Noninvasive Transcranial Brain Stimulation Research Articles

Noninvasive transcranial brain stimulation in central post-stroke pain: A systematic review.

The aim of this systematic review is to analyze the efficacy of noninvasive brain stimulation (NBS) in the treatment of central post-stroke pain (CPSP). We included randomized controlled trials testing the efficacy of transcranial magnetic stimulation (TMS) or transcranial direct current stimulation versus placebo or other usual therapy in patients with CPSP. Articles in English, Portuguese, Spanish, Italian, and French were included. A bibliographic search was independently conducted on June 1, 2022, by two authors, using the databases MEDLINE (PubMed), Embase (Elsevier), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science Core Collection. The risk of bias was assessed using the second version of the Cochrane risk of bias (RoB 2) tool and the certainty of the evidence was evaluated through Grading of Recommendations Assessment, Development and Evaluation. A total of 2,674 records were identified after removing duplicates, of which 5 eligible studies were included, involving a total of 119 patients. All five studies evaluated repetitive TMS, four of which stimulated the primary motor cortex (M1) and one stimulated the premotor/dorsolateral prefrontal cortex. Only the former one reported a significant pain reduction in the short term, while the latter one was interrupted due to a consistent lack of analgesic effect. NBS in the M1 area seems to be effective in reducing short-term pain; however, more high-quality homogeneous studies, with long-term follow-up, are required to determine the efficacy of this treatment in CSPS.

Photoacoustic: A Versatile Nongenetic Method for High-Precision Neuromodulation.

High-precision neuromodulation plays a pivotal role in elucidating fundamental principles of neuroscience and treating specific neurological disorders. Optical neuromodulation, enabled by spatial resolution defined by the diffraction limit at the submicrometer scale, is a general strategy to achieve such precision. Optogenetics offers single-neuron spatial resolution with cellular specificity, whereas the requirement of genetic transfection hinders its clinical application. Direct photothermal modulation, an alternative nongenetic optical approach, often associates a large temperature increase with the risk of thermal damage to surrounding tissues.Photoacoustic (also called optoacoustic) neural stimulation is an emerging technology for neural stimulation with the following key features demonstrated. First, the photoacoustic approach demonstrated high efficacy without the need for genetic modification. The generated pulsed ultrasound upon ns laser pulses with energy ranging from a few μJ to tens of μJ is sufficient to activate wild-type neurons. Second, the photoacoustic approach provides sub-100-μm spatial precision. It overcomes the fundamental wave diffraction limit of ultrasound by harnessing the localized ultrasound field generated through light absorption. A spatial precision of 400 μm has been achieved in rodent brains using a fiber-based photoacoustic emitter. Single-cell stimulation in neuronal cultures in vitro and in brain slices ex vivo is achieved using tapered fiber-based photoacoustic emitters. This precision is 10 to 100 times better than that for piezo-based low-frequency ultrasound and is essential to pinpoint a specific region or cell population in a living brain. Third, compared to direct photothermal stimulation via temperature increase, photoacoustic stimulation requires 40 times less laser energy dose to evoke neuron activities and is associated with a minimal temperature increase of less than 1 °C, preventing potential thermal damage to neurons. Fourth, photoacoustics is a versatile approach and can be designed in various platforms aiming at specific applications. Our team has shown the design of fiber-based photoacoustic emitters, photoacoustic nanotransducers, soft biocompatible photoacoustic films, and soft photoacoustic lenses. Since they interact with neurons through ultrasound without the need for direct contact, photoacoustic enables noninvasive transcranial and dura-penetrating brain stimulation without compromising high precision.In this Account, we will first review the basic principles of photoacoustic and discuss the key design elements of PA transducers for neural modulation guided by the principle. We will also highlight how these design goals were achieved from a materials chemistry perspective. The design of different PA interfaces, their unique capability, and their applications in neural systems will be reviewed. In the end, we will discuss the remaining challenges and future perspectives for this technology.

