Optimal Stimulation Parameters Research Articles

Magnetic Stimulation as a Therapeutic Approach for Brain Modulation and Repair: Underlying Molecular and Cellular Mechanisms.

Neurological and psychiatric diseases generally have no cure, so innovative non-pharmacological treatments, including non-invasive brain stimulation, are interesting therapeutic tools as they aim to trigger intrinsic neural repair mechanisms. A common brain stimulation technique involves the application of pulsed magnetic fields to affected brain regions. However, investigations of magnetic brain stimulation are complicated by the use of many different stimulation parameters. Magnetic brain stimulation is usually divided into two poorly connected approaches: (1) clinically used high-intensity stimulation (0.5-2 Tesla, T) and (2) experimental or epidemiologically studied low-intensity stimulation (μT-mT). Human tests of both approaches are reported to have beneficial outcomes, but the underlying biology is unclear, and thus optimal stimulation parameters remain ill defined. Here, we aim to bring together what is known about the biology of magnetic brain stimulation from human, animal, and in vitro studies. We identify the common effects of different stimulation protocols; show how different types of pulsed magnetic fields interact with nervous tissue; and describe cellular mechanisms underlying their effects-from intracellular signalling cascades, through synaptic plasticity and the modulation of network activity, to long-term structural changes in neural circuits. Recent advances in magneto-biology show clear mechanisms that may explain low-intensity stimulation effects in the brain. With its large breadth of stimulation parameters, not available to high-intensity stimulation, low-intensity focal magnetic stimulation becomes a potentially powerful treatment tool for human application.

Active contact proximity to the cerebellothalamic tract predicts initial therapeutic current requirement with DBS for ET: an application of 7T MRI.

To characterize how the proximity of deep brain stimulation (DBS) active contact locations relative to the cerebellothalamic tract (CTT) affect clinical outcomes in patients with essential tremor (ET). DBS is an effective treatment for refractory ET. However, the role of the CTT in mediating the effect of DBS for ET is not well characterized. 7-Tesla (T) MRI-derived tractography provides a means to measure the distance between the active contact and the CTT more precisely. A retrospective review was conducted of 12 brain hemispheres in 7 patients at a single center who underwent 7T MRI prior to ventral intermediate nucleus (VIM) DBS lead placement for ET following failed medical management. 7T-derived diffusion tractography imaging was used to identify the CTT and was merged with the post-operative CT to calculate the Euclidean distance from the active contact to the CTT. We collected optimized stimulation parameters at initial programing, 1- and 2-year follow up, as well as a baseline and postoperative Fahn-Tolosa-Marin (FTM) scores. The therapeutic DBS current mean (SD) across implants was 1.8 mA (1.8) at initial programming, 2.5 mA (0.6) at 1 year, and 2.9 mA (1.1) at 2-year follow up. Proximity of the clinically-optimized active contact to the CTT was 3.1 mm (1.2), which correlated with lower current requirements at the time of initial programming (R2 = 0.458, p = 0.009), but not at the 1- and 2-year follow up visits. Subjects achieved mean (SD) improvement in tremor control of 77.9% (14.5) at mean follow-up time of 22.2 (18.9) months. Active contact distance to the CTT did not predict post-operative tremor control at the time of the longer term clinical follow up (R2 = -0.073, p = 0.58). Active DBS contact proximity to the CTT was associated with lower therapeutic current requirement following DBS surgery for ET, but therapeutic current was increased over time. Distance to CTT did not predict the need for increased current over time, or longer term post-operative tremor control in this cohort. Further study is needed to characterize the role of the CTT in long-term DBS outcomes.

Alternating current stimulation promotes neurite outgrowth and plasticity in neurons through activation of the PI3K/AKT signaling pathway.

