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Magnetic temporal interference for noninvasive and focal brain stimulation
Abstract
Objective . Noninvasive focal stimulation of deep brain regions has been a major goal for neuroscience and neuromodulation in the past three decades. Transcranial magnetic stimulation (TMS), for instance, cannot target deep regions in the brain without activating the overlying tissues and has poor spatial resolution. In this manuscript, we propose a new concept that relies on the temporal interference (TI) of two high-frequency magnetic fields generated by two electromagnetic solenoids. Approach . To illustrate the concept, custom solenoids were fabricated and optimized to generate temporal interfering electric fields for rodent brain stimulation. C-Fos expression was used to track neuronal activation. Main result . C-Fos expression was not present in regions impacted by only one high-frequency magnetic field indicating ineffective recruitment of neural activity in non-target regions. In contrast, regions impacted by two fields that interfere to create a low-frequency envelope display a strong increase in c-Fos expression. Significance . Therefore, this magnetic temporal interference solenoid-based system provides a framework to perform further stimulation studies that would investigate the advantages it could bring over conventional TMS systems.
... According to references [9][10][11][12][13][14][15], both temporal interference transcranial magnetic stimulation and temporal interference transcranial electrical stimulation are deep brain stimulation schemes based on the principle of temporal interference. Adjusting the spatial position of the coil can generate a low-frequency envelope-induced superimposed electric field in the target area, making neurons follow this low-frequency envelope oscillation to generate electrical activity. ...
... Zonghao Xin et al. proposed a four-leaf clover two-layer coil model based on the research of Majid Memarian Sorkhabi, which can increase the induced electric field intensity under the time interference lowfrequency envelope and optimize the target focus area [13]. Adam Khalifa et al. designed and optimized a custom solenoid capable of generating temporally interfering induced electric fields to stimulate the rodent brain and express neurons for tracing through the C-Fos activation situation [14]. The results showed no C-Fos expression in the region affected by only one high-frequency magnetic field, indicating that the recruitment of neural activity in the non-target region was ineffective. ...
... The innermost white matter of the brain was a sphere with a radius of 70 mm [39,40]. Here, it should be emphasized that the reason for choosing the five-layer sphere model instead of the real human brain model in this article is because the concentric sphere model has been used in multiple studies [9,14,31,41] with high accuracy and little difference from the real head model. It can be used for qualitative and quantitative analysis to a certain extent. ...
Temporal interference magnetic stimulation is a novel noninvasive deep brain neuromodulation technology that can solve the problem of balance between focus area and stimulation depth. However, at present, the stimulation target of this technology is relatively single, and it is difficult to realize the coordinated stimulation of multiple brain regions, which limits its application in the modulation of multiple nodes in the brain network. This paper first proposes a multi-target temporal interference magnetic stimulation system with array coils. The array coils are composed of seven coil units with an outer radius of 25 mm, and the spacing between coil units is 2 mm. Secondly, models of human tissue fluid and the human brain sphere are established. Finally, the relationship between the movement of the focus area and the amplitude ratio of the difference frequency excitation sources under time interference is discussed. The results show that in the case of a ratio of 1:5, the peak position of the amplitude modulation intensity of the induced electric field has moved 45 mm; that is, the movement of the focus area is related to the amplitude ratio of the difference frequency excitation sources. The conclusion is that multi-target temporal interference magnetic stimulation with array coils can simultaneously stimulate multiple network nodes in the brain region; rough positioning can be performed by controlling the conduction of different coils, fine-tuning the position by changing the current ratio of the conduction coils, and realizing accurate stimulation of multiple targets in the brain area.
... Furthermore, deep brain regions can be stimulated with deep TMS (dTMS) using a specialized coil known as the Hesed coil (Zangen et al., 2005). Additionally, repetitive magnetic temporal interference (rTMI), which utilizes the electrotemporal interference of high-frequency TMS holds promise for selectively modulating deep-brain targets (Khalifa et al., 2023). Finally, multi-locus TMS (mTMS) is an approach that uses an array of electronically controlled coils, allowing for the shifting and re-orienting of the induced E-field (Koponen et al., 2018). ...
... However, the absorption of light by hair limits tPBM applications outside of the forehead region, intranasally or through the oral cavity (Salehpour et al., 2018;Askalsky and Iosifescu, 2019). While tPBM traditionally uses a continuous wave, recent work explores pulsed wave tPBM, allowing for short, high-power pulses (Tang et al., 2023). Thus far conclusive evidence regarding the efficacy of tPBM for depression and dementia is yet to emerge (Salehpour et al., 2021;Vieira et al., 2023). ...
Non-invasive brain stimulation (NIBS) is a complex and multifaceted approach to modulating brain activity and holds the potential for broad accessibility. This work discusses the mechanisms of the four distinct approaches to modulating brain activity non-invasively: electrical currents, magnetic fields, light, and ultrasound. We examine the dual stochastic and deterministic nature of brain activity and its implications for NIBS, highlighting the challenges posed by inter-individual variability, nebulous dose-response relationships, potential biases and neuroanatomical heterogeneity. Looking forward, we propose five areas of opportunity for future research: closed-loop stimulation, consistent stimulation of the intended target region, reducing bias, multimodal approaches, and strategies to address low sample sizes.
... Recent work has also proposed adapting temporal interference to other modalities, including transcranial magnetic stimulation (TMS) 44,45 . The neurophysiological effects of these methods have not yet been fully characterized, but users will still need to contend with similar issues related to sub-optimal electrode/coil placement and incomplete demodulation. ...
Electrical stimulation can regulate brain activity, producing clear clinical benefits, but focal and effective neuromodulation often requires surgically implanted electrodes. Recent studies argue that temporal interference (TI) stimulation may provide similar outcomes non-invasively. During TI, scalp electrodes generate multiple electrical fields in the brain, modulating neural activity only at their intersection. Despite considerable enthusiasm for this approach, little empirical evidence demonstrates its effectiveness, especially under conditions suitable for human use. Here, using single-neuron recordings in non-human primates, we establish that TI reliably alters the timing, but not the rate, of spiking activity. However, we show that TI requires strategies—high carrier frequencies, multiple electrodes, and amplitude-modulated waveforms—that also limit its effectiveness. Combined, these factors make TI 80 % weaker than other forms of non-invasive brain stimulation. Although unlikely to cause widespread neuronal entrainment, TI may be ideal for disrupting pathological oscillatory activity, a hallmark of many neurological disorders.
... For target regions confined to a specific area, a temporal interference signalling method is required not only to modulate and increase the focality of the applied signal but also to reduce unnecessary stimulation of non-target areas [41]. Magnetic Temporal Interference (MTI) is a concept intertwined with TMS and tDCS to improve the focality and precision of stimulation through amplitude-modulated interference signalling [42,43]. Recent studies have shown that with a four-coil MTI system, the maximum achieved depth, focality and the coil electric field intensity were 1.6 cm, 5.1 cm 2 , and, 523.93 V/m, at a sinusoidal oscillation frequency of 10 Hz (Table 1, in [41]). ...
