot region and central peri‐Rolandic cortex was increased significantly relative to other cortical regions (p = 8.6 × 10−4, Mann–Whitney U test). Our findings indicate that CM‐DBS can be an effective treatment for patients with IGE, highlight the importance of accurate targeting and targeting analysis, and within the context of prior work, suggest that ideal CM‐DBS targets may be syndrome specific. [ABSTRACT FROM AUTHOR]

Neuropeptides are abundant signaling molecules that control neuronal activity and behavior in all animals. Owing in part to its well-defined and compact nervous system, Caenorhabditis elegans has been one of the primary model organisms used to investigate how neuropeptide signaling networks are organized and how these neurochemicals regulate behavior. We here review recent work that has expanded our understanding of the neuropeptidergic signaling network in C. elegans by mapping the evolutionary conservation, the molecular expression, the receptor–ligand interactions, and the system-wide organization of neuropeptide pathways in the C. elegans nervous system. We also describe general insights into neuropeptidergic circuit motifs and the spatiotemporal range of peptidergic transmission that have emerged from in vivo studies on neuropeptide signaling. With efforts ongoing to chart peptide signaling networks in other organisms, the C. elegans neuropeptidergic connectome can serve as a prototype to further understand the organization and the signaling dynamics of these networks at organismal level. [ABSTRACT FROM AUTHOR]

The innervation of the antennal heart of the cockroach Periplaneta americana was studied with immunocytochemical techniques on both the light and electron microscopic levels. The antennal heart is innervated by two efferent systems, both using one biogenic amine in combination with neuropeptides. In one, we found co-localization of serotonin with proctolin and allatostatin. These fibers most likely originate from paired neurons located in the suboesophageal ganglion. In the second system, we found octopamine co-localized with the short neuropeptide F. The source of this second system is dorsal unpaired median (DUM) neurons, also located in the suboesophageal ganglion. The possible effects of these neuromediators on different targets are discussed. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions The cerebellar cognitive affective syndrome (CCAS) encompasses cognitive and affective symptoms in patients with cerebellar disorders, for which no proven treatment is available.Our primary objective was to study the effect of cerebellar anodal transcranial direct current stimulation (tDCS) on cognitive performance in CCAS patients. Secondary effects on ataxia severity, mood, and quality of life were explored.We performed a randomized, double‐blind, sham‐controlled trial. Thirty‐five patients with CCAS were included and received 10 sessions of 20 minutes sham (n = 17) or real (n = 18) tDCS, with a current of 2 mA. Cognitive performance was assessed using executive function subtests of the computerized Test of Attentional Performance (TAP), with the composite as primary endpoint. Secondary outcomes were ataxia severity, mood, and quality of life. Outcomes were evaluated 1, 3, 6, and 12 months post‐intervention.Cerebellar tDCS was well tolerated and no serious adverse events related to the intervention occurred. No significant tDCS effect was found on cognitive performance. Improvement on the TAP was observed in the sham group 1 month post‐treatment (estimate = −0.248, 95% CI, −0.49 to −0.01), but not clinically relevant. A positive tDCS effect was observed for ataxia severity 1 month post‐treatment (estimate = −0.985, 95% CI, −1.94 to −0.03).Ten sessions of 20 minutes cerebellar anodal tDCS did not prove efficacious for CCAS‐related cognitive impairment, but a significant positive effect of tDCS was found for ataxia severity, aligning with previous findings indicative of tDCS as a therapeutic neuromodulation tool in cerebellar disorders. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective: We investigated if theta burst stimulation could enhance recovery by reducing key symptoms when implemented acutely post fracture in participants with an isolated upper limb fracture. Methods/Design: This was a pilot study with a randomized matched pair, sham-controlled, participant-blind design of a 10-day prolonged continuous theta burst stimulation protocol. Two main groups were included: I) participants with isolated upper limb fracture receiving active theta burst stimulation and II) patients with isolated upper limb fracture receiving SHAM/placebo. Another group (III) of healthy individuals was the reference group. Disability and pain intensity were collected through questionnaires (disabilities of the Arm, Shoulder, and Hand as well as numerical rating scale (NRA)) at three time points (baseline; 72 hrs after intervention, 3 mos after injury). Group III completed the baseline assessment. Results: Seventy-nine participants were enrolled. Individuals in the ACTIVE and SHAM groups had similar baseline measures. For disability, the interaction between intervention and time approached significance (F = 2.33; P = 0.11), whereas it was significant for pain (F = 3.42; P = 0.04). At 3 mos after injury, the ACTIVE group reported reduced disability (F = 4.71; P = 0.04) and pain (F = 5.84; P = 0.02) at 3 mos after injury compared to the SHAM group, with clinical measures from ACTIVE group being like controls. Conclusions: In isolated upper limb fracture patients, a 10-day theta burst stimulation intervention implemented acutely posttraumatic had beneficial effects on symptoms of functional recovery and pain at 3 mos after trauma. [ABSTRACT FROM AUTHOR]