Brain Neuromodulation Effects on Sport and Nutrition: A Narrative Review

Study purpose. At the end of the twentieth century, the development of highly reliable and painless non-invasive transcranial brain stimulation techniques and devices has aroused great scientific and clinical interest in numerous fields. In neuroscience, since the introduction of innovative and non-invasive devices such as the brain stimulator, the investigation of cortical processes and their neural basis has played a fundamental role. Furthermore, neuroscientists are attracted to therapeutic applications for the treatment of food craving. This narrative review is aimed to explain the growing and constant interest of neuroscientific experimentation in the field of non-invasive transcranial stimulation. Material and methods. After an introduction explaining the historical evolution of NIBS, we will try to provide an overview of the two stimulation techniques (TMS and tDCS); we will describe the different types of stimulation that can be performed using these techniques, the excitatory/inhibitory effects, and the various mechanisms of action at the level of brain activity. Results. We will also provide some elucidations regarding the implications of the facilitative/inhibitory effects, and how these stimulation methods can be used to advance knowledge of the neurofunctional organization of the brain. Conclusion. The results of the study showed the effect of brain neuromodulation on sports and nutrition.

TACS facilitates flickering driving by boosting steady-state visual evoked potentials

Objective. There has become of increasing interest in transcranial alternating current stimulation (tACS) since its inception nearly a decade ago. tACS in modulating brain state is an active area of research and has been demonstrated effective in various neuropsychological and clinical domains. In the visual domain, much effort has been dedicated to brain rhythms and rhythmic stimulation, i.e. tACS. However, less is known about the interplay between the rhythmic stimulation and visual stimulation. Approach. Here, we used steady-state visual evoked potential (SSVEP), induced by flickering driving as a widely used technique for frequency-tagging, to investigate the aftereffect of tACS in healthy human subjects. Seven blocks of 64-channel electroencephalogram were recorded before and after the administration of 20min 10Hz tACS, while subjects performed several blocks of SSVEP tasks. We characterized the physiological properties of tACS aftereffect by comparing and validating the temporal, spatial, spatiotemporal and signal-to-noise ratio (SNR) patterns between and within blocks in real tACS and sham tACS. Main results. Our result revealed that tACS boosted the 10Hz SSVEP significantly. Besides, the aftereffect on SSVEP was mitigated with time and lasted up to 5 min. Significance. Our results demonstrate the feasibility of facilitating the flickering driving by external rhythmic stimulation and open a new possibility to alter the brain state in a direction by noninvasive transcranial brain stimulation.

Computational optimization of transcranial focused ultrasound stimulation: Toward noninvasive, selective stimulation of deep brain structures

Low-intensity focused ultrasound is emerging as a high-resolution highly selective alternative to standard noninvasive transcranial brain stimulation techniques. A major challenge in using ultrasound devices is designing a stimulator capable of efficiently focusing the acoustic wave to selectively target a specific brain region by compensating for the wavefront distortions induced by the intact skull. Single-element transducers are efficient in stimulating cortical areas in both non-human and human primates. However, reaching deeper brain structures with millimeter resolution and high specificity requires the use of ad hoc multi-element devices characterized by a specific number of piezoelectric elements that optimize the energy deposition in the focal region while simultaneously minimizing the off-focus dispersion. The high cost and complexity of adequately controlling the thousands of elements used generally for such stimulators have limited their use in neuromodulation applications. This study defines the optimal configuration of a multi-element stimulator for low-intensity focused ultrasound through a full-wave realistic numerical model that includes both the stimulator geometry and a detailed anatomical head model. The performance of the device was evaluated. We investigated the influence of the number of piezoelectric elements in the stimulator on its transcranial focusing capabilities. Our results confirm that the focusing optimization improves as the number of elements increased (from 16 to 256). With only 96 point-sources, there was a good trade-off between cost and focusing efficiency. Our study provides a cost-effective stimulator design that enables a standard focusing procedure and a steering technique enacted without prior knowledge about the skull's local acoustic impedance.