This paper presents an innovative approach to wireless cellular stimulation therapy through the design of a magnetoelectric (ME) microdevice. Traditional electrophysiological stimulation techniques for neural and deep brain stimulation face limitations due to their reliance on electronics, electrode arrays, or the complexity of magnetic induction. In contrast, the proposed ME microdevice offers a self-contained, controllable, battery-free, and electronics-free alternative, holding promise for targeted precise stimulation of biological cells and tissues. The designed microdevice integrates core shell ME materials with remote coils which applies magnetic temporal interference (MTI) signals, leading to the generation of a bipolar local electric stimulation current operating at low frequencies which is suitable for precise stimulation. The nonlinear property of the magnetostrictive core enables the demodulation of remotely applied high-frequency electromagnetic fields, resulting in a localized, tunable, and manipulatable electric potential on the piezoelectric shell surface. This potential, triggers electrical spikes in neural cells, facilitating stimulation. Rigorous computational simulations support this concept, highlighting a significantly high ME coupling factor generation of 550 V/m·Oe. The high ME coupling is primarily attributed to the operation of the device in its mechanical resonance modes. This achievement is the result of a carefully designed core shell structure operating at the MTI resonance frequencies, coupled with an optimal magnetic bias, and predetermined piezo shell thickness. These findings underscore the potential of the engineered ME core shell as a candidate for wireless and minimally invasive cellular stimulation therapy, characterized by high resolution and precision. These results open new avenues for injectable material structures capable of delivering effective cellular stimulation therapy, carrying implications across neuroscience medical devices, and regenerative medicine.
... Recent work has also proposed adapting temporal interference to other modalities, especially transcranial magnetic stimulation (TMS) (e.g., Khalifa et al., 2023;Labruna et al., 2023). The neurophysiological effects of these methods have not yet been fully characterized, but users will still need to contend with similar issues related to suboptimal electrode/coil placement and incomplete demodulation. ...
Electrical stimulation can regulate brain activity, producing clear clinical benefits, but focal and effective neuromodulation often requires surgically implanted electrodes. Recent studies argue that temporal interference (TI) stimulation may provide similar outcomes non-invasively. During TI, scalp electrodes generate multiple electrical fields in the brain, modulating neural activity only where they overlap. Despite considerable enthusiasm for this approach, little empirical evidence demonstrates its effectiveness, especially under conditions suitable for human use. Here, using single-neuron recordings in non-human primates, we show that TI reliably alters the timing of spiking activity. However, we find that the strategies which improve the focality of TI — high frequencies, multiple electrodes, and amplitude-modulated waveforms — also limit its effectiveness. Combined, they make TI 80% weaker than other forms of non-invasive brain stimulation. Although this is too weak to cause widespread neuronal entrainment, it may be ideally suited for disrupting pathological synchronization, a hallmark of many neurological disorders.
... Compared with conventional TMS, temporal interference TMS can provide a deeper and more focal brain stimulation. Based on this, Khalifa et al. (2023) developed a novel two-solenoid coil to stimulate temporal interference. The results of the experiments on mice revealed that temporal interference with TMS could significantly increase the expression of c-Fos in the deeper layers of the mouse brain without affecting the overlaying tissue. ...
Numerous studies have assessed the effect of Temporal Interference (TI) on human performance. However, a comprehensive literature review has not yet been conducted. Therefore, this review aimed to search PubMed and Web of Science databases for TI-related literature and analyze the findings. We analyzed studies involving preclinical, human, and computer simulations, and then discussed the mechanism and safety of TI. Finally, we identified the gaps and outlined potential future directions. We believe that TI is a promising technology for the treatment of neurological movement disorders, due to its superior focality, steerability, and tolerability compared to traditional electrical stimulation. However, human experiments have yielded fewer and inconsistent results, thus animal and simulation experiments are still required to perfect stimulation protocols for human trials.
Repetitive transcranial magnetic stimulation (rTMS) is commonly used to study the brain or as a treatment for neurological disorders, but the neural circuits and molecular mechanisms it affects remain unclear. To determine the molecular mechanisms of rTMS and the brain regions they occur in, we used spatial transcriptomics to map changes to gene expression across the mouse brain in response to two commonly used rTMS protocols. Our results revealed that rTMS alters the expression of genes related to several cellular processes and neural plasticity mechanisms across the brain, which was both brain region– and rTMS protocol–dependent. In the cortex, the effect of rTMS was dependent not only on the cortical region but also on each cortical layer. These findings uncover the diverse molecular mechanisms induced by rTMS, which will be useful in interpreting its effects on cortical and subcortical circuits.
In temporal interference (TI) stimulation, neuronal cells react to two interfering sinusoidal electric fields with a slightly different frequency (, in the range of about 1–4 kHz, in the range of about 1–100 Hz). It has been previously observed that for the same input intensity, the neurons do not react to a purely sinusoidal signal at or . This study seeks a better understanding of the largely unknown mechanisms underlying TI neuromodulation. To this end, single‐compartment models are used to simulate computationally the response of neurons to the sinusoidal and TI waveform. This study compares five different neuron models: Hodgkin‐Huxley (HH), Frankenhaeuser–Huxley (FH), along with leaky, exponential, and adaptive‐exponential integrate‐and‐fire (IF). It was found that IF models do not entirely reflect the experimental behavior while the HH and FH model did qualitatively replicate the observed neural responses. Changing the time constants and steady state values of the ion gates in the FH model alters the response to both the sinusoidal and TI signal, possibly reducing the firing threshold of the sinusoidal input below that of the TI input. The results show that in the modified (simplified) model, TI stimulation is not qualitatively impacted by nonlinearities in the current–voltage relation. In contrast, ion channels have a significant impact on the neuronal response. This paper offers insights into neuronal biophysics and computational models of TI stimulation.
Magnetic stimulation using implantable devices may offer a promising alternative to other stimulation methods such as transcranial magnetic stimulation (TMS) or electric stimulation using implantable devices. This alternative may increase the selectivity of stimulation compared to TMS, and eliminate the need to expose tissue to metals in the body, as is required in electric stimulation using implantable devices. However, previous studies of magnetic stimulation of the sciatic nerve used large coils, with a diameter of several tens of mm, and a current intensity in the order of kA. Since such large coils and high current intensity are not suitable for implantable devices, we investigated the feasibility of using a smaller implantable coil and lower current to elicit neuronal responses. A coil with a diameter of 3 mm and an inductance of 1 mH was used as the implantable stimulator. Before in vivo experiments, we used 3D computational models to estimate the minimum stimulus intensity required to elicit neuronal responses, resulting in a threshold current above 3.5 A. In in vivo experiments, we observed successful nerve stimulation via compound muscle action potentials elicited in hind-limb muscles when the applied current was above 3.8 A, a significantly reduced current than that used in conventional magnetic stimulation.