The endocannabinoid system plays a critical role in modulating both peripheral and central nervous system function. Despite being present throughout the animal kingdom, there has been relatively little investigation of the endocannabinoid system beyond traditional animal models. In this study, we report on the identification and characterization of a putative fatty acid amide hydrolase (FAAH) in the medicinal leech, Hirudo verbana. FAAH is the primary enzyme responsible for metabolizing the endocannabinoid signaling molecule arachidonoyl ethanolamide (anandamide or AEA) and therefore plays a critical role in regulating AEA levels in the nervous system. mRNA encoding Hirudo FAAH (HirFAAH) is expressed in the leech central nervous system (CNS) and sequence analysis suggests that this is an orthologue of FAAH-2 observed in vertebrates. Functionally, HirFAAH has serine hydrolase activity based on activity-based protein profiling (ABPP) studies using the fluorophosphonate probe TAMRA-FP. HirFAAH also hydrolyzes arachidonyl 7-amino, 4-methyl coumarin amide (AAMCA), a substrate specific to FAAH. Hydrolase activity during both the ABPP and AAMCA assays was eliminated by a mutation at a conserved catalytic serine. Activity was also blocked by the known FAAH inhibitor, URB597. Treatment of Hirudo ganglia with URB597 potentiated synapses made by the pressure-sensitive mechanosensory neuron (P cell), mimicking the effects of exogenously applied AEA. The Hirudo CNS has been a useful system in which to study properties of endocannabinoid modulation of nociception relevant to vertebrates. Therefore, this characterization of HirFAAH is an important contribution to comparative studies of the endocannabinoid system. [ABSTRACT FROM AUTHOR]

With over 16 years of experience in clinical, research, and educational activities related to transcranial magnetic stimulation (TMS), I have written this article exploring the ethical dimensions of TMS. This article aims to provide valuable and informative content for those unfamiliar with TMS as well as those just starting in the field. Specifically, this article elaborates on four principles of medical ethics, including those applicable to TMS therapy, the disparity between public medical insurance coverage and medical indications in private practice for TMS therapy, and issues concerning research ethics in practice. I also provide recommendations regarding roles and strategies for adoption by academia and those in this field dedicated to making TMS therapy accessible to a larger patient population in a suitable manner. Lastly, it is my hope that this article will serve as a contemporary "Ethics of TMS Neuromodulation", resonating with the inherent human pursuit of "truth, goodness, and beauty" for a sound mind and spirit. [ABSTRACT FROM AUTHOR]