Gamma transcranial alternating current stimulation in patients with negative symptoms in schizophrenia: A case series

Non-invasive transcranial brain stimulation therapies, such as transcranial direct current stimulation, have been found to improve negative symptoms in schizophrenia. Another new technique is transcranial alternating current stimulation (tACS). Here we report a series of three patient treated with twice-daily 10min prefrontal 40Hz tACS stimulation over ten days. Patients showed an improvement in the Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, and subjective well-being. Furthermore, there was an improvement in the Trail Making Test and word fluency. ytACS merits further investigation in the treatment of schizophrenia symptoms.

Realistic modeling of mesoscopic ephaptic coupling in the human brain.

Several decades of research suggest that weak electric fields may influence neural processing, including those induced by neuronal activity and proposed as a substrate for a potential new cellular communication system, i.e., ephaptic transmission. Here we aim to model mesoscopic ephaptic activity in the human brain and explore its trajectory during aging by characterizing the electric field generated by cortical dipoles using realistic finite element modeling. Extrapolating from electrophysiological measurements, we first observe that modeled endogenous field magnitudes are comparable to those in measurements of weak but functionally relevant self-generated fields and to those produced by noninvasive transcranial brain stimulation, and therefore possibly able to modulate neuronal activity. Then, to evaluate the role of these fields in the human cortex in large MRI databases, we adapt an interaction approximation that considers the relative orientation of neuron and field to estimate the membrane potential perturbation in pyramidal cells. We use this approximation to define a simplified metric (EMOD1) that weights dipole coupling as a function of distance and relative orientation between emitter and receiver and evaluate it in a sample of 401 realistic human brain models from healthy subjects aged 16–83. Results reveal that ephaptic coupling, in the simplified mesoscopic modeling approach used here, significantly decreases with age, with higher involvement of sensorimotor regions and medial brain structures. This study suggests that by providing the means for fast and direct interaction between neurons, ephaptic modulation may contribute to the complexity of human function for cognition and behavior, and its modification across the lifespan and in response to pathology.

Neurophysiological examination combined with functional intraoperative navigation using TMS in patients with brain tumor near the central region-a pilot study.

Feasibility and value of non-invasive transcranial magnetic brain stimulation (TMS MAGVENTURE® MagPro R30 Denmark) for preoperative diagnosis and surgical planning of brain tumor operations in everyday clinical practice. A prospective monocentric study was conducted, which included preoperative neurological and electrophysiological examination, TMS, and display of functional data in the navigation system (LOCALITE® TMS Navigator Germany). During surgery, the TMS data were correlated with the intraoperative monitoring (IOM). Twenty-four hours to 96h and after at least 3months, follow-ups with neurological, electrophysiological examinations and TMS stimulation were performed. Twenty-five patients with tumors in or near by the primary motor cortex region were included in the study. Twenty-one patients completed preoperative and first postoperative TMS and the neurological examination. Eight of 21 patients showed slight worsening of primary motor cortex function, 8 patients had an unchanged state, and 4 patients showed an improvement early after surgery. The changes of the electrophysiological examination like significant delay of the latency and/or reduced amplitudes matched well with the postoperative neurological outcome: if patients showed a worsening of the SEP's and MEP's, the postoperative results revealed deterioration. A preoperatively performed TMS using the MAGVENTURE® MagPro R30 and the LOCALITE® TMS Navigator could be established in our clinical daily practice and allowed a safe and reliable mapping of the primary motor cortex in order to minimize the risk of postoperative neurological deficits and improve the neurological outcome of the patients.

Tracking Changes in Brain Network Connectivity under Transcranial Current Stimulation.

Noninvasive transcranial brain stimulation has been widely used in experimental and clinical applications to perturb the brain activity, aiming at promoting synaptic plasticity or enhancing functional connectivity within targeted brain regions. However, there are different types of neurostimulations and various choices of stimulation parameters; how these choices influence the intermediate neurophysiological effects and brain connectivity remain incompletely understood. We propose several quantitative methods to investigate the brain connectivity of an epileptic patient before and after transcranial alternating/direct current stimulation (tACS/tDCS). The neuro-feedback derived from our analyses may provide useful cues for the effectiveness of neurostimulation.