As a commonly used physical intervention, electrical stimulation (ES) has been demonstrated to be effective in the treatment of central nervous system disorders. Currently, researchers are studying the effects of electrical stimulation on individual neurons and neural networks, which are dependent on factors such as stimulation intensity, duration, location, and neuronal properties. However, the exact mechanism of action of electrical stimulation remains unclear. In some cases, repeated or prolonged electrical stimulation can lead to changes in the morphology or function of the neuron. In this study, immunofluorescence staining and Sholl analysis are used to assess changes in the neurite number and axon length to determine the optimal pattern and stimulation parameters of ES for neurons. Neuronal death and plasticity are detected by TUNEL staining and microelectrode array assays, respectively. mRNA sequencing and bioinformatics analysis are applied to predict the key targets of the action of ES on neurons, and the identified targets are validated by western blot analysis and qRT-PCR. The effects of alternating current stimulation (ACS) on neurons are more significant than those of direct current stimulation (DCS), and the optimal parameters are 3 μA and 20 min. ACS stimulation significantly increases the number of neurites, the length of axons and the spontaneous electrical activity of neurons, significantly elevates the expression of growth-associated protein-43 (GAP-43) without significant changes in the expression of neurotrophic factors. Furthermore, application of PI3K/AKT-specific inhibitors significantly abolishes the beneficial effects of ACS on neurons, confirming that the PI3K/AKT pathway is an important potential signaling pathway in the action of ACS.

Optimal parameters for rapid (invisible) frequency tagging using MEG

Frequency tagging has been demonstrated to be a useful tool for identifying representational-specific neuronal activity in the auditory and visual domains. However, the slow flicker (<30 Hz) applied in conventional frequency tagging studies is highly visible and might entrain endogenous neuronal oscillations. Hence, stimulation at faster frequencies that is much less visible and does not interfere with endogenous brain oscillatory activity is a promising new tool. In this study, we set out to examine the optimal stimulation parameters of rapid frequency tagging (RFT/RIFT) with magnetoencephalography (MEG) by quantifying the effects of stimulation frequency, size and position of the flickering patch. Rapid frequency tagging using flickers above 50 Hz results in almost invisible stimulation which does not interfere with slower endogenous oscillations; however, the signal is weaker as compared to tagging at slower frequencies so certainty over the optimal parameters of stimulation delivery are crucial. The here presented results examining the frequency range between 60 Hz and 96 Hz suggest that RFT induces brain responses with decreasing strength up to about 84 Hz. In addition, even at the smallest flicker patch (2°) focally presented RFT induces a significant and measurable oscillatory brain signal (steady state visual evoked potential/field, SSVEP/F) at the stimulation frequency (66 Hz); however, the elicited response increases with patch size. While focal RFT presentation elicits the strongest response, off-centre presentations do generally mainly elicit a measureable response if presented below the horizontal midline. Importantly, the results also revealed considerable individual differences in the neuronal responses to RFT stimulation. Finally, we discuss the comparison of oscillatory measures (coherence and power) and sensor types (planar gradiometers and magnetometers) in order to achieve optimal outcomes. Based on our extensive findings we set forward concrete recommendations for using rapid frequency tagging in human cognitive neuroscience investigations.

Transcranial Magnetic Stimulation (rTMS) on the Precuneus in Alzheimer's Disease: A Literature Review.

The current literature review aimed to evaluate the effectiveness of rTMS on the precuneus as a potential treatment for Alzheimer's disease (AD). Although the number of studies specifically targeting the precuneus is limited, the results from this review suggest the potential benefits of this approach. Future studies should focus on exploring the long-term effects of rTMS on the precuneus in Alzheimer's disease patients, as well as determining the optimal stimulation parameters and protocols for this population. Additionally, investigating the effects of rTMS on the precuneus in combination with other brain regions implicated in AD may provide valuable insights into the development of effective treatment for this debilitating neurodegenerative disorder.

Vagus Nerve Stimulation (VNS) Therapy System in pharmacoresistant epilepsy: A literature review

Abstract Epilepsy affects approximately 50 million of people worldwide and 30% of them are resistant to drugs. Neuromodulation is becoming a key option in patients with drug-resistant epilepsy who are not feasible for resective surgery. Vagus nerve stimulation (VNS) is the most commonly used adjunctive neuromodulatory method in every patient aged 4 years and older who is unsuitable for resective surgery. It is a minimally invasive, non-teratogenic, extracranial pacemaker-like device which delivers electrical stimuli to the vagus nerve and desynchronize aberrant cerebral rhythms involved in epileptogenesis. In this review we approached the information and clinical data of VNS development history, clinical applications and possible mechanism of action. We will also review optimal stimulation parameters and information about closed and open loop devices. Vagus nerve stimulation is safe, efficient with no significant side effects and substantial cost-saving benefit, that also shows an important improvement in mood, behavior, cognition and quality of life. The overall responder rate was observed in more than 50% of patients. On the other hand, it is not clear which patients will respond to this method of treatment and why the response is not immediate, there are no available biomarkers or other features like age, sex, seizure type/epileptic syndrome to predict response to vagus nerve stimulation therapy. The VNS Therapy System continues to be an important prospect in the treatment of pharmacoresistant epilepsy, that requires further studies in order to ensure the most advantageous therapeutic response.