Repetitive transcranial magnetic stimulation (rTMS) is a widespread technique in neuroscience and medicine, however its mechanisms are not well known. In this review, we consider intensity as a key therapeutic parameter of rTMS, and review the studies that have examined the biological effects of rTMS using magnetic fields that are orders of magnitude lower that those currently used in the clinic. We discuss how extensive characterisation of “low intensity” rTMS has set the stage for translation of new rTMS parameters from a mechanistic evidence base, with potential for innovative and effective therapeutic applications. Low-intensity rTMS demonstrates neurobiological effects across healthy and disease models, which include depression, injury and regeneration, abnormal circuit organisation, tinnitus etc. Various short and long-term changes to metabolism, neurotransmitter release, functional connectivity, genetic changes, cell survival and behaviour have been investigated and we summarise these key changes and the possible mechanisms behind them. Mechanisms at genetic, molecular, cellular and system levels have been identified with evidence that low-intensity rTMS and potentially rTMS in general acts through several key pathways to induce changes in the brain with modulation of internal calcium signalling identified as a major mechanism. We discuss the role that preclinical models can play to inform current clinical research as well as uncover new pathways for investigation.
Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that has been clinically applied for neural modulation. Conventional TMS systems are restricted by the trade-off between depth penetration and the focality of the induced electric field. In this study, we integrated the concept of temporal interference (TI) stimulation, which has been demonstrated as a non-invasive deep-brain stimulation method, with magnetic stimulation in a four-coil configuration. The attenuation depth and spread of the electric field were obtained by performing numerical simulation. Consequently, the proposed temporally interfered magnetic stimulation scheme was demonstrated to be capable of stimulating deeper regions of the brain model while maintaining a relatively narrow spread of the electric field, in comparison to conventional TMS systems. These results demonstrate that TI magnetic stimulation could be a potential candidate to recruit brain regions underneath the cortex. Additionally, by controlling the geometry of the coil array, an analogous relationship between the field depth and focality was observed, in the case of the newly proposed method. The major limitations of the methods, however, would be the considerable intensity and frequency of the input current, followed by the frustration in the thermal management of the hardware.
Background
Electrical stimulation in the kilohertz-frequency range has gained interest in the field of neuroscience. The mechanisms underlying stimulation in this frequency range, however, are poorly characterized to date.
Objective/Hypothesis
To summarize the manifold biological effects elicited by kilohertz-frequency stimulation in the context of the currently existing literature and provide a mechanistic framework for the neural responses observed in this frequency range.
Methods
A comprehensive search of the peer-reviewed literature was conducted across electronic databases. Relevant computational, clinical, and mechanistic studies were selected for review.
Results
The effects of kilohertz-frequency stimulation on neural tissue are diverse and yield effects that are distinct from conventional stimulation. Broadly, these can be divided into 1) subthreshold, 2) suprathreshold, 3) synaptic and 4) thermal effects. While facilitation is the dominating mechanism at the subthreshold level, desynchronization, spike-rate adaptation, conduction block, and non-monotonic activation can be observed during suprathreshold kilohertz-frequency stimulation. At the synaptic level, kilohertz-frequency stimulation has been associated with the transient depletion of the available neurotransmitter pool – also known as synaptic fatigue. Finally, thermal effects associated with extrinsic (environmental) and intrinsic (associated with kilohertz-frequency stimulation) temperature changes have been suggested to alter the neural response to stimulation paradigms.
Conclusion
The diverse spectrum of neural responses to stimulation in the kilohertz-frequency range is distinct from that associated with conventional stimulation. This offers the potential for new therapeutic avenues across stimulation modalities. However, stimulation in the kilohertz-frequency range is associated with distinct challenges and caveats that need to be considered in experimental paradigms.
Background
Temporal interference (TI) stimulation of the brain generates amplitude-modulated electric fields oscillating in the kHz range with the goal of non-invasive targeted deep brain stimulation. Yet, the current intensities required in human (sensitivity) to modulate deep brain activity and if superficial brain region are spared (selectivity) at these intensities remains unclear.
Objective
We developed an experimentally constrained theory for TI sensitivity to kHz electric field given the attenuation by membrane low-pass filtering property, and for TI selectivity to deep structures given the distribution of modulated and unmodulated electric fields in brain.
Methods
The electric field threshold to modulate carbachol-induced gamma oscillations in rat hippocampal slices was determined for unmodulated 0.05–2 kHz sine waveforms, and 5 Hz amplitude-modulated waveforms with 0.1–2 kHz carrier frequencies. The neuronal effects are replicated with a computational network model to explore the underlying mechanisms, and then coupled to a validated current-flow model of the human head.
Results
Amplitude-modulated electric fields are stronger in deep brain regions, while unmodulated electric fields are maximal at the cortical regions. Both experiment and model confirmed the hypothesis that spatial selectivity of temporal interference stimulation depends on the phasic modulation of neural oscillations only in deep brain regions. Adaptation mechanism (e.g. GABAb) enhanced sensitivity to amplitude modulated waveform in contrast to unmodulated kHz and produced selectivity in modulating gamma oscillation (i.e. Higher gamma modulation in amplitude modulated vs unmodulated kHz stimulation). Selection of carrier frequency strongly affected sensitivity to amplitude modulation stimulation. Amplitude modulated stimulation with 100 Hz carrier frequency required ∼5 V/m (corresponding to ∼13 mA at the scalp surface), whereas, 1 kHz carrier frequency ∼60 V/m (∼160 mA) and 2 kHz carrier frequency ∼80 V/m (∼220 mA) to significantly modulate gamma oscillation. Sensitivity is increased (scalp current required decreased) for theoretical neuronal membranes with faster time constants.
Conclusion
The TI sensitivity (current required at the scalp) depends on the neuronal membrane time-constant (e.g. axons) approaching the kHz carrier frequency. TI selectivity is governed by network adaption (e.g. GABAb) that is faster than the amplitude-modulation frequency. Thus, we show neuronal and network oscillations time-constants determine the scalp current required and the selectivity achievable with TI in humans.
Temporal interference (TI) is a non-invasive neurostimulation technique that utilizes high-frequency external electric fields to stimulate deep neuronal structures without affecting superficial, off-target structures. TI represents a potential breakthrough for treating conditions, such as Parkinson’s disease and chronic pain. However, early clinical work on TI stimulation was met with mixed outcomes challenging its fundamental mechanisms and applications. Here, we apply established physics to study the mechanisms of TI with the goal of optimizing it for clinical use. We argue that TI stimulation cannot work via passive membrane filtering, as previously hypothesized. Instead, TI stimulation requires an ion-channel mediated signal rectification process. Unfortunately, this mechanism is also responsible for high-frequency conduction block in off-target tissues, thus challenging clinical applications of TI. In consequence, we propose a set of experimental controls that should be performed in future experiments to refine our understanding and practice of TI stimulation. A record of this paper’s transparent peer review process is included in the Supplemental Information.
