Non-invasive Deep Brain Stimulation Research Articles

Non-invasive deep brain stimulation: interventional targeting of deep brain areas in neurological disorders.

Non-invasive deep brain stimulation: interventional targeting of deep brain areas in neurological disorders.

Generators of the frequency-following response in the subthalamic nucleus: implications for non-invasive deep brain stimulation

Generators of the frequency-following response in the subthalamic nucleus: implications for non-invasive deep brain stimulation

Non-Invasive Deep-Brain Stimulations by Spatio-Temporal Fourier Synthesis

A new type of non-invasive deep-brain stimulation is conceived and demonstrated by computer simulations. The process is based on spatio-temporal Fourier synthesis using multiple electrode pairs with sinusoidal current drive to limit skin sensations and concentrate the stimulus power to a small spatial volume and into large rare spikes in the time domain, while the signal power at the skin is steady and small. Exotic time signals are also shown, such as the cases of high-frequency prime harmonics, quasi-random and chirping stimulations. The first one is able to generate sharp spikes with low frequency while its carriers are high-frequency harmonics that easily conduct via the skin and brain tissue. Open questions are, among others, the best shapes and timing of spikes. The answers require experimental tests and explorations in animal models and human subjects.

Non-invasive stimulation of the human striatum disrupts reinforcement learning of motor skills.

Reinforcement feedback can improve motor learning, but the underlying brain mechanisms remain underexplored. In particular, the causal contribution of specific patterns of oscillatory activity within the human striatum is unknown. To address this question, we exploited a recently developed non-invasive deep brain stimulation technique called transcranial temporal interference stimulation (tTIS) during reinforcement motor learning with concurrent neuroimaging, in a randomized, sham-controlled, double-blind study. Striatal tTIS applied at 80 Hz, but not at 20 Hz, abolished the benefits of reinforcement on motor learning. This effect was related to a selective modulation of neural activity within the striatum. Moreover, 80 Hz, but not 20 Hz, tTIS increased the neuromodulatory influence of the striatum on frontal areas involved in reinforcement motor learning. These results show that tTIS can non-invasively and selectively modulate a striatal mechanism involved in reinforcement learning, expanding our tools for the study of causal relationships between deep brain structures and human behaviour.

A study on the regulation of motor behavior in mouse based on temporal interference

Temporal interference (TI) as a new neuromodulation technique can be applied to non-invasive deep brain stimulation. In order to verify its effectiveness in the regulation of motor behavior in animals, this paper uses the TI method to focus the envelope electric field to the ventral posterior lateral nucleus (VPL) of the thalamus in the deep brain of mouse to regulate left- and right-turning motor behavior. The focusability of TI in the mouse VPL was analyzed by finite element method, and the focus area and volume were obtained by numerical calculation. A stimulator was used to generate TI current to stimulate the mouse VPL to verify the effectiveness of the TI stimulation method, and the accuracy of the focus location was further determined by c-Fos immunofluorescence experiments. The results showed that the electric field generated by TI stimulation was able to focus on the VPL nuclei when the stimulation current reached 800 μA; the mouse were able to make corresponding left and right turns according to the stimulation position; and the c-Fos positive cell markers in the VPL nuclei increased significantly after stimulation. This study confirms the feasibility of TI in regulating animal motor behavior and provides a non-invasive stimulation method for brain tissue for animal robots.

Shielded Cone Coil Array for Non-Invasive Deep Brain Magnetic Stimulation.

Non-invasive deep brain stimulation using transcranial magnetic stimulation is a promising technique for treating several neurological disorders, such as Alzheimer's and Parkinson's diseases. However, the currently used coils do not demonstrate the required stimulation performance in deep regions of the brain, such as the hippocampus, due to the rapid decay of the field inside the head. This study proposes an array that uses the cone coil method for deep stimulation. This study investigates the impact of magnetic core and shielding on field strength, focality, decay rate, and safety. The coil's size and shape effects on the electric field distribution in deep brain areas are also examined. The finite element method is used to calculate the induced electric field in a realistic human head model. The simulation results indicate that the magnetic core and shielding increase the electric field intensity and enhance focality but do not improve the field decay rate. However, the decay rate can be reduced by increasing the coil size at the expense of focality. By adopting an optimum cone structure, the proposed five-coil array reduces the electric field attenuation rate to reach the stimulation threshold in deep regions while keeping all other regions within safety limits. In vitro and in vivo experimental results using a head phantom and a dead pig's head validate the simulated results and confirm that the proposed design is a reliable and efficient candidate for non-invasive deep brain magnetic stimulation.