Non-invasive transcranial alternating current stimulation of spatially resolved phosphenes.

This study focused on the use of Non-Invasive Transcranial Alternating Current Stimulation (NITACS) to induce and map phosphenes (spark-like percepts in the visual field) in healthy individuals. The study found optimal stimulation parameters to induce reliable phosphenes without skin irritation or pain. The results suggest NITACS can be used as a tool to investigate the relationship between facial stimulation location and phosphene localization within the field of vision (FOV) and raise questions about the origin of phosphenes generated through NITACS. The outcomes of this study could serve as a source of inspiration for creating non-invasive visual aids in the future.

Transcranial magnetic stimulation: the road to clinical therapy for dystonia

Despite many research studies, transcranial magnetic stimulation (TMS) is not yet an FDA-approved clinical therapy for dystonia patients. This review describes the four major challenges that have historically hindered the clinical translation of TMS. The four challenges described are limited types of clinical trial designs, limited evidence on objective behavioral measures, variability in the TMS clinical response, and the extensive TMS parameters to optimize for clinical therapy. Progress has been made to diversify the types of clinical trial design available to clinical researchers, identify evidence-based objective behavioral measures, and reduce the variability in TMS clinical response. Future studies should identify objective behavioral measures for other dystonia subtypes and expand the optimal TMS stimulation parameters for clinical therapy. Our review highlights the key progress made to overcome these barriers and gaps that remain for TMS to develop into a long-lasting clinical therapy for dystonia patients.

Multi-session transcutaneous auricular vagus nerve stimulation for Parkinson's disease: evaluating feasibility, safety, and preliminary efficacy.

In pre-clinical animal models of Parkinson's disease (PD), vagus nerve stimulation (VNS) can rescue motor deficits and protect susceptible neuronal populations. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a non-invasive alternative to traditional invasive cervical VNS. This is the first report summarizing the safety, feasibility, and preliminary efficacy of repeated sessions of taVNS in participants with PD. To evaluate the feasibility, safety, and possible efficacy of taVNS for motor and non-motor symptoms in mild to moderate PD. This is a double-blind, sham controlled RCT (NCT04157621) of taVNS in 30 subjects with mild to moderate PD without cognitive impairment. Participants received 10, 1-h taVNS sessions (25 Hz, 200% of sensory threshold, 500 μs pulse width, 60 s on and 30 s off) over a 2-week period. Primary outcome measures were feasibility and safety of the intervention; secondary outcomes included the MDS-UPDRS, cognitive function and self-reported symptom improvement. taVNS treatment was feasible, however, daily in-office visits were reported as being burdensome for participants. While five participants in the taVNS group and three in the sham group self-reported one or more minor adverse events, no major adverse events occurred. There were no group differences on blood pressure and heart rate throughout the intervention. There were no group differences in MDS-UPDRS scores or self-reported measures. Although global cognitive scores remained stable across groups, there was a reduction in verbal fluency within the taVNS group. taVNS was safe, and well-tolerated in PD participants. Future studies of taVNS for PD should explore at-home stimulation devices and optimize stimulation parameters to reduce variability and maximize engagement of neural targets.

Newer Neuromodulation Techniques for Psychiatric Disorders: A 2023 Update

Neuromodulation is a promising therapeutic approach for psychiatric disorders, offering alternatives to traditional treatments. This update focuses on newer techniques developed till 2023. Transcranial magnetic stimulation (TMS) remains widely used for depression and mood disorders. Advances in TMS technology have optimized stimulation parameters and personalized treatment plans using neuroimaging and AI algorithms. Deep brain stimulation (DBS) has made progress in refining targeting and programming, aided by advanced imaging techniques. Closed-loop DBS adjusts parameters based on real-time feedback, providing on-demand symptom control. Vagus nerve stimulation (VNS) has shown efficacy in depression and epilepsy, with advancements in precise stimulation protocols and closed-loop devices. Emerging techniques like tDCS, TENS, and focused ultrasound offer portability and minimal side effects. Ongoing research aims to refine parameters and explore new targets. These advancements hold promise for improving treatment outcomes and personalized care. Further research and clinical trials are necessary for widespread implementation.