Dual-mode non-invasive brain stimulation using repetitive transcranial magnetic stimulation and transcranial direct current stimulation is known to help neurorehabilitation in patients with stroke. However, this neuromodulation effect may vary depending on the lesion location of patients with stroke, and the basis in lesion location for this is insufficient. This study aims to investigate the difference in neuromodulation effectiveness according to the lesion location after dual-mode brain stimulation using electroencephalography signals. Eight patients with ischemic subacute stroke and 11 healthy controls participated in this study. Brain stimulation was conducted in one session per day for a total of 10 days over the motor cortex, electroencephalography was measured for 5 min with eyes closed, and motor function was evaluated before and after dual-mode stimulation. The lesion location was divided into an infratentorial stroke (ITS) and a supratentorial stroke (STS) based on tentorium cerebelli. In addition, we focused on the mu and beta bands related to motor function. In terms of intrahemispheric connectivity, the mu weighted phase lag index over the contralesional primary motor cortex was significantly higher in only ITS before stimulation compared to healthy controls, and mu Granger causality over the ipsilesional primary motor cortex was significantly higher in both ITS and STS after stimulation compared to healthy controls. In contrast, from the perspective of interhemispheric connectivity, the laterality of beta Granger causality before stimulation in ITS was lower than that of healthy controls and significantly increased after stimulation. The effect of brain stimulation may vary depending on the lesion location of patients with stroke, and these findings provide indicative insights into effective dual-mode stimulation interventions for neurorehabilitation. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) has long been the conventional method for targeting deep brain structures, but noninvasive alternatives like transcranial Temporal Interference Stimulation (tTIS) are gaining traction. Research has shown that alternating current influences brain oscillations through neural modulation. Understanding how neurons respond to the stimulus envelope, particularly considering tTIS's high-frequency carrier, is vital for elucidating its mechanism of neuronal engagement. This study aims to explore the focal effects of tTIS across varying amplitudes and modulation depths in different brain regions. An excitatory-inhibitory network using the Izhikevich neuron model was employed to investigate responses to tTIS and compare them with transcranial Alternating Current Stimulation (tACS). We utilized a multi-scale model that integrates brain tissue modeling and network computational modeling to gain insights into the neuromodulatory effects of tTIS on the human brain. By analyzing the parametric space, we delved into phase, amplitude, and frequency entrainment to elucidate how tTIS modulates endogenous alpha oscillations. Our findings highlight a significant difference in current intensity requirements between tTIS and tACS, with tTIS requiring notably higher intensity. We observed distinct network entrainment patterns, primarily due to tTIS's high-frequency component, whereas tACS exhibited harmonic entrainment that tTIS lacked. Spatial resolution analysis of tTIS, conducted via computational modeling and brain field distribution at a 13 Hz stimulation frequency, revealed modulation in deep brain areas, with minimal effects on the surface. Notably, we observed increased power within intrinsic and stimulation bands beneath the electrodes, attributed to the high stimulus signal amplitude. Additionally, Phase Locking Value (PLV) showed slight increments in non-deep areas. Our analysis indicates focal stimulation using tTIS, prompting further investigation into the necessity of high amplitudes to significantly affect deep brain regions, which warrants validation through clinical experiments. [ABSTRACT FROM AUTHOR]

Increased sympathetic and reduced parasympathetic nerve activity is associated with disease progression and poor outcomes in patients with chronic heart failure. The demonstration that markers of autonomic imbalance and vagal dysfunction, such as reduced heart rate variability and baroreflex sensitivity, hold prognostic value in patients with chronic heart failure despite modern therapies encourages the research for neuromodulation strategies targeting the vagus nerve. However, the approaches tested so far have yielded inconclusive results. This review aims to summarize the current knowledge about the role of the parasympathetic nervous system in chronic heart failure, describing the pathophysiological background, the methods of assessment, and the rationale, limits, and future perspectives of parasympathetic stimulation either by drugs or bioelectronic devices. [ABSTRACT FROM AUTHOR]