Pulse-width modulated temporal interference (PWM-TI) brain stimulation

BackgroundElectrical stimulation involving temporal interference of two different kHz frequency sinusoidal electric fields (temporal interference (TI)) enables non-invasive deep brain stimulation, by creating an electric field that is amplitude modulated at the slow difference frequency (within the neural range), at the target brain region. ObjectiveHere, we investigate temporal interference neural stimulation using square, rather than sinusoidal, electric fields that create an electric field that is pulse-width, but not amplitude, modulated at the difference frequency (pulse-width modulated temporal interference, (PWM-TI)). Methods/ResultsWe show, using ex-vivo single-cell recordings and in-vivo calcium imaging, that PWM-TI effectively stimulates neural activity at the difference frequency at a similar efficiency to traditional TI. We then demonstrate, using computational modelling, that the PWM stimulation waveform induces amplitude-modulated membrane potential depolarization due to the membrane's intrinsic low-pass filtering property. ConclusionsPWM-TI can effectively drive neural activity at the difference frequency. The PWM-TI mechanism involves converting an envelope amplitude-fixed PWM field to an amplitude-modulated membrane potential via the low-pass filtering of the passive neural membrane. Unveiling the biophysics underpinning the neural response to complex electric fields may facilitate the development of new brain stimulation strategies with improved precision and efficiency.

Noninvasive Deep Brain Stimulation via Temporal Interference Electric Fields Enhanced Motor Performance of Mice and Its Neuroplasticity Mechanisms.

A noninvasive deep brain stimulation via temporal interference (TI) electric fields is a novel neuromodulation technology, but few advances about TI stimulation effectiveness and mechanisms have been reported. One hundred twenty-six mice were selected for the experiment by power analysis. In the present study, TI stimulation was proved to stimulate noninvasively primary motor cortex (M1) of mice, and 7-day TI stimulation with an envelope frequency of 20 Hz (∆f =20 Hz), instead of an envelope frequency of 10 Hz (∆f =10 Hz), could obviously improve mice motor performance. The mechanism of action may be related to enhancing the strength of synaptic connections, improving synaptic transmission efficiency, increasing dendritic spine density, promoting neurotransmitter release, and increasing the expression and activity of synapse-related proteins, such as brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), and glutamate receptor protein. Furthermore, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and its upstream BDNF play an important role in the enhancement of locomotor performance in mice by TI stimulation. To our knowledge, it is the first report about TI stimulation promoting multiple motor performances and describing its mechanisms. TI stimulation might serve as a novel promising approach to enhance motor performance and treat dysfunction in deep brain regions.

Monopolar tDCS might affect brainstem reflexes: A computational and neurophysiological study

ObjectiveTo assess whether monopolar multi-electrode transcranial direct current stimulation (tDCS) montages might selectively affect deep brain structures through computational predictions and neurophysiological assessment. MethodsElectric field distribution in deep brain structures (i.e., thalamus and midbrain) were estimated through computational models simulating tDCS with two monopolar and two monopolar multi-electrode montages. Monopolar multi-electrode tDCS was then applied to healthy subject, and effects on pontine and medullary circuitries was evaluated studying changes in blink reflex (BR) and masseter inhibitory reflex (MIR). ResultsComputational results suggest that tDCS with monopolar multi-electrode montages might induce electric field intensities in deep brain structure comparable to those in grey matter, while neurophysiological results disclosed that BR and MIR were selectively modulated by tDCS only when cathode was placed over the right deltoid. ConclusionsMulti-electrode tDCS (anodes over motor cortices, cathode over right deltoid) could induce significant electric fields in the thalamus and midbrain, and selectively affect brainstem neural circuits. SignificanceMulti-electrode tDCS (anodes over motor cortices, cathode over right deltoid) might be further explored to affect brainstem activity, also in the context of non-invasive deep brain stimulation.