Optimal neuromuscular electrical stimulation parameters after spinal cord injury

Neuromuscular electrical stimulation (NMES) is often used to activate muscles impaired after spinal cord injury to elicit functional activities or to facilitate exercise. However, in addition to the cost and availability of NMES and the inherent muscle fatigue that is associated with its use may limit its widespread utilization. Optimizing stimulation parameters during NMES-induced contractions could maximize force production with less fatigue. Purpose To examine the interrelationship of pulse duration and pulse frequency on torque production and muscle fatigue in both impaired and non-impaired skeletal muscle of men and women. Methods Individuals with [n = 14 (6 females), 38 ± 13 yr; 175 ± 11 cm; 76 ± 20 kg] and without [n = 14 (6 females), 29 ± 8 yr; 175 ± 9 cm; 74 ± 14 kg] spinal cord injury (SCI) participated. Muscle torque was recorded during a series of NMES-induced isometric muscle contractions using different combinations of pulse durations and frequencies. Additionally, two different muscle fatigue protocols (20 and 50 Hz/200µs) were utilized to elicit repeat isometric muscle contractions (1s on and 1s off × 3 min). Results There was a statistically significant linear trend for pulse charge (the product of pulse frequency and pulse duration) on isometric torque production in participants without (p < 0.001, η2 = 0.79), and in participants with SCI (p < 0.001, η2 = 0.66), with higher total pulse charge generating higher torque values. Participants with SCI had significantly greater muscle fatigue for both muscle fatigue protocols (p < 0.05). Conclusions NMES protocols should consider using longer pulse durations with lower frequencies to maximize force production for individuals with SCI. However, because mechanisms of muscle fatigue may be different for impaired muscle when compared to non-impaired muscle, further studies on protocols to offset fatigue are warranted.

Sympathetic components in left and right human cervical vagus nerve: implications for vagus nerve stimulation.

Cervical vagus nerve stimulation is in a great variety of clinical situations indicated as a form of treatment. It is textbook knowledge that at the cervical level the vagus nerve contains many different fiber classes. Yet, recently, several reports have shown that this nerve also may contain an additional class of potentially noradrenergic fibers, suggested to denote efferent sympathetic fibers. As such, the nature and presence of these fibers should be considered when choosing a stimulation protocol. We have studied human vagus material extracted from dissection room cadavers in order to further confirm the presence of this class of fibers, to study their origin and direction within the nerve and to determine their distribution and variability between subjects and pairs of left and right nerves of the same individual. Sections were studied with immunohistochemical techniques using antibodies against tyrosine hydroxylase (TH: presumed to indicate noradrenergic fibers), myelin basic protein and neurofilament. Our results show that at least part of the TH-positive fibers derive from the superior cervical ganglion or sympathetic trunk, do not follow a cranial but take a peripheral course through the nerve. The portion of TH-positive fibers is highly variable between individuals but also between the left and right pairs of the same individual. TH-positive fibers can distribute and wander throughout the fascicles but maintain a generally clustered appearance. The fraction of TH-positive fibers generally diminishes in the left cervical vagus nerve when moving in a caudal direction but remains more constant in the right nerve. These results may help to determine optimal stimulation parameters for cervical vagus stimulation in clinical settings.