The entorhinal cortex (EC) and hippocampal (HC) connectivity is the main source of episodic memory formation and consolidation. The entorhinal– hippocampal (EC-HC) connection is classified as canonically glutamatergic and, more recently, has been characterized as a non-canonical GABAergic connection. Recent evidence shows that both EC and HC receive inputs from dopaminergic, cholinergic, and noradrenergic projections that modulate the mnemonic processes linked to the encoding and consolidation of memories. In the present review, we address the latest findings on the EC-HC connectivity and the role of neuromodulations during the mnemonic mechanisms of encoding and consolidation of memories and highlight the value of the cross-species approach to unravel the underlying cellular mechanisms known. Furthermore, we discuss how EC-HC connectivity early neurodegeneration may contribute to the dysfunction of episodic memories observed in aging and Alzheimer’s disease (AD). Finally, we described how exercise may be a fundamental tool to prevent or decrease neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction: A current thrust in neurology involves using exogenous neuromodulation of cranial nerves (e.g, vagus, trigeminal) to treat the signs and symptoms of various neurological disorders. These techniques also have the potential to augment cognitive and/or sensorimotor functions in healthy individuals. Although much is known about the clinical effects of trigeminal nerve stimulation (TNS), effects on sensorimotor and cognitive functions such as learning have received less attention, despite their potential impact on neurorehabilitation. Here we describe the results of experiments aimed at assessing the effects of TNS on motor learning, which was behaviorally characterized using an upper extremity visuomotor adaptation paradigm. Objective: Assessing the effects of TNS on motor learning. Methods: Motor learning was behaviorally characterized using an upper extremity visuomotor adaptation paradigm. In Experiment 1, effects of offline TNS using clinically tested frequencies (120 and 60 Hz) were characterized. Sixty-three healthy young adults received TNS before performing a task that involved reaching with perturbed hand visual feedback. In Experiment 2, the effects of 120 and 60 Hz online TNS were characterized with the same task. Sixty-three new participants received either TNS or sham stimulation concurrently with perturbed visual feedback. Results: Experiment 1 results showed that 60 Hz stimulation was associated with slower rates of learning than both sham and 120 Hz stimulation, indicating frequency-dependent effects of TNS. Experiment 2 however showed no significant differences among stimulation groups. A post-hoc, cross-study comparison of the 60 Hz offline and online TNS results showed a statistically significant improvement in learning rates with online stimulation relative to offline, pointing to timing-dependent effects of TNS on visuomotor learning. Discussion: The results indicate that both the frequency and timing of TNS can influence rates of motor learning in healthy adults. This suggests that optimization of one or both parameters could potentially increase learning rates, which would provide new avenues for enhancing performance in healthy individuals and augmenting rehabilitation in patients with sensorimotor dysfunction resulting from stroke or other neurological disorders. [ABSTRACT FROM AUTHOR]

Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for noninvasive brain stimulation (NIBS). TUS delivered in a theta (5 Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30–60 min, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex. We delivered four interventions: (1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), (2) real cTBS150 followed by sham tbTUS (cTBS only), (3) real cTBS150 followed by real tbTUS (metaplasticity), and (4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation (ICF), and short-interval intracortical facilitation before and up to 90 min after plasticity intervention. Plasticity effects lasted at least 60 min longer when tbTUS was primed with cTBS150 compared with tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed. Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggests that metaplasticity can be harnessed in the therapeutic development of TUS. [ABSTRACT FROM AUTHOR]

The clinical applications of neurotechnology are rapidly expanding, and the combination of different approaches could be more effective and precise to treat brain disorders. This Perspective discusses the potential and challenges of "multimodal neuromodulation," which combines modalities such as electrical, magnetic, and ultrasound stimulation. The clinical applications of neurotechnology are rapidly expanding, and the combination of different approaches could be more effective and precise to treat brain disorders. This Perspective discusses the potential and the challenges of 'multi-modal neuromodulation', which combines modalities such as electrical, magnetic and ultrasound stimulation. [ABSTRACT FROM AUTHOR]