"ConnectToBrain" : Synergy project for therapeutic closed-loop stimulation of brain network disorders

Therapeutic non-invasive transcranial brain stimulation with previous treatment protocols showed at best moderate effect sizes and large interindividual variability with asubstantial proportion of non-responders. A currently intensively discussed approach to address these problems is individualized closed-loop stimulation. ConnectToBrain is asynergy project funded by the European Research Council to develop noninvasive closed-loop therapeutic stimulation of network disorders of the human brain.It consists of three main pillars: (1)development of amultichannel transcranial magnetic stimulation (mTMS) coil array that covers nearly all of the cerebral cortex and enables highly precise electronic control of location, direction, intensity and timing of the induced electrical fields, (2)development of real-time analysis of activity and connectivity in brain networks using electroencephalography (EEG) for instantaneous spatial and temporal control of stimulation (brain state-dependent, closed-loop stimulation) and adaptive optimization of treatment effects by machine learning and (3)translation of these neurotechnological innovations into physiological and clinical studies.

S26. Transcranial Direct Current Stimulation in Obsessive-Compulsive Disorder: Electric Field Models and Considerations for the Optimal Montage of Electrodes

Transcranial Direct Current Stimulation (tDCS) is a non-invasive transcranial brain stimulation (NTBS) approach. It has been studied as a treatment for Obsessive-Compulsive Disorder (OCD). As there are several candidate regions for targeting OCD relevant networks by NTBS, previous studies considerably vary in terms of electrode montages used. For guiding research on tDCS for OCD, we critically review the current evidence for different montages and their mechanistic actions hypothesized based on computational models of electric fields (EFs).

Is There a Future for Non-invasive Brain Stimulation as a Therapeutic Tool?

Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. These techniques can induce long lasting changes in cortical excitability by promoting synaptic plasticity and thus may represent a therapeutic option in neuropsychiatric disorders. On the other hand, despite these techniques have become popular, the fragility and variability of the after effects are the major challenges that non-invasive transcranial brain stimulation currentlyfaces. Several factors may account for such a variability such as biological variations, measurement reproducibility, and the neuronal state of the stimulated area. One possible strategy, to reduce this variability is to monitor the neuronal state in real time using EEG and trigger TMS pulses only at pre-defined state. In addition, another strategy under study is to use the spaced application of multiple NIBS protocols within a session to improve the reliability and extend the duration of NIBS effects. Further studies, although time consuming, are required for improving the so far limited effect sizes of NIBS protocols for treatment of neurological or psychiatric disorders.

No Modulatory Effects when Stimulating the Right Inferior Frontal Gyrus with Continuous 6 Hz tACS and tRNS on Response Inhibition: A Behavioral Study.

Response inhibition is the cognitive process required to cancel an intended action. During that process, a “go” reaction is intercepted particularly by the right inferior frontal gyrus (rIFG) and presupplementary motor area (pre-SMA). After the commission of inhibition errors, theta activity (4–8 Hz) is related to the adaption processes. In this study, we intend to examine whether the boosting of theta activity by electrical stimulation over rIFG reduces the number of errors and the reaction times in a response inhibition task (Go/NoGo paradigm) during and after stimulation. 23 healthy right-handed adults participated in the study. In three separate sessions, theta tACS at 6 Hz, transcranial random noise (tRNS) as a second stimulation condition, and sham stimulation were applied for 20 minutes. Based on behavioral data, this study could not show any effects of 6 Hz tACS as well as full spectrum tRNS on response inhibition in any of the conditions. Since many findings support the relevance of the rIFG for response inhibition, this could mean that 6 Hz activity is not important for response inhibition in that structure. Reasons for our null findings could also lie in the stimulation parameters, such as the electrode montage or the stimulation frequency, which are discussed in this article in more detail. Sharing negative findings will have (1) positive impact on future research questions and study design and will improve (2) knowledge acquisition of noninvasive transcranial brain stimulation techniques.