Transcranial direct current stimulation—current level of evidence and potential application scenarios—English version

In Europe, anterior thalamic stimulation, vagus nerve stimulation, and focal cortex stimulation are the only approved neurostimulation therapies for drug-resistant epilepsy. However, they are invasive and have limited availability and effectiveness. First reports on the use of transcranial direct current stimulation (tDCS) in epilepsy are promising and give hope for an alternative, non-invasive neurostimulation modality. What is the current level of evidence for the use of tDCS in epilepsy and what could be potential application scenarios? Safety and effectiveness data on the use of tDCS in epilepsy were summarized based on a PubMed literature search. Cathodal tDCS is associated with only mild and transient side effects like paresthesia, tiredness, or difficulties in concentrating. There is no evidence for seizure induction under cathodal tDCS. A single stimulation over 20 min can already induce a seizure frequency reduction of more than 40% in the four subsequent weeks, with effect enhancement under repeated and spaced stimulation using an interstimulation interval of 9–20 min. tDCS would not only extent the spectrum of treatments for epilepsy, it could also allow for reduction of the drug and side-effect load and potentially predict the treatment outcome for implantable devices. The literature data confirm the safe and effective use of cathodal tDCS in patients with drug-resistant epilepsy. Further studies are required to optimize stimulation parameters, to improve effectiveness, and to verify safety and effectiveness aspects in long-term application.

ID: 218319 Neural Network Modeling of Vagus Nerve Stimulation in the in vivo Canine Cardiovascular System

Cardiovascular diseases present a growing and prevalent health risk to the general public. Vagus nerve stimulation has been suggested as a potential treatment strategy for cardiovascular diseases. However, choosing the optimal stimulation parameters remains an obstacle in the successful application of this advanced electroceutical therapy.

ID: 212051 EM Exposure During Non-Invasive Brain Stimulation Applications: Impact of Uncertainties on Treatment Relevant Metrics

Performance and safety of non-invasive brain stimulation (NIBS) techniques (e.g., transcranial electric stimulation (tES) or temporal interference stimulation (TIS)) rely on the precise delivery of stimulation dose (typically electric (E-)field related quantities) to targets. The assessment of uncertainty associated with electromagnetic (EM) dose calculated by finite-element method (FEM) simulations using detailed anatomical human head models to optimize stimulation parameters (e.g., electrode positions, current intensities) and predict safety and performance metrics is therefore essential. We systematically investigated the impact of experimental and modelling sources of uncertainty/variability on tES exposure and exposure-derived quantities (maximum amplitude modulation for TIS, focality of stimulation, etc.).

ID: 214607 First-in-Human Study Protocol to Evaluate a Multiphase Spinal Cord Stimulation System With Remote Device Management

Short-term clinical results from the BENEFIT-02 study1 provided evidence to support the use of novel multiphase spinal cord stimulation (SCS) to aid in the management of chronic low back and leg pain. Other recent SCS paradigms require in-person reprogramming and stimulation adjustments to optimize stimulation parameters. It is hypothesized that providing patients with more convenient access to optimize SCS therapy through remote device management (i.e., automated remote device monitoring and remote programming) may improve their experience with SCS therapy. BENEFIT-03 (NCT04683718) is the first long-term study of an SCS system with remote management capabilities.

ID: 197800 Image-Guided Programming Reduces Initial DBS Programming Time in Parkinson's Disease Patients

Optimization of Deep Brain Stimulation (DBS) programming usually consists of an empirical trial-and-error process involving appraisal of various stimulation parameters to determine optimal settings. This process can be inefficient, lengthy, and burdensome for the patient. The use of a visualization tool capable of illustrating the location of the DBS lead within the individual's segmented anatomy and volume of tissue activated (VTA) may have the potential to reach optimal stimulation parameters in a shorter, more efficient fashion.

Test and re-test reliability of optimal stimulation targets and parameters for personalized neuromodulation.

Protocols have been proposed to optimize neuromodulation targets and parameters to increase treatment efficacies for different neuropsychiatric diseases. However, no study has investigated the temporal effects of optimal neuromodulation targets and parameters simultaneously via exploring the test-retest reliability of the optimal neuromodulation protocols. In this study, we employed a publicly available structural and resting-state functional magnetic resonance imaging (fMRI) dataset to investigate the temporal effects of the optimal neuromodulation targets and parameters inferred from our customized neuromodulation protocol and examine the test-retest reliability over scanning time. 57 healthy young subjects were included in this study. Each subject underwent a repeated structural and resting state fMRI scan in two visits with an interval of 6 weeks between two scanning visits. Brain controllability analysis was performed to determine the optimal neuromodulation targets and optimal control analysis was further applied to calculate the optimal neuromodulation parameters for specific brain states transition. Intra-class correlation (ICC) measure was utilized to examine the test-retest reliability. Our results demonstrated that the optimal neuromodulation targets and parameters had excellent test-retest reliability (both ICCs > 0.80). The test-retest reliability of model fitting accuracies between the actual final state and the simulated final state also showed a good test-retest reliability (ICC > 0.65). Our results indicated the validity of our customized neuromodulation protocol to reliably identify the optimal neuromodulation targets and parameters between visits, which may be reliably extended to optimize the neuromodulation protocols to efficiently treat different neuropsychiatric disorders.