In this study, we present a temporal interference (TI) concept to achieve focal and steerable stimulation in the targeted brain area through transcranial magnetic stimulation (TMS). This method works by inducing two high-frequency electric fields with a slight frequency difference via two independent coils. The intrinsic nonlinear nature of the nerve membrane, which acts as a low-pass filter, does not allow the nerve to engage at high frequencies. Instead, neurons at the intersection of two electric fields can follow the frequency difference of the two fields. For 3D MRI-derived head models, the finite element method is used to compute the electric field induced by the time-varying magnetic field along with the electric field penetration depth and the activated volume for the specific coil parameters. A deeper stimulation with an acceptable spatial spread can be obtained by controlling the intersection of the fields by finding the optimal position and orientation of the two coils. Moreover, by changing the voltage ratio of the coils, and not their mechanical orientation, the intended area can be dynamically driven. The computational results show that the TI technique is an efficient approach to resolve the electric field depth-focality trade-off, which can be a reasonable alternative to complex coil designs. The system proposed in this paper shows a great promise for a more dynamic and focused magnetic stimulation.
Background:
Rodent models are fundamental in unraveling cellular and molecular mechanisms of transcranial magnetic stimulation (TMS)-induced effects on the brain. However, proper translation of human TMS protocols to animal models have been restricted by the lack of rodent-specific focal TMS coils.
Objective:
We aimed to improve TMS focalization in rodent brain with a novel small, cooled, and rodent-specific TMS coil.
Methods:
A rodent-specific 25-mm figure-of-eight TMS coil was developed. Stimulation focalization was simulated in silico for the rodent coil and a commercial human 50-mm figure-of-eight TMS coil. Both coils were also compared in vivo by electromyography measurements of brachialis motor evoked potential (MEP) responses to TMS at different brain sites in anesthetized rats (n = 6). Focalization was determined from the coils' level of stimulation laterality. Differences in MEPs were statistically analyzed with repeated-measures, within-subjects, ANOVA.
Results:
In silico simulation results deemed the human coil insufficient for unilateral stimulation of the rat motor cortex, whereas lateralized electrical field induction was projected attainable with the rodent coil. Cortical, in vivo MEP amplitude measurements from multiple points in each hemisphere, revealed unilateral activation of the contralateral brachialis muscle, in absence of ipsilateral brachialis activation, with both coils.
Conclusion:
Computer simulations motivated the design of a smaller rodent-specific TMS coil, but came short in explaining the capability of a larger commercial human coil to induce unilateral MEPs in vivo. Lateralized TMS, as demonstrated for both TMS coils, corroborates their use in translational rodent studies, to elucidate mechanisms of action of therapeutic TMS protocols.
Purpose of review:
After three decades of clinical research on repetitive transcranial magnetic stimulation (rTMS), major depressive disorder (MDD) has proven to be the primary field of application. MDD poses a major challenge for health systems worldwide, emphasizing the need for improving clinical efficacy of existing rTMS applications and promoting the development of novel evidence-based rTMS treatment approaches.
Recent findings:
Several promising new avenues have been proposed: novel stimulation patterns, targets, and coils; combinatory treatments and maintenance; and personalization and stratification of rTMS parameters, and treatment of subpopulations.
Summary:
This opinion review summarizes current knowledge in the field and addresses the future direction of rTMS treatment in MDD, facilitating the establishment of this clinical intervention method as a standard treatment option and continuing to improve response and remission rates, and take the necessary steps to personalize rTMS-based treatment approaches.
Introduction. Transcranial magnetic stimulation (TMS) is used for treating neurological disorders. Rapid pulses of magnetic field are delivered via a high-current coil situated over the scalp and induce an electric field in the brain. There has been limited fundamental scientific research on TMS and to progress it would be ideal to mimic the electric field of human TMS with mice. Animal models provide good mechanistic insight, but their use is hindered by lack of stimulating coils comparable in focus and intensity with human stimulation. Methods. We outline the engineering challenges in producing appropriate coils. It is unclear what should be optimized in the design of a mouse coil. We model the electric field, heat generation and ring-down time for cylindrical coils and use results to select a coil design consisting of 70 turns of 0.4 mm diameter copper wire wrapped around a 5 mm diameter soft ferrite core. Results and Discussion. While the magnetic flux density scales as the reciprocal of length-scale, the electric field does not scale with length, meaning that a large current is required to mimic the electric field of humans. To maximize electric field, one must minimize the coil's inductance resulting in reduced ring-down time for the coil and significant heating. A ferrite core allows ring-down time to remain high and reduces heating. Our coil gave 180 mT at 30 V supply, with a temperature increase of 5°C after 1200 pulses at 5 Hz. The B-field below the core has a full-width-at-half-maximum of 6 mm, similar in size to a mouse brain. Conclusions. We have produced a mouse coil that offers increased B-field and reduced heating. There is considerable scope for improving electric field, but further physical analysis may lead to field strength more similar to that obtained in human TMS.
Modulating the function of the insular cortex could be a novel therapeutic strategy to treat addiction to a variety of drugs of abuse as this region has been implicated in mediating drug reward and addictive processes. The recent advent of the H-coil has permitted the targeting of deeper brain structures which was not previously feasible. The goal of this study was to bilaterally target the insular region using the H-coil with repetitive Transcranial Magnetic Stimulation (rTMS) and subsequently measure changes in dopamine levels using Positron Emission Tomography (PET) with [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO). This was a within-subject, crossover, blinded and sham-controlled pilot study. Eight healthy, right-handed subjects, aged 19-45, participated in the investigation. All subjects underwent 3 PHNO-PET scans preceded by rTMS (sham, 1 Hz or 10 Hz), on 3 separate days. Low frequency rTMS (1 Hz), targeting the insular cortex, significantly decreased dopamine levels in the substantia nigra, sensorimotor striatum and associative striatum. Replicating this study in tobacco smokers or alcoholics would be a logical follow-up to assess whether H-coil stimulation of the bilateral insula can be employed as a treatment option for addiction.
Trial registration:
NCT02212405.
We report a noninvasive strategy for electrically stimulating neurons at depth. By delivering to the brain multiple electric fields at frequencies too high to recruit neural firing, but which differ by a frequency within the dynamic range of neural firing, we can electrically stimulate neurons throughout a region where interference between the multiple fields results in a prominent electric field envelope modulated at the difference frequency. We validated this temporal interference (TI) concept via modeling and physics experiments, and verified that neurons in the living mouse brain could follow the electric field envelope. We demonstrate the utility of TI stimulation by stimulating neurons in the hippocampus of living mice without recruiting neurons of the overlying cortex. Finally, we show that by altering the currents delivered to a set of immobile electrodes, we can steerably evoke different motor patterns in living mice.
Objective: Deep transcranial magnetic stimulation (dTMS) has been recently used in several clinical studies as diagnostic and therapeutic tool. However, electric field (E) distributions induced in the brain by dTMS are still unknown. This paper provides a characterization of the induced E distributions in the brain of a realistic human model due to 16 different coil configurations. Methods: The scalar potential finite-element method was used to calculate the E distributions differentiating the brain structures, e.g., cortex, white matter, anterior cingulated cortex, cerebellum, thalamus, hypothalamus, nucleus accumbens, amygdale, and hippocampus. Results: Our results support that the double cone coils and the large diameter circular coils are more prone to activate deeper brain structures but are also characterized by a reduced focality on the surface of the cortex, with the consequent possible counter effect of stimulating regions not of interest. The Hesed coils, although their ability to reach deep brain tissues is lower, seem to be more able to reduce the effect on other brain regions where the stimulation is undesired. Conclusion: All the coil configurations resulted subjected to a depth-focality tradeoff. Significance: Since there is not a configuration that is capable of achieving a stimulation both deep and focal, the selection of the most suitable coil settings for a specific clinical application should be based on a balanced evaluation between these two different needs.