Thermogenetics is a promising neuromodulation technique based on the use of heat-sensitive ion channels. However, on the way to its clinical application, a number of questions have to be addressed. First, to avoid immune response in future human applications, human ion channels should be studied as thermogenetic actuators. Second, heating levels necessary to activate these channels in vivo in brain tissue should be studied and cytotoxicity of these temperatures addressed. Third, the possibility and safety of chronic neuromodulation has to be demonstrated. In this study, we present a comprehensive framework for thermogenetic neuromodulation in vivo using the thermosensitive human ion channel hTRPV1. By targeting hTRPV1 expression to excitatory neurons of the mouse brain and activating them within a non-harmful temperature range with a fiber-coupled infrared laser, we not only induced neuronal firing and stimulated locomotion in mice, but also demonstrated that thermogenetics can be employed for repeated neuromodulation without causing evident brain tissue injury. Our results lay the foundation for the use of thermogenetic neuromodulation in brain research and therapy of neuropathologies. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion An in‐depth and detailed facial assessment is critical in treating and achieving desirable dermal filler and neurotoxin results.An acronym called A.S.S.E.S.S. simplifies an often complex and overwhelming amount of data needed to assimilate when performing facial filler and neurotoxin injections. Applying this method to patients in six simple steps provides a starting point and offers a guideline to capture key details for a more comprehensive facial assessment. The A.S.S.E.S.S. acronym stands for animate, shape, side, external, symmetry, and shadows and is helpful in following a methodical approach in analyzing facial shape, profile, and natural facial curves in both static and dynamic states.Following a regimented A.S.S.E.S.S. approach prior to treating filler and neurotoxin patients allows providers a straightforward guide to achieve a desirable facial shape and profile.This stepwise facial assessment establishes a logical and detailed approach to ensure the important aspects of facial details are appreciated in creating reliable and pleasing filler and neurotoxin results. [ABSTRACT FROM AUTHOR]

Introduction: Proprioceptive error of estimated fingertip position in twodimensional space is reduced with the addition of tactile stimulation applied at the fingertip. Tactile input does not disrupt the participants' estimation strategy, as the individual error vector maps maintain their overall structure. This relationship suggests integration of proprioception and tactile information improves proprioceptive estimation, which can also be improved with trained mental focus and attention. Task attention and arousal are physiologically regulated by the reticular activating system (RAS), a brainstem circuit including the locus coeruleus (LC). There is direct and indirect evidence that these structures can be modulated by non-invasive trigeminal nerve stimulation (nTNS), providing an opportunity to examine nTNS effect on the integrative relationship of proprioceptive and tactile information. Methods: Fifteen right-handed participants performed a simple right-handed proprioceptive estimation task with tactile feedback (touch) and no tactile (hover) feedback. Participants repeated the task after nTNS administration. Stimulation was delivered for 10 min, and stimulation parameters were 3,000 Hz, 50 µs pulse width, with a mean of 7 mA. Error maps across the workspace are generated using polynomial models of the participants' target responses. Results: Error maps did not demonstrate significant vector direction changes between conditions for any participant, indicating that nTNS does not disrupt spatial proprioception estimation strategies. A linear mixed model regression with nTNS epoch, tactile condition, and the interaction as factors demonstrated that nTNS reduced proprioceptive error under the hover condition only. Discussion: We argue that nTNS does not disrupt spatial proprioceptive error maps but can improve proprioceptive estimation in the absence of tactile feedback. However, we observe no evidence that nTNS enhances tactileproprioceptive integration as the touch condition does not exhibit significantly reduced error after nTNS. [ABSTRACT FROM AUTHOR]

The editorial "Neuromodulation technology: advances in optics and acoustics" published in Frontiers in Cellular Neuroscience discusses the transformative potential of neuromodulation technologies in treating neurological disorders and advancing neuroscience research. The article highlights recent innovations in optical and acoustic methods that offer minimally invasive neuromodulation with higher spatial and temporal resolution. It also explores the use of optical tools like retinal prostheses and optogenetics, as well as acoustic modulation through sonogenetics, to manipulate neural activity for therapeutic and research purposes. The integration of these technologies shows promise for more effective treatments and deeper insights into brain function, although challenges in research translation and regulatory processes remain. [Extracted from the article]