Reduction of Porencephalic Cyst Along with the Revival of Motor Control Using the Deep Brain Sound Stimulation (DBSS) Technology as a Novel Approach

A porencephalic cyst is a rare disorder, with the etiology of brain parenchymal loss as a result of perinatal cerebral ischemia or hemorrhage leading to the accumulation of cerebrospinal fluid within the parenchyma. It is diagnosed radiologically, and management depends on the clinical manifestations. The present case depicts a porencephalic cyst presenting with cerebral right-sided hemiparesis in adulthood. The cyst dimensions measured 2.6*0.6*0.5 cm in the left lateral ventricle with associated hemiparesis of the right side at the time of the first MRI scan before Deep Brain Sound Stimulation (DBSS) sessions. A reduction in the size of the cyst to 16*7*7 mm and then to a subsequent 8 mm was documented during a novel, non-invasive deep brain stimulation via sound (DBSS) treatment. In addition, right upper and lower limb power increased to 5/5 with improved coordination in a complete neurological evaluation. DEXA scan showed an increased bone density and muscle bulk.

Low-Intensity Focused Ultrasound Neuromodulation for Stroke Recovery: A Novel Deep Brain Stimulation Approach for Neurorehabilitation?

Stroke as the leading cause of adult long-term disability and has a significant impact on patients, society and socio-economics. Non-invasive brain stimulation (NIBS) approaches such as transcranial magnetic stimulation (TMS) or transcranial electrical stimulation (tES) are considered as potential therapeutic options to enhance functional reorganization and augment the effects of neurorehabilitation. However, non-invasive electrical and magnetic stimulation paradigms are limited by their depth focality trade-off function that does not allow to target deep key brain structures critically important for recovery processes. Transcranial ultrasound stimulation (TUS) is an emerging approach for non-invasive deep brain neuromodulation. Using non-ionizing, ultrasonic waves with millimeter-accuracy spatial resolution, excellent steering capacity and long penetration depth, TUS has the potential to serve as a novel non-invasive deep brain stimulation method to establish unprecedented neuromodulation and novel neurorehabilitation protocols. The purpose of the present review is to provide an overview on the current knowledge about the neuromodulatory effects of TUS while discussing the potential of TUS in the field of stroke recovery, with respect to existing NIBS methods. We will address and discuss critically crucial open questions and remaining challenges that need to be addressed before establishing TUS as a new clinical neurorehabilitation approach for motor stroke recovery.

Non-invasive deep brain stimulation therapies for neuroregeneration

Non-invasive deep brain stimulation therapies for neuroregeneration

Triple tSMS system (“SHIN jiba”) for non-invasive deep brain stimulation: a validation study in healthy subjects

BackgroundTranscranial static magnetic field stimulation (tSMS) using a small and strong neodymium (NdFeB) magnet can temporarily suppress brain functions below the magnet. It is a promising non-invasive brain stimulation modality because of its competitive advantages such as safety, simplicity, and low-cost. However, current tSMS is insufficient to effectively stimulate deep brain areas due to attenuation of the magnetic field with the distance from the magnet. The aim of this study was to develop a brand-new tSMS system for non-invasive deep brain stimulation.MethodsWe designed and fabricated a triple tSMS system with three cylindrical NdFeB magnets placed close to each other. We compared the strength of magnetic field produced by the triple tSMS system with that by the current tSMS. Furthermore, to confirm its function, we stimulated the primary motor area in 17 healthy subjects with the triple tSMS for 20 min and assessed the cortical excitability using the motor evoked potential (MEP) obtained by transcranial magnetic stimulation.ResultsOur triple tSMS system produced the magnetic field sufficient for neuromodulation up to 80 mm depth from the magnet surface, which was 30 mm deeper than the current tSMS system. In the stimulation experiment, the triple tSMS significantly reduced the MEP amplitude, demonstrating a successful inhibition of the M1 excitability in healthy subjects.ConclusionOur triple tSMS system has an ability to produce an effective magnetic field in deep areas and to modulate the brain functions. It can be used for non-invasive deep brain stimulation.