Rodent models of transcranial magnetic stimulation (TMS) play a crucial role in aiding the understanding of the cellular and molecular mechanisms underlying TMS induced plasticity. Rodent-specific TMS have previously been used to deliver focal stimulation at the cost of stimulus intensity (12mT). Here we describe two novel TMS coils designed to deliver repetitive TMS (rTMS) at greater stimulation intensities whilst maintaining spatial resolution. Two circular coils (8 mm outer diameter) were constructed with either an air or pure iron core. Peak magnetic field strength for the air and iron-cores were 90mT and 120mT respectively, with the iron-core coil exhibiting less focality. Coil temperature and magnetic field stability for the two coils undergoing rTMS, were similar at1Hz but varied at 10Hz. Finite element modelling of 10Hz rTMS with the iron-core in a simplified rat brain model suggests a peak electric field of 85 V/m and 12.7 V/m, within the skull and the brain respectively. Delivering 10Hz rTMS to the motor cortex of anaesthetised rats with the iron-core coil significantly increased motor evoked potential amplitudes immediately after stimulation (n=4). Our results suggest these novel coils generate modest magnetic and electric fields, capable of altering cortical excitability and provide an alternative method to investigate the mechanisms underlying rTMS-induced plasticity in an experimental setting.
Objectives:
This study characterizes and validates a recently developed dedicated circular rat coil for small animal repetitive Transcranial Magnetic Stimulation (rTMS).
Materials and methods:
The electric (E) field distribution was calculated in a three-dimensional (3D) spherical rat head model and coil cooling performance was characterized. Motor threshold (MT) in rats (n = 12) was determined using two current directions, MT variability (n = 16) and laterality (n = 11) of the stimulation was assessed. Finally, 2-deoxy-2-((18) F)fluoro-D-glucose ([(18) F]-FDG) small animal Positron Emission Tomography (µPET) after sham and 1, 10, and 50 Hz rTMS stimulation (n = 9) with the new Cool-40 Rat Coil (MagVenture, Denmark) was performed.
Results:
The coil could produce high E-fields of maximum 220 V/m and more than 100 V/m at depths up to 5.3 mm in a ring-shaped distribution. No lateralization of stimulation was observed. Independent of the current direction, reproducible MT measurements were obtained at low percentages (27 ± 6%) of the maximum machine output (MO, MagPro X100 [MagVenture, Denmark]). At this intensity, rTMS with long pulse trains is feasible (1 Hz: continuous stimulation; 5 Hz: 1000 pulses; 10 Hz and 50 Hz: 272 pulses). When compared to sham, rTMS at different frequencies induced decreases in [(18) F]-FDG-uptake bilaterally mainly in dorsal cortical regions (visual, retrosplenial, and somatosensory cortices) and increases mainly in ventral regions (entorhinal cortex and amygdala).
Conclusion:
The coil is suitable for rTMS in rats and achieves unprecedented high E-fields at high stimulation frequencies and long durations with however a rather unfocal rat brain stimulation. Reproducible MEPs as well as alterations in cerebral glucose metabolism following rTMS were demonstrated.
A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.
Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a treatment for neurological and psychiatric disorders. Although the induced field is focused on a target region during rTMS, adjacent areas also receive stimulation at a lower intensity and the contribution of this perifocal stimulation to network-wide effects is poorly defined. Here, we examined low-intensity rTMS (LI-rTMS)-induced changes on a model neural network using the visual systems of normal (C57Bl/6J wild-type, n = 22) and ephrin-A2A5−/− (n = 22) mice, the latter possessing visuotopic anomalies. Mice were treated with LI-rTMS or sham (handling control) daily for 14 d, then fluorojade and fluororuby were injected into visual cortex. The distribution of dorsal LGN (dLGN) neurons and corticotectal terminal zones (TZs) was mapped and disorder defined by comparing their actual location with that predicted by injection sites. In the afferent geniculocortical projection, LI-rTMS decreased the abnormally high dispersion of retrogradely labeled neurons in the dLGN of ephrin-A2A5−/− mice, indicating geniculocortical map refinement. In the corticotectal efferents, LI-rTMS improved topography of the most abnormal TZs in ephrin-A2A5−/− mice without altering topographically normal TZs. To investigate a possible molecular mechanism for LI-rTMS-induced structural plasticity, we measured brain derived neurotrophic factor (BDNF) in the visual cortex and superior colliculus after single and multiple stimulations. BDNF was upregulated after a single stimulation for all groups, but only sustained in the superior colliculus of ephrin-A2A5−/− mice. Our results show that LI-rTMS upregulates BDNF, promoting a plastic environment conducive to beneficial reorganization of abnormal cortical circuits, information that has important implications for clinical rTMS.
Repetitive transcranial magnetic stimulation (rTMS) is a widely-used method for modulating cortical excitability in humans, by mechanisms thought to involve use-dependent synaptic plasticity. For example, when low frequency rTMS (LF rTMS) is applied over the motor cortex, in humans, it predictably leads to a suppression of the motor evoked potential (MEP), presumably reflecting long-term depression (LTD) - like mechanisms. Yet how closely such rTMS effects actually match LTD is unknown. We therefore sought to (1) reproduce cortico-spinal depression by LF rTMS in rats, (2) establish a reliable animal model for rTMS effects that may enable mechanistic studies, and (3) test whether LTD-like properties are evident in the rat LF rTMS setup. Lateralized MEPs were obtained from anesthetized Long-Evans rats. To test frequency-dependence of LF rTMS, rats underwent rTMS at one of three frequencies, 0.25, 0.5, or 1 Hz. We next tested the dependence of rTMS effects on N-methyl-D-aspartate glutamate receptor (NMDAR), by application of two NMDAR antagonists. We find that 1 Hz rTMS preferentially depresses unilateral MEP in rats, and that this LTD-like effect is blocked by NMDAR antagonists. These are the first electrophysiological data showing depression of cortical excitability following LF rTMS in rats, and the first to demonstrate dependence of this form of cortical plasticity on the NMDAR. We also note that our report is the first to show that the capacity for LTD-type cortical suppression by rTMS is present under barbiturate anesthesia, suggesting that future neuromodulatory rTMS applications under anesthesia may be considered.
