Brain stimulation for treatment-resistant depression.

Depression is one of the main public health problems in the world, having a high prevalence and being considered the main cause of disability. An important portion of patients does not respond to treatment with the initial trial of conventional antidepressants in the current depressive episode of moderate to severe intensity, which characterizes treatment-resistant depression. In this context, non-invasive neuromodulation procedures use an electric current or magnetic field to modulate the central nervous system, and they represent a new option for patients with treatment-resistant depression.

Neurocognitive, physiological, and biophysical effects of transcranial alternating current stimulation.

Transcranial alternating current stimulation (tACS) can modulate human neural activity and behavior. Accordingly, tACS has vast potential for cognitive research and brain disorder therapies. The stimulation generates oscillating electric fields in the brain that can bias neural spike timing, causing changes in local neural oscillatory power and cross-frequency and cross-area coherence. tACS affects cognitive performance by modulating underlying single or nested brain rhythms, local or distal synchronization, and metabolic activity. Clinically, stimulation tailored to abnormal neural oscillations shows promising results in alleviating psychiatric and neurological symptoms. We summarize the findings of tACS mechanisms, its use for cognitive applications, and novel developments for personalized stimulation.

Non-invasive transcranial brain modulation for neurological disorders treatment: A narrative review.

Noninvasive brain stimulation/modulation is a rapidly emerging technique that has been implemented in different clinical applications. The commonly noninvasive techniques used in neurological manipulations include photobiomodulation (PBM), transcranial electrical stimulation (TES), transcranial magnetic stimulation (TMS), and ultrasound stimulation (USS). These techniques have the ability to excite, inhibit, or modulate neuronal activity in targeted brain areas to obtain the required therapeutic effects. However, each technique owns its unique mechanism of action that relies on specific parameters suitable for treating certain neurological disorders. Neurological disorders such as epilepsy, Parkinson's disease (PD), Alzheimer's disease (AD), and depression have been treated by one or more of these noninvasive techniques. The therapeutic outcomes of these techniques for neurological diseases are promising, yet with limitations. In the present review, the mechanisms of action of these different brain stimulation/modulation modalities were explored and a synopsis of their applications in the treatment of certain neurological disorders was provided. Moreover, methodological issues, limitations, and open questions were presented. Furthermore, some future directions were suggested.

Non-invasive brain stimulation and neuroenhancement.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

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.

Prefrontal resting-state connectivity and antidepressant response: no associations in the ELECT-TDCS trial.

Functional and structural MRI of prefrontal cortex (PFC) may provide putative biomarkers for predicting the treatment response to transcranial direct current stimulation (tDCS) in depression. A recent MRI study from ELECT-TDCS (Escitalopram versus Electrical Direct-Current Theror Depression Study) showed that depression improvement after tDCS was associated with gray matter volumes of PFC subregions. Based thereon, we investigated whether antidepressant effects of tDCS are similarly associated with baseline resting-state functional connectivity (rsFC). A subgroup of 51 patients underwent baseline rsFC-MRI. All patients of ELECT-TDCS were randomized to three treatment arms for 10 weeks (anodal-left, cathodal-right PFC tDCS plus placebo medication; escitalopram 10 mg/day for 3 weeks and 20 mg/day thereafter plus sham tDCS; and placebo medication plus sham tDCS). RsFC was calculated for various PFC regions and analyzed in relation to the individual antidepressant response. There was no significant association between baseline PFC connectivity of essential structural regions, nor any other PFC regions (after correction for multiple comparisons) and patients' individual antidepressant response. This study did not reveal an association between antidepressants effects of tDCS and baseline rsFC, unlike the gray matter volume findings. Thus, the antidepressant effects of tDCS may be differentially related to structural and functional MRI measurements.

Brain damage by trauma.

Traumatic brain injury (TBI) represents a major clinical and economic challenge for health systems worldwide, and it is considered one of the leading causes of disability in young adults. The recent development of brain-computer interface (BCI) tools to target cognitive and motor impairments has led to the exploration of these techniques as potential therapeutic tools in patients with TBI. However, little evidence has been gathered so far to support applicability and efficacy of BCIs for TBI in a clinical setting. In the present chapter, results from studies using BCI approaches in conscious patients with TBI or in animal models of TBI as well as an overview of future directions in the use of BCIs to treat cognitive symptoms in this patient population will be presented.

Value and limitations of intracranial recordings for validating electric field modeling for transcranial brain stimulation.

Comparing electric field simulations from individualized head models against in-vivo intra-cranial recordings is considered the gold standard for direct validation of computational field modeling for transcranial brain stimulation and brain mapping techniques such as electro- and magnetoencephalography. The measurements also help to improve simulation accuracy by pinning down the factors having the largest influence on the simulations. Here we compare field simulations from four different automated pipelines against intracranial voltage recordings in an existing dataset of 14 epilepsy patients. We show that modeling differences in the pipelines lead to notable differences in the simulated electric field distributions that are often large enough to change the conclusions regarding the dose distribution and strength in the brain. Specifically, differences in the automatic segmentations of the head anatomy from structural magnetic resonance images are a major factor contributing to the observed field differences. However, the differences in the simulated fields are not reflected in the comparison between the simulations and intra-cranial measurements. This apparent mismatch is partly explained by the noisiness of the intra-cranial measurements, which renders comparisons between the methods inconclusive. We further demonstrate that a standard regression analysis, which ignores uncertainties in the simulations, leads to a strong bias in the estimated linear relationship between simulated and measured fields. Ignoring this bias leads to the incorrect conclusion that the models systematically misestimate the field strength in the brain. We propose a new Bayesian regression analysis of the data that yields unbiased parameter estimates, along with their uncertainties, and gives further insights to the fit between simulations and measurements. Specifically, the unbiased results give only weak support for systematic misestimations of the fields by the models.

["ConnectToBrain" : Synergy project for therapeutic closed-loop stimulation of brain network disorders]. / "ConnectToBrain" : Synergy-Projekt zur Closed-loop-Stimulationstherapie von Netzwerkerkrankungen des Gehirns.

Therapeutic non-invasive transcranial brain stimulation with previous treatment protocols showed at best moderate effect sizes and large interindividual variability with a substantial proportion of non-responders. A currently intensively discussed approach to address these problems is individualized closed-loop stimulation. ConnectToBrain is a synergy 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 a multichannel 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.

Effects of electrode angle-orientation on the impact of transcranial direct current stimulation on motor cortex excitability.

BACKGROUND: For effects of transcranial direct current stimulation (tDCS), electrical field distribution and coverage of the target areas play a decisive role. METHODS: We explored the effect of different angle-orientations of tDCS electrodes applied over the upper limb motor cortex (M1) on motor cortex excitability in healthy volunteers. Sixteen individuals received 1 mA anodal