Targeted plasticity therapy (TPT) utilizes vagus nerve stimulation (VNS) to promote improvements in function following neurological injury and disease. During TPT, a brief burst of VNS induces neuromodulator release, which when paired with relevant behavioral events can influence functionally relevant neuroplasticity. Functional improvements following TPT are therefore in part mediated by neuromodulator signaling. Unfortunately, comorbidities associated with neurological disease often result in altered cognitive states that can influence neuromodulator signaling, potentially impeding neuroplasticity induced by TPT. Aside from altered cognitive states, cardiorespiratory rhythms also affect neuromodulator signaling, due to the vagus nerve’s role in relaying visceral sensory information from the cardiovascular and respiratory systems. Moreover, precise VNS delivery during specific periods of the cardiorespiratory rhythms may further improve TPT. Ultimately, understanding the impact of patient-specific states on neuromodulator signaling may likely facilitate optimized VNS delivery, paving the way for personalized neuromodulation during TPT. Overall, this review explores challenges and considerations for developing advanced TPT paradigms, focusing on altered cognitive states and cardiorespiratory rhythms. We specifically discuss the possible impact of these cognitive states and autonomic rhythms on neuromodulator signaling and subsequent neuroplasticity. Altered cognitive states (arousal deficits or pain) could affect VNS intensity, while cardiorespiratory rhythmsmay further inform optimized timing of VNS. We propose that understanding these interactions will lead to the development of personalized state dependent VNS paradigms for TPT. [ABSTRACT FROM AUTHOR]

Advancements in optoelectronic biointerfaces have revolutionized healthcare by enabling targeted stimulation and monitoring of cells, tissues, and organs. Photostimulation, a key application, offers precise control over biological processes, surpassing traditional modulation methods with increased spatial resolution and reduced invasiveness. This perspective highlights three approaches in non-genetic optoelectronic photostimulation: nanostructured phototransducers for cellular stimulation, micropatterned photoelectrode arrays for tissue stimulation, and thin-film flexible photoelectrodes for multiscale stimulation. Nanostructured phototransducers provide localized stimulation at the cellular or subcellular level, facilitating cellular therapy and regenerative medicine. Micropatterned photoelectrode arrays offer precise tissue stimulation, critical for targeted therapeutic interventions. Thin-film flexible photoelectrodes combine flexibility and biocompatibility for scalable medical applications. Beyond neuromodulation, optoelectronic biointerfaces hold promise in cardiology, oncology, wound healing, and endocrine and respiratory therapies. Future directions include integrating these devices with advanced imaging and feedback systems, developing wireless and biocompatible devices for long-term use, and creating multifunctional devices that combine photostimulation with other therapies. The integration of light and electronics through these biointerfaces paves the way for innovative, less invasive, and more accurate medical treatments, promising a transformative impact on patient care across various medical fields. Highlights: • Non-genetic optoelectronic biointerfaces revolutionize healthcare by enabling precise biological stimulation and monitoring. • Key methods include nanostructured phototransducers, micropatterned arrays, and thin-film flexible electrodes. • Future advancements will integrate imaging, develop wireless devices, and create multifunctional therapies, transforming patient care. [ABSTRACT FROM AUTHOR]