Transcranial ultrasound can alter brain function transiently and nondestructively, offering a new tool to study brain function now and inform future therapies. Previous research on neuromodulation implemented pulsed low-frequency (250-700 kHz) ultrasound with spatial peak temporal average intensities (ISPTA) of 0.1-10 W/cm(2). That work used transducers that either insonified relatively large volumes of mouse brain (several mL) with relatively low-frequency ultrasound and produced bilateral motor responses, or relatively small volumes of brain (on the order of 0.06 mL) with relatively high-frequency ultrasound that produced unilateral motor responses. This study seeks to increase anatomical specificity to neuromodulation with modulated focused ultrasound (mFU). Here, 'modulated' means modifying a focused 2-MHz carrier signal dynamically with a 500-kHz signal as in vibro-acoustography, thereby creating a low-frequency but small volume (approximately 0.015 mL) source of neuromodulation. Application of transcranial mFU to lightly anesthetized mice produced various motor movements with high spatial selectivity (on the order of 1 mm) that scaled with the temporal average ultrasound intensity. Alone, mFU and focused ultrasound (FUS) each induced motor activity, including unilateral motions, though anatomical location and type of motion varied. Future work should include larger animal models to determine the relative efficacy of mFU versus FUS. Other studies should determine the biophysical processes through which they act. Also of interest is exploration of the potential research and clinical applications for targeted, transcranial neuromodulation created by modulated focused ultrasound, especially mFU's ability to produce compact sources of ultrasound at the very low frequencies (10-100s of Hertz) that are commensurate with the natural frequencies of the brain.
This paper reports on a design for a coil for transcranial magnetic stimulation. The design shows potential for improving the penetration depth of the magnetic field, allowing stimulation of subcortical structures within the brain. The magnetic and induced electric fields in the human head have been calculated with finite element electromagnetic modeling software and compared with empirical measurements. Results show that the coil design used gives improved penetration depth, but also indicates the likelihood of stimulation of additional tissue resulting from the spatial distribution of the magnetic field.
The localization of effects from magnetic coil stimulation is not immediately obvious. We measured the magnetic fields produced by several different coils and compared the results with theoretical calculations. Magnetic stimuli were delivered from a Cadwell MES-10 magnetic stimulator using 3 circular coils (one 9 cm in diameter; two with an angulated extension, 5 and 9 cm in diameter) and twin oval coils arranged in a butterfly shape (each coil approximately 4 cm in diameter) and from a Novametrix Magstim 200 using two circular flat-spiral coils (6.7 and 14 cm in diameter). Peak-induced strength of the magnetic field was recorded with a measuring loop (1 cm in diameter) at different distances from the center of the coil. When the measuring loop was moved in the same plane laterally from the center of the coil, for all coils except the butterfly-shaped coil, the field was highest in the center and fell off near the circumference of the coil. The field dropped progressively when measurements were made more distant from the plane of the coils. The electric field induced from the magnetic coil could be calculated from the coil geometry. For all coils except the butterfly-shaped coil, the largest electric field was at the circumference of the coils. The 6.7 cm flat-spiral coil induced currents similar to those induced by the larger coils but more focally. The butterfly-shaped coil induced the largest currents under its center, where the circumferences of the two component coils come together. The component of the electric field parallel to the wire in the center of this coil was the largest and most localized.
This article summarizes the achievements that have been accumulated about the role of c-Fos as a transcription factor and as a functional marker of activated neurons. Since its discovery, more than a decade ago, as an inducible immediate-early gene encoding a transcription factor, or third messenger, involved in stimulus-transcription coupling and mediation of extracellular signals to long-term changes in cellular phenotype, c-fos became the most widely used powerful tool to delineate individual neurons as well as extended circuitries that are responsive to wide variety of external stimuli. There still remain uncertainties as to how general is the c-fos induction in the central neurons, and whether the threshold of c-fos induction is comparable along a certain neuronal circuit. The major limitation of this technology is that c-fos does not mark cells with a net inhibitory synaptic or transcriptional drive, and c-fos induction, as a generic marker of trans-synaptic activation, does not provide evidence for transcriptional activation of specific target genes in a certain cell type of interest. The first part of the review focuses on recent functional data on c-fos as transcription factor, while the second part discusses c-fos as a cellular marker of transcriptional activity in the stress-related circuitry.
Transcranial magnetic stimulation (TMS) allows for quantification of motor system excitability. While routinely used in humans, application in other species is rare and little is known about the characteristics of animal TMS. The unique features of TMS, i.e., predominantly interneuronal stimulation at low intensity and non-invasiveness, are particularly useful in evaluating injury and recovery in animal models. This study was conducted to characterize the rodent motor evoked potential to TMS (MEPTMS) and to develop a methodology for reproducible assessment of motor excitability in the rat. MEPTMS were compared with responses evoked by electrical stimulation of cervical spinal cord (MEPCES) and peripheral nerve. MEP were recorded by subcutaneous electrodes implanted bilaterally over the calf. Animals remained under propofol infusion and restrained in a stereotactic frame while TMS followed by CES measurements were obtained before and after 2 h of idle time. TMS was applied using a 5-cm-diameter figure-of-eight coil. MEPTMS had onset latencies of 6.7+/-1.3 ms. Latencies decreased with higher stimulation intensity (r=-0.7, P<0.05). Two morphologies, MEPTMS, 1 and MEPTMS, 2, were distinguished by latency of the first negative peak (N1), overall shape, and amplitude. MEPTMS, 2 were more frequent at higher stimulation intensity. While recruitment curves for MEPTMS, 1 followed a sigmoid course, no supramaximal response was reached for MEPTMS, 2. Mid-cervical spinal transection completely abolished any response to TMS. MEPCES showed a significantly shorter latency (5.29+/-0.24, P<0.0001). Two types of MEPCES resembling MEPTMS, 1 and 2 were observed. Neither MEPTMS nor MEPCES changed on repeat assessment after 2 h. This study demonstrates the feasibility and reproducibility of TMS in the rat. Sigmoid recruitment curves for MEPTMS, 1 suggest input-output properties similar to those of the human corticospinal system. Latency differences between CES and TMS point to a supraspinal origin of the MEPTMS. The two morphologies likely reflect different cortical or subcortical origins of MEPTMS.
We investigate the effect of tissue heterogeneity and anisotropy on the electric field and current density distribution induced in the brain during magnetic stimulation. Validation of the finite-element (FE) calculations in a homogeneous isotropic sphere showed that the magnitude of the total electric field can be calculated to within an error of approximately 5% in the region of interest, even in the presence of a significant surface charge contribution. We used a high conductivity inclusion within a sphere of lower conductivity to simulate a lesion due to an infarct. Its effect is to increase the electric field induced in the surrounding low conductivity region. This boost is greatest in the vicinity of interfaces that lie perpendicular to the current flow. For physiological values of the conductivity distribution, it can reach a factor of 1.6 and extend many millimeters from the interface. We also show that anisotropy can significantly alter the electric field and current density distributions. Either heterogeneity or anisotropy can introduce a radial electric field component, not present in a homogeneous isotropic conductor. Heterogeneity and anisotropy are predicted to significantly affect the distribution of the electric field induced in the brain. It is, therefore, expected that anatomically faithful FE models of individual brains which incorporate conductivity tensor data derived from diffusion tensor measurements, will provide a better understanding of the location of possible stimulation sites in the brain.
Pain is a clinical syndrome arising from a variety of etiologies in a heterogeneous population, which makes successfully treating the individual patient difficult. Organizations and governments recognize the need for tailored and specific therapies, which drives pain research. This review summarizes the different types of pain assessments currently being used and the various rodent models that have been developed to recapitulate the human pain condition.