Guiding transcranial brain stimulation by EEG/MEG to interact with ongoing brain activity and associated functions: A position paper.

Non-invasive transcranial brain stimulation (NTBS) techniques have a wide range of applications but also suffer from a number of limitations mainly related to poor specificity of intervention and variable effect size. These limitations motivated recent efforts to focus on the temporal dimension of NTBS with respect to the ongoing brain activity. Temporal patterns of ongoing neuronal activity, in particular brain oscillations and their fluctuations, can be traced with electro- or magnetoencephalography (EEG/MEG), to guide the timing as well as the stimulation settings of NTBS. These novel, online and offline EEG/MEG-guided NTBS-approaches are tailored to specifically interact with the underlying brain activity. Online EEG/MEG has been used to guide the timing of NTBS (i.e., when to stimulate): by taking into account instantaneous phase or power of oscillatory brain activity, NTBS can be aligned to fluctuations in excitability states. Moreover, offline EEG/MEG recordings prior to interventions can inform researchers and clinicians how to stimulate: by frequency-tuning NTBS to the oscillation of interest, intrinsic brain oscillations can be up- or down-regulated. In this paper, we provide an overview of existing approaches and ideas of EEG/MEG-guided interventions, and their promises and caveats. We point out potential future lines of research to address challenges.

The impact of large structural brain changes in chronic stroke patients on the electric field caused by transcranial brain stimulation.

Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) are two types of non-invasive transcranial brain stimulation (TBS). They are useful tools for stroke research and may be potential adjunct therapies for functional recovery. However, stroke often causes large cerebral lesions, which are commonly accompanied by a secondary enlargement of the ventricles and atrophy. These structural alterations substantially change the conductivity distribution inside the head, which may have potentially important consequences for both brain stimulation methods. We therefore aimed to characterize the impact of these changes on the spatial distribution of the electric field generated by both TBS methods. In addition to confirming the safety of TBS in the presence of large stroke-related structural changes, our aim was to clarify whether targeted stimulation is still possible. Realistic head models containing large cortical and subcortical stroke lesions in the right parietal cortex were created using MR images of two patients. For TMS, the electric field of a double coil was simulated using the finite-element method. Systematic variations of the coil position relative to the lesion were tested. For TDCS, the finite-element method was used to simulate a standard approach with two electrode pads, and the position of one electrode was systematically varied. For both TMS and TDCS, the lesion caused electric field “hot spots” in the cortex. However, these maxima were not substantially stronger than those seen in a healthy control. The electric field pattern induced by TMS was not substantially changed by the lesions. However, the average field strength generated by TDCS was substantially decreased. This effect occurred for both head models and even when both electrodes were distant to the lesion, caused by increased current shunting through the lesion and enlarged ventricles. Judging from the similar peak field strengths compared to the healthy control, both TBS methods are safe in patients with large brain lesions (in practice, however, additional factors such as potentially lowered thresholds for seizure-induction have to be considered). Focused stimulation by TMS seems to be possible, but standard tDCS protocols appear to be less efficient than they are in healthy subjects, strongly suggesting that tDCS studies in this population might benefit from individualized treatment planning based on realistic field calculations.

Transcranial brain stimulation: closing the loop between brain and stimulation.

Purpose of reviewTo discuss recent strategies for boosting the efficacy of noninvasive transcranial brain stimulation to improve human brain function.Recent findingsRecent research exposed substantial intra- and inter-individual variability in response to plasticity-inducing transcranial brain stimulation. Trait-related and state-related determinants contribute to this variability, challenging the standard approach to apply stimulation in a rigid, one-size-fits-all fashion. Several strategies have been identified to reduce variability and maximize the plasticity-inducing effects of noninvasive transcranial brain stimulation. Priming interventions or paired associative stimulation can be used to ‘standardize’ the brain-state and hereby, homogenize the group response to stimulation. Neuroanatomical and neurochemical profiling based on magnetic resonance imaging and spectroscopy can capture trait-related and state-related variability. Fluctuations in brain-states can be traced online with functional brain imaging and inform the timing or other settings of transcranial brain stimulation. State-informed open-loop stimulation is aligned to the expression of a predefined brain state, according to prespecified rules. In contrast, adaptive closed-loop stimulation dynamically adjusts stimulation settings based on the occurrence of stimulation-induced state changes.SummaryApproaches that take into account trait-related and state-related determinants of stimulation-induced plasticity bear considerable potential to establish noninvasive transcranial brain stimulation as interventional therapeutic tool.