Hyperbaric oxygen therapy (HBOT) has recently emerged as a promising neuromodulatory modality for treating several neurological and psychological disorders. Various studies indicate that HBOT can promote brain recovery and neuroplasticity through the modulation of key cellular and molecular mechanisms. HBOT affects multiple primary pathways and cellular functions including mitochondrial biogenesis and function (increased Bcl-2, reduced Bax, and enhanced ATP production), neurogenesis (upregulation of Wnt-3 and VEGF/ERK signaling), synaptogenesis (elevated GAP43 and synaptophysin expression), and anti-inflammatory responses (reduced TNF-a and IL-6). These mechanisms contribute to significant clinical benefits, such as enhanced cognitive function, improved recovery from traumatic brain injury and post-concussion syndrome, and symptom reduction in conditions like post-traumatic stress disorder and fibromyalgia. By influencing these molecular targets, HBOT offers a novel approach to neuromodulation that warrants further exploration. This review discusses the representative mechanisms of action of HBOT and highlights its therapeutic neuromodulatory effects and potential clinical applications across various neurological and psychiatric conditions. [ABSTRACT FROM AUTHOR]

In this study, we develop new reverse engineering (RE) techniques to identify the organization of the synaptic inputs generating firing patterns of populations of neurons. We tested these techniques in silico to allow rigorous evaluation of their effectiveness, using remarkably extensive parameter searches enabled by massively-parallel computation on supercomputers. We chose spinal motoneurons as our target neural system, since motoneurons process all motor commands and have well-established input-output properties. One set of simulated motoneurons was driven by 300,000+ simulated combinations of excitatory, inhibitory, and neuromodulatory inputs. Our goal was to determine if these firing patterns had sufficient information to allow RE identification of the input combinations. Like other neural systems, the motoneuron input-output system is likely non-unique. This non-uniqueness could potentially limit this RE approach, as many input combinations can produce similar outputs. However, our simulations revealed that firing patterns contained sufficient information to sharply restrict the solution space. Thus, our RE approach successfully generated estimates of the actual simulated patterns of excitation, inhibition, and neuromodulation, with variances accounted for ranging from 75-90%. It was striking that nonlinearities induced in firing patterns by the neuromodulation inputs did not impede RE, but instead generated distinctive features in firing patterns that aided RE. These simulations demonstrate the potential of this form of RE analysis. It is likely that the ever-increasing capacity of supercomputers will allow increasingly accurate RE of neuron inputs from their firing patterns from many neural systems. [ABSTRACT FROM AUTHOR]

The ability to modulate specific neural circuits and simultaneously visualize and measure brain activity with MRI would greatly impact our understanding of brain function in health and disease. The combination of neurostimulation methods and functional MRI in animal models have already shown promise in elucidating fundamental mechanisms associated with brain activity. We developed an innovativemagnetogenetics neurostimulation technology that can trigger neural activity through magnetic fields. Similar to other genetic-based neuromodulation methods, magnetogenetics offers cell-, area-, and temporal- specific control of neural activity. Themagnetogenetic protein--Electromagnetic Perceptive Gene (EPG)--is activated by non-invasive magnetic fields, providing a unique way to target neural circuits by the MRI static and gradient fields while simultaneously measuring their effect on brain activity. EPG was expressed in rat's visual cortex and the amplitude of low-frequency fluctuation, resting-state functional connectivity (FC), and sensory activation was measured using a 7T MRI. The results demonstrate that EPG-expressing rats had significantly higher signal fluctuations in the visual areas and stronger FC in sensory areas consistent with known anatomical visuosensory and visuomotor connections. This new technology complements the existing neurostimulation toolbox and provides a means to study brain function in a minimally-invasive way which was not possible previously. [ABSTRACT FROM AUTHOR]