Objective:
Obsessive-compulsive disorder (OCD) is a chronic and disabling condition that often responds unsatisfactorily to pharmacological and psychological treatments. Converging evidence suggests a dysfunction of the cortical-striatal-thalamic-cortical circuit in OCD, and a previous feasibility study indicated beneficial effects of deep transcranial magnetic stimulation (dTMS) targeting the medial prefrontal cortex and the anterior cingulate cortex. The authors examined the therapeutic effect of dTMS in a multicenter double-blind sham-controlled study.
Methods:
At 11 centers, 99 OCD patients were randomly allocated to treatment with either high-frequency (20 Hz) or sham dTMS and received daily treatments following individualized symptom provocation, for 6 weeks. Clinical response to treatment was determined using the Yale-Brown Obsessive Compulsive Scale (YBOCS), and the primary efficacy endpoint was the change in score from baseline to posttreatment assessment. Additional measures were response rates (defined as a reduction of ≥30% in YBOCS score) at the posttreatment assessment and after another month of follow-up.
Results:
Eighty-nine percent of the active treatment group and 96% of the sham treatment group completed the study. The reduction in YBOCS score among patients who received active dTMS treatment was significantly greater than among patients who received sham treatment (reductions of 6.0 points and 3.3 points, respectively), with response rates of 38.1% and 11.1%, respectively. At the 1-month follow-up, the response rates were 45.2% in the active treatment group and 17.8% in the sham treatment group. Significant differences between the groups were maintained at follow-up.
Conclusions:
High-frequency dTMS over the medial prefrontal cortex and anterior cingulate cortex significantly improved OCD symptoms and may be considered as a potential intervention for patients who do not respond adequately to pharmacological and psychological interventions.
Background:
Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique used for research and clinical applications. Existent TMS coils are limited in their precision of spatial targeting (focality), especially for deeper targets.
Objective: This paper presents a methodology for designing TMS coils to achieve optimal trade-off between the depth and focality of the induced electric field (E-field), as well as the energy required by the coil.
Methods: A multi-objective optimization technique is used for computationally designing TMS coils that achieve optimal trade-offs between E-field focality, depth, and energy (fdTMS coils). The fdTMS coil winding(s) maximize focality (minimize the volume of the brain region with E-field above a given threshold) while reaching a target at a specified depth and not exceeding predefined peak E-field strength and required coil energy. Spherical and MRI-derived head models are used to compute the fundamental depth-focality trade-off as well as focality-energy trade-offs for specific target depths.
Results: Across stimulation target depths of 1.0-3.4 cm from the brain surface, the suprathreshold volume can be theoretically decreased by 42%-55% compared to existing TMS coil designs. The suprathreshold volume of a figure-8 coil can be decreased by 36%, 44%, or 46%, for matched, doubled, or quadrupled energy. For matched focality and energy, the depth of a figure-8 coil can be increased by 22%.
Conclusion: Computational design of TMS coils could enable more selective targeting of the induced E-field. The presented results appear to be the first significant advancement in the depth-focality trade-off of TMS coils since the introduction of the figure-8 coil three decades ago, and likely represent the fundamental physical limit.
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Background:
Transcranial magnetic stimulation (TMS) allows focal, non-invasive stimulation of the cortex. A TMS pulse is inherently weakly coupled to the cortex; thus, magnetic stimulation requires both high current and high voltage to reach sufficient intensity. These requirements limit, for example, the maximum repetition rate and the maximum number of consecutive pulses with the same coil due to the rise of its temperature.
Objective:
To develop methods to optimise, design, and manufacture energy-efficient TMS coils in realistic head geometry with an arbitrary overall coil shape.
Methods:
We derive a semi-analytical integration scheme for computing the magnetic field energy of an arbitrary surface current distribution, compute the electric field induced by this distribution with a boundary element method, and optimise a TMS coil for focal stimulation. Additionally, we introduce a method for manufacturing such a coil by using Litz wire and a coil former machined from polyvinyl chloride.
Results:
We designed, manufactured, and validated an optimised TMS coil and applied it to brain stimulation. Our simulations indicate that this coil requires less than half the power of a commercial figure-of-eight coil, with a 41% reduction due to the optimised winding geometry and a partial contribution due to our thinner coil former and reduced conductor height. With the optimised coil, the resting motor threshold of abductor pollicis brevis was reached with the capacitor voltage below 600 V and peak current below 3000 A.
Conclusion:
The described method allows designing practical TMS coils that have considerably higher efficiency than conventional figure-of-eight coils.
Since the development of transcranial magnetic stimulation (TMS) in the early 1980s, a range of repetitive TMS (rTMS) protocols are now available to modulate neuronal plasticity in clinical and non-clinical populations. However, despite the wide application of rTMS in humans, the mechanisms underlying rTMS-induced plasticity remain uncertain. Animal and in vitro models provide an adjunct method of investigating potential synaptic and non-synaptic mechanisms of rTMS-induced plasticity. This review summarizes in vitro experimental studies, in vivo studies with intact rodents, and preclinical models of selected neurological disorders—Parkinson’s disease, depression, and stroke. We suggest that these basic research findings can contribute to the understanding of how rTMS-induced plasticity can be modulated, including novel mechanisms such as neuroprotection and neurogenesis that have significant therapeutic potential.
To explore the field characteristics and design tradeoffs of coils for deep transcranial magnetic stimulation (dTMS).
We simulated parametrically two dTMS coil designs on a spherical head model using the finite element method, and compare them with five commercial TMS coils, including two that are FDA approved for the treatment of depression (ferromagnetic-core figure-8 and H1 coil).
Smaller coils have a focality advantage over larger coils; however, this advantage diminishes with increasing target depth. Smaller coils have the disadvantage of producing stronger field in the superficial cortex and requiring more energy. When the coil dimensions are large relative to the head size, the electric field decay in depth becomes linear, indicating that, at best, the electric field attenuation is directly proportional to the depth of the target. Ferromagnetic cores improve electrical efficiency for targeting superficial brain areas; however magnetic saturation reduces the effectiveness of the core for deeper targets, especially for highly focal coils. Distancing winding segments from the head, as in the H1 coil, increases the required stimulation energy.
Among standard commercial coils, the double cone coil offers high energy efficiency and balance between stimulated volume and superficial field strength. Direct TMS of targets at depths of ∼4cm or more results in superficial stimulation strength that exceeds the upper limit in current rTMS safety guidelines. Approaching depths of ∼6cm is almost certainly unsafe considering the excessive superficial stimulation strength and activated brain volume.
Coil design limitations and tradeoffs are important for rational and safe exploration of dTMS.
Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited.
To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP).
Open-label trial with a sham lead-in phase.
Academic medical center. Patients Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation.
Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation.
A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase.
The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration clinicaltrials.gov Identifier: NCT00367003.
Repetitive transcranial magnetic stimulation (rTMS) is a novel non-invasive method with anti-depressant properties. However, the mechanism of activation on the cellular level is unknown. Twelve hours after the last chronic rTMS treatment (14 days, once per day, 20 Hz, 10 s, 75% machine output, the transcription factor c-fos was markedly increased in neurons in layers I-IV and VI of the parietal cortex and in few scattered neurons in the hippocampus of Sprague-Dawley rats. The cortical activation was not blocked by the NMDA antagonist MK-801. The increase of c-fos was not paralleled by an increased glial response and activation of cortical growth factors. Thus, it is concluded that chronic rTMS differentially activates parietal cortical layers and this might be involved in mediating anti-depressant activity in other brain areas.