Action spectra and mechanisms of (in) efficiency of bipolar electric pulses at electroporation

The reversal of the electric field direction inhibits various biological effects of nanosecond electric pulses (nsEP). This feature, known as “bipolar cancellation,” enables interference targeting of nsEP bioeffects remotely from stimulating electrodes, for prospective applications such as precise cancer ablation and non-invasive deep brain stimulation. This study was undertaken to achieve the maximum cancellation of electroporation, by quantifying the impact of the pulse shape, duration, number, and repetition rate across a broad range of electric field strengths. Monolayers of endothelial cells (BPAE) were electroporated in a non-uniform electric field. Cell membrane permeabilization was quantified by YO-PRO-1 (YP) dye uptake and correlated to local electric field strength. For most conditions tested, adding an opposite polarity phase reduced YP uptake by 50–80 %. The strongest cancellation, which reduced YP uptake by 95–97 %, was accomplished by adding a 50 % second phase to 600-ns pulses delivered at a high repetition rate of 833 kHz. Strobe photography of nanosecond kinetics of membrane potential in single CHO cells revealed the temporal summation of polarization by individual unipolar nsEP applied at sub-MHz rate, leading to enhanced electroporation. In contrast, there was no summation for bipolar pulses, and increasing their repetition rate suppressed electroporation. These new findings are discussed in the context of bipolar cancellation mechanisms and remote focusing applications.

Focal non-invasive deep-brain stimulation with temporal interference for the suppression of epileptic biomarkers.

IntroductionNeurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 and 165 Hz, to various deep-seated targets, such as the Mesio-temporal lobe (MTL), which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely an increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs).Materials and methodsIn the current study, we use Temporal Interference (TI) stimulation to provide a non-invasive DBS (130 Hz) of the MTL, specifically the hippocampus, in both mouse models of epilepsy, and scale the method using human cadavers to demonstrate the potential efficacy in human patients. Simulations for both mice and human heads were performed to calculate the best coordinates to reach the hippocampus.ResultsThis non-invasive DBS increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. We therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs. TCS in human cadavers. Results show a better penetration of TI fields into the human hippocampus as compared with TCS.SignificanceThese results constitute the first proof of the feasibility and efficiency of TI to stimulate at depth an area without impacting the surrounding tissue. The data tend to show the sufficiently focal character of the induced effects and suggest promising therapeutic applications in epilepsy.

EMvelop stimulation: minimally invasive deep brain stimulation using temporally interfering electromagnetic waves

Objective. Recently, the temporal interference stimulation (TIS) technique for focal noninvasive deep brain stimulation (DBS) was reported. However, subsequent computational modeling studies on the human brain have shown that while TIS achieves higher focality of electric fields than state-of-the-art methods, further work is needed to improve the stimulation strength. Here, we investigate the idea of EMvelop stimulation, a minimally invasive DBS setup using temporally interfering gigahertz (GHz) electromagnetic (EM) waves. At GHz frequencies, we can create antenna arrays at the scale of a few centimeters or less that can be endocranially implanted to enable longitudinal stimulation and circumvent signal attenuation due to the scalp and skull. Furthermore, owing to the small wavelength of GHz EM waves, we can optimize both amplitudes and phases of the EM waves to achieve high intensity and focal stimulation at targeted regions within the safety limit for exposure to EM waves. Approach. We develop a simulation framework investigating the propagation of GHz EM waves generated by line current antenna elements and the corresponding heat generated in the brain tissue. We propose two optimization flows to identify antenna current amplitudes and phases for either maximal intensity or maximal focality transmission of the interfering electric fields with EM waves safety constraint. Main results. A representative result of our study is that with two endocranially implanted arrays of size × each, we can achieve an intensity of 12 V m−1 with a focality of at a target deep in the brain tissue. Significance. In this proof-of-principle study, we show that the idea of EMvelop stimulation merits further investigation as it can be a minimally invasive way of stimulating deep brain targets and offers benefits not shared by prior methodologies of electrical or magnetic stimulation.