Objectives: Non-invasive vagus nerve stimulation (nVNS) is an emerging neuromodulation technique in recent years, which plays a role in nervous system diseases, psychiatric diseases, and autoimmune diseases. However, there is currently no comprehensive analysis of all the literature published in this field. Therefore, in this article, a bibliometric analysis will be conducted on all the literature published in the field of nVNS in the past 20 years. Methods: All articles and reviews published in this field from 2004 to 2023 were extracted from the WOS core database. VOSviewer 1.6.18.0, Scimago Graphica, CiteSpace 6.2.R2, and Excel 2021 were used to analyze the number of publications, participating countries, institutions, authors, references, and research hotspots in this field. Results: A total of 843 articles were included in the bibliometric analysis of nVNS. Over the past 20 years, the number of publications in this field has gradually increased, reaching a peak in 2023. The United States and China ranked top two in terms of publication volume, and institutions from these two countries also ranked high in terms of publication volume, citation count, and collaboration intensity. Rong Peijing is the author with the most publications, while Bashar W Badran is the most cited author. Articles in the field of nVNS were most frequently published in Frontiers in Neuroscience, while Brain Stimulation had the most citations. Currently, research hotspots in nVNS mainly focus on its application in diseases and related mechanisms. Conclusion: We conducted a comprehensive analysis of the field of nVNS, clarifying the previous research directions, which is helpful to expand its indications and promote clinical application. [ABSTRACT FROM AUTHOR]

Focused ultrasound can non-invasively modulate neural activity, but whether effective stimulation parameters generalize across brain regions and cell types remains unknown. We used focused ultrasound coupled with fiber photometry to identify optimal neuromodulation parameters for four different arousal centers of the brain in an effort to yield overt changes in behavior. Applying coordinate descent, we found that optimal parameters for excitation or inhibition are highly distinct, the effects of which are generally conserved across brain regions and cell types. Optimized stimulations induced clear, target-specific behavioral effects, whereas non-optimized protocols of equivalent energy resulted in substantially less or no change in behavior. These outcomes were independent of auditory confounds and, contrary to expectation, accompanied by a cyclooxygenase-dependent and prolonged reduction in local blood flow and temperature with brain-region-specific scaling. These findings demonstrate that carefully tuned and targeted ultrasound can exhibit powerful effects on complex behavior and physiology. [Display omitted] • Optimal ultrasound neuromodulation parameters generalize across neuronal cell types • Distinct parameters for excitation and inhibition are identified • Targeted stimulation induces site-specific behavioral changes • COX2-dependent vasoconstriction and brain cooling occur with excitatory protocols The field of focused ultrasound (FUS) neuromodulation is undergoing rapid growth but is limited by our understanding of effective waveform parameters and cell-type effects. Murphy et al. combine deep-brain optical readouts with FUS technology to uncover waveforms for inducing powerful, bidirectional neuromodulation across a collection of therapeutically important brain cell types. [ABSTRACT FROM AUTHOR]

Bioelectronic implantable devices are adept at facilitating continuous monitoring of health and enabling the early detection of diseases, offering insights into the physiological conditions of various bodily organs. Furthermore, these advanced systems have therapeutic capabilities in neuromodulation, demonstrating their efficacy in addressing diverse medical conditions through the precise delivery of stimuli directly to specific targets. This comprehensive review explores developments and applications of bioelectronic devices within the biomedical field. Special emphasis is placed on the evolution of closed‐loop systems, which stand out for their dynamic treatment adjustments based on real‐time physiological feedback. The integration of Artificial Intelligence (AI) and edge computing technologies is discussed, which significantly bolster the diagnostic and therapeutic functions of these devices. By addressing elemental analyses, current challenges, and future directions in implantable devices, the review aims to guide the pathway for advances in bioelectronic devices. [ABSTRACT FROM AUTHOR]

In addition to the essential structural and catalytic functions of zinc, evolution has adopted synaptic zinc as a neuromodulator. In the brain, synaptic zinc is released primarily from glutamatergic neurons, notably in the neocortex, hippocampus, amygdala, and auditory brainstem. In these brain areas, synaptic zinc is essential for neuronal and sensory processing fine-tuning. But what niche does zinc fill in neural signaling that other neuromodulators do not? Here, we discuss the evolutionary history of zinc as a signaling agent and its eventual adoption as an essential neuromodulator in the mammalian brain. We then attempt to describe the unique roles that zinc has carved out of the vast and diverse landscape of neuromodulators. [ABSTRACT FROM AUTHOR]