Permethrin, a type I pyrethroid insecticide, is known to affect sodium channels of neurons and prolong sodium currents. On the other hand, the expression of brain-derived neurotrophic factor (BDNF) and c-fos genes is activated through Ca(2+) influx into neurons, in an activity-dependent manner. In this study, therefore, we investigated whether permethrin influenced the Ca(2+) signal-induced expression of these genes. In primary culture of mouse cerebellar granule cells (CGCs), stimulation with veratridine, a potent agonist for sodium channels, which causes membrane depolarization in neurons, induced c-fos and BDNF mRNA expression accompanying the Ca(2+) influx into neurons. Pretreatment with permethrin at doses nontoxic to CGCs repressed the induction of these genes dose dependently, with trans-permethrin more potent than cis-permethrin. Consistent with this, the increase in Ca(2+) influx caused by veratridine was repressed by permethrin. The membrane depolarization induced by elevating the potassium (K(+)) concentration in medium (high K(+)) caused the activation of c-fos and BDNF genes, which was also repressed by permethrin. Immunoblotting analysis of c-Fos and a gel-mobility assay of AP-1 DNA-binding activity supported the decrease in c-Fos synthesis in permethrin-treated CGCs. The type II pyrethroid cypermethrin also affected the expression of these genes but less effectively than permethrin. Thus, pyrethroids inhibit the activity-dependent gene expression in neurons.
We investigated neuronal response to repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) in terms of c-Fos expression. In rats at postnatal day 49, six rTMS sessions induced widespread nuclear c-Fos-like immunoreactivity in frontal cortex, lateral orbital cortex, striatum, lateral septal nucleus, piriform cortex, dentate gyrus, Ammon's horn, cingulate cortex, parietal cortex, thalamus, occipital cortex, and amygdala; this reactivity was greater than with two sessions of rTMS or sham rTMS. ECS produced even stronger c-Fos expression than six sessions of rTMS in all regions except thalamus (no difference) and striatum (stronger with rTMS). Thus, functional modification of neuroanatomic substrates as demonstrated by c-Fos expression may partially differ between rTMS and ECS.
Repetitive transcranial magnetic stimulation (rTMS) is suggested to be a potentially useful treatment in major depression. In order to optimize rTMS for therapeutic use, it is necessary to understand the neurobiological mechanisms involved, particularly the nature of the neurochemical changes induced. Using intracerebral microdialysis in urethane-anesthetized and conscious adult male Wistar rats, we monitored the effects of acute rTMS (20 Hz) on the intrahippocampal, intraaccumbal and intrastriatal release patterns of dopamine and its metabolites (homovanillic acid, 3,4-dihydroxyphenylacetic acid). The stimulation parameters were adjusted according to the results of accurate MRI-based computer-assisted reconstructions of the current density distributions induced by rTMS in the rat brain, ensuring stimulation of frontal brain regions. In the dorsal hippocampus, the shell of the nucleus accumbens and the dorsal striatum the extracellular concentration of dopamine was significantly elevated in response to rTMS. Taken together, these data provide the first in vivo evidence that acute rTMS of frontal brain regions has a modulatory effect on both the mesolimbic and the mesostriatal dopaminergic systems. This increase in dopaminergic neurotransmission may contribute to the beneficial effects of rTMS in the treatment of affective disorders and Parkinson's disease.
Transcranial magnetic stimulation (TMS) is increasingly used as a research tool for functional brain mapping in cognitive neuroscience. Despite being mostly tolerable, side effects of TMS could influence task performance in behavioural TMS studies. In order to test this issue, healthy subjects assessed the discomfort caused by the stimulation during a verbal working memory task. We investigated the relation between subjective disturbance and task performance. Subjects were stimulated during the delay period of a delayed-match-to-sample task above cortical areas that had been identified before to be involved in working memory. Task performance and subjective disturbance due to side effects were monitored. The subjects' grade of discomfort correlated with the error rates: the higher the discomfort, the more errors were made. Conclusively, TMS side effects may bias task performance in cognitive neuroscience studies and may thereby lead to misinterpretation of results. We emphasize the importance of controlling side effects of the stimulation as a source of biasing effects in TMS studies.
A quick-acting, quick-reversing method for blocking action potentials in peripheral nerves could be used in the treatment of muscle spasticity and pain. A high-frequency alternating-current (HFAC) sinusoidal waveform is one possible means for providing this type of block. HFAC was used to block peripheral motor nerve activity in an in vivo mammalian model. Frequencies from 10 to 30 kHZ at amplitudes of between 2 and 10 V were investigated. A complete and reversible motor block was obtained at all frequencies. The block threshold amplitudes showed a linear relationship with frequency, the lowest threshold being at 10 kHZ. HFAC block has three phases: an onset response; a period of asynchronous firing; and a steady state of complete or partial block. The onset response and the asynchronous firing can be minimized by using an optimal frequency-amplitude combination. In general, the onset response was lowest for the combination of 30 kHZ and 10 V.
We tested whether transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression.
In a double-blind, multisite study, 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted five times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3000 pulses/session, for 4-6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD.
Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well tolerated with a low dropout rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain.
Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.
The sensitivity of brain tissue to weak extracellular electric fields is important in assessing potential public health risks of extremely low frequency (ELF) fields, and potential roles of endogenous fields in brain function. Here we determine the effect of applied electric fields on membrane potentials and coherent network oscillations. Applied DC electric fields change transmembrane potentials in CA3 pyramidal cell somata by 0.18 mV per V m(-1) applied. AC sinusoidal electric fields have smaller effects on transmembrane potentials: sensitivity drops as an exponential decay function of frequency. At 50 and 60 Hz it is approximately 0.4 that for DC fields. Effects of fields of < or = 16 V m(-1) peak-to-peak (p-p) did not outlast application. Kainic acid (100 nm) induced coherent network oscillations in the beta and gamma bands (15-100 Hz). Applied fields of > or = 6 V m(-1) p-p (2.1 V m(-1) r.m.s.) shifted the gamma peak in the power spectrum to centre on the applied field frequency or a subharmonic. Statistically significant effects on the timing of pyramidal cell firing within the oscillation appeared at distinct thresholds: at 50 Hz, 1 V m(-1) p-p (354 mV m(-1) r.m.s.) had statistically significant effects in 71% of slices, and 0.5 V m(-1) p-p (177 mV m(-1) r.m.s.) in 20%. These threshold fields are consistent with current environmental guidelines. They correspond to changes in somatic potential of approximately 70 microV, below membrane potential noise levels for neurons, demonstrating the emergent properties of neuronal networks can be more sensitive than measurable effects in single neurons.
Resonance, oscillation and the intrinsic
- Brain
Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil
- Zangen
Transcranial magnetic stimulation of rodents
- Funke