Combining non-invasive transcranial brain stimulation with neuroimaging and electrophysiology: Current approaches and future perspectives

Non-invasive transcranial brain stimulation (NTBS) techniques such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (TCS) are important tools in human systems and cognitive neuroscience because they are able to reveal the relevance of certain brain structures or neuronal activity patterns for a given brain function. It is nowadays feasible to combine NTBS, either consecutively or concurrently, with a variety of neuroimaging and electrophysiological techniques. Here we discuss what kind of information can be gained from combined approaches, which often are technically demanding. We argue that the benefit from this combination is twofold. Firstly, neuroimaging and electrophysiology can inform subsequent NTBS, providing the required information to optimize where, when, and how to stimulate the brain. Information can be achieved both before and during the NTBS experiment, requiring consecutive and concurrent applications, respectively. Secondly, neuroimaging and electrophysiology can provide the readout for neural changes induced by NTBS. Again, using either concurrent or consecutive applications, both “online” NTBS effects immediately following the stimulation and “offline” NTBS effects outlasting plasticity-inducing NTBS protocols can be assessed. Finally, both strategies can be combined to close the loop between measuring and modulating brain activity by means of closed-loop brain state-dependent NTBS. In this paper, we will provide a conceptual framework, emphasizing principal strategies and highlighting promising future directions to exploit the benefits of combining NTBS with neuroimaging or electrophysiology.

Erratum to “Consensus Paper: Probing Homeostatic Plasticity of Human Cortex With Non-invasive Transcranial Brain Stimulation”. Brain Stimulation 8 (2015) 442–454

Erratum to “Consensus Paper: Probing Homeostatic Plasticity of Human Cortex With Non-invasive Transcranial Brain Stimulation”. Brain Stimulation 8 (2015) 442–454

Consensus Paper: Probing Homeostatic Plasticity of Human Cortex With Non-invasive Transcranial Brain Stimulation.

Homeostatic plasticity is thought to stabilize neural activity around a set point within a physiologically reasonable dynamic range. Over the last ten years, a wide range of non-invasive transcranial brain stimulation (NTBS) techniques have been used to probe homeostatic control of cortical plasticity in the intact human brain. Here, we review different NTBS approaches to study homeostatic plasticity on a systems level and relate the findings to both, physiological evidence from in vitro studies and to a theoretical framework of homeostatic function. We highlight differences between homeostatic and other non-homeostatic forms of plasticity and we examine the contribution of sleep in restoring synaptic homeostasis. Finally, we discuss the growing number of studies showing that abnormal homeostatic plasticity may be associated to a range of neuropsychiatric diseases.

Consensus Paper: Probing Homeostatic Plasticity of Human Cortex With Non-invasive Transcranial Brain Stimulation.

Homeostatic plasticity is thought to stabilize neural activity around a set point within a physiologically reasonable dynamic range. Over the last ten years, a wide range of non-invasive transcranial brain stimulation (NTBS) techniques have been used to probe homeostatic control of cortical plasticity in the intact human brain. Here, we review different NTBS approaches to study homeostatic plasticity on a systems level and relate the findings to both, physiological evidence from in vitro studies and to a theoretical framework of homeostatic function. We highlight differences between homeostatic and other non-homeostatic forms of plasticity and we examine the contribution of sleep in restoring synaptic homeostasis. Finally, we discuss the growing number of studies showing that abnormal homeostatic plasticity may be associated to a range of neuropsychiatric diseases.