Modeling Instantaneous Firing Rate of Deep Brain Stimulation Target Neuronal Ensembles in the Basal Ganglia and Thalamus

ObjectiveDeep brain stimulation (DBS) is an effective treatment for movement disorders, including Parkinson disease and essential tremor. However, the underlying mechanisms of DBS remain elusive. Despite the capability of existing models in interpreting experimental data qualitatively, there are very few unified computational models that quantitatively capture the dynamics of the neuronal activity of varying stimulated nuclei—including subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and ventral intermediate nucleus (Vim)—across different DBS frequencies. Materials and MethodsBoth synthetic and experimental data were used in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work, and the experimental data were provided using single-unit microelectrode recordings (MERs) during DBS (microelectrode stimulation). Based on these data, we developed a novel mathematical model to represent the firing rate of neurons receiving DBS, including neurons in STN, SNr, and Vim—across different DBS frequencies. In our model, the DBS pulses were filtered through a synapse model and a nonlinear transfer function to formulate the firing rate variability. For each DBS-targeted nucleus, we fitted a single set of optimal model parameters consistent across varying DBS frequencies. ResultsOur model accurately reproduced the firing rates observed and calculated from both synthetic and experimental data. The optimal model parameters were consistent across different DBS frequencies. ConclusionsThe result of our model fitting was in agreement with experimental single-unit MER data during DBS. Reproducing neuronal firing rates of different nuclei of the basal ganglia and thalamus during DBS can be helpful to further understand the mechanisms of DBS and to potentially optimize stimulation parameters based on their actual effects on neuronal activity.

Low-intensity pulsed ultrasound increases neurotrophic factors secretion and suppresses inflammation in in vitro models of peripheral neuropathies

Objective. In this study, we aimed to verify the beneficial effects of low-intensity pulsed ultrasound (LIPUS) stimulation on two cell types: H2O2-treated RSC96 Schwann cells and THP-1 macrophages, used to model neuropathic inflammation. Approach. Using a set-up guaranteeing a fine control of the ultrasound dose at the target, different frequencies (38 kHz, 1 MHz, 5 MHz) and different intensities (20, 100, 500 mW cm−2) were screened to find the most effective experimental conditions for triggering beneficial effects on metabolic activity and release of neurotrophic cytokines (β-nerve growth factor, brain-derived neurotrophic factor, glial cell-derived neurotrophic factor) of RSC96 cells. The combination of parameters resulting the optimal one was applied to evaluate anti-inflammatory effects in terms of reactive oxygen species (ROS) and tumor necrosis factor-α (TNF-α) production, also investigating a possible anti-oxidant activity and mechanotransduction pathway for the anti-inflammatory process. The same optimal combination of parameters was then applied to THP-1 cells, differentiated into M1 and M2 phenotypes, to assess the effect on the expression and release of pro-inflammatory markers (TNF-α, interleukin (IL)-1β, IL-6, IL-8) and anti-inflammatory ones (IL-10 and CD206). Main results. 5 MHz and 500 mW cm−2 were found as the optimal stimulation parameters on RSC96 cells. Such parameters were also found to suppress ROS and TNF-α in the same cell line, thus highlighting a possible anti-inflammatory effect, involving the NF-kB pathway. An anti-oxidant effect induced by LIPUS was also observed. Finally, the same LIPUS parameters did not induce any differentiation towards the M1 phenotype of THP-1 cells, whereas they decreased TNF-α and IL-8 gene expression, reduced IL-8 cytokine release and increased IL-10 cytokine release in M1-polarized THP-1 cells. Significance. This study represents the first step towards the use of precisely controlled LIPUS for the treatment of peripheral neuropathies.