Multipair transcranial temporal interference stimulation for improved focalized stimulation of deep brain regions: A simulation study

Temporal interference stimulation (TIS) has been proved to be effective in stimulating deep brain regions while avoiding the stimulation of neocortical regions in animal experiments. In the traditional TIS, two alternating currents are injected with different frequencies via two electrode pairs attached to the scalp. In the human brain, however, it is difficult to achieve a focal stimulation of deep brain structures due to the high complexity of human brain structures. In this study, we hypothesized that the use of multiple electrode pairs may contribute to the more focalized delivery of temporal interference (TI) currents to the target site in the deep area of the brain. Based on this hypothesis, we proposed a novel multipair TIS method that employs more than two electrode pairs for improved focalized stimulation of the deep brain region (in this study, the head of the right hippocampus). Three realistic finite element models were used to validate the feasibility of the proposed multipair TIS. Additional electrode pairs were sequentially added to the conventional two-electrode pairs with the aim of maximizing the delivery of TI currents to the target while minimizing TI currents in the neocortical regions. The results confirmed that the multipair TIS provides better focalized stimulation than the conventional two-pair TIS for all three head models. It is expected that the proposed multipair TIS can be used to enhance the effectiveness of noninvasive deep brain stimulation.

Long term study of motivational and cognitive effects of low-intensity focused ultrasound neuromodulation in the dorsal striatum of nonhuman primates

Noninvasive brain stimulation using transcranial focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2–0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for non-invasive deep brain stimulation.

Designing and Pilot Testing a Novel Transcranial Temporal Interference Stimulation Device for Neuromodulation.

Transcranial temporal interference stimulation (tTIS) has been proposed as a new neuromodulation technology for non-invasive deep-brain stimulation (DBS). However, few studies have detailed the design method of a tTIS device and provided system validation. Thus, a detailed design and validation scheme of a novel tTIS device for animal brain stimulation are presented in this study. In the proposed tTIS device, a direct digital synthesizer (DDS) was used to generate a sine wave potential of different frequencies, which was converted to an adjustable sine wave current. A current transformer was used to produce electrical isolation of different channels, which eliminated the current crosstalk between channels and greatly increased the load capacity by amplifying the output voltage. Several in vitro experiments were first conducted to validate the tTIS device. Our results indicated that the error percentages of the stimulation currents were within ±2%. Current crosstalk between channels was almost completely eliminated. Then, in vivo electric field measurement shows that the 2-pole arrangement may provide better cortical targeting than the 4-pole mode. A pilot animal experiment was conducted in which evoked motion and electromyographic activation of the contralateral forelimb were observed, which indicated that the 2-pole tTIS had successfully activated the primary motor cortex in a rat. Motor activation induced by the 2-pole tTIS demonstrated the feasibility and safety potential when applying our tTIS device for neuromodulation.

Temporal Interference Stimulation Regulates Eye Movements and Neural Activity in the Mice Superior Colliculus.

Temporal interference (TI) stimulation is a novel electrical stimulation technique which offers noninvasive deep brain stimulation (NDBS) in mice. The purpose of this study is to investigate the effect of TI stimulation on deep layers superior colliculus (SC) nerve activity and eye movements in mice. Six male C57BL / 6J mice were used in this study. Different parameters of TI stimulation were applied to the deep layers of mice SC. Each TI stimulation lasted for 20 seconds and were repeated five times. We analyzed the synchronous recording of Ca2+ signals in deep layers mice SC and the eye movement amplitudes. Our results show that TI stimulation can evoke eye movements and the neural activity in deep layers of mice SC. Changing the difference frequency of TI stimulation can regulate the frequency of the nerve activity and eye movements. Granger causality analysis indicates that the neural activity in deep layers of mice SC may cause the eye movements during TI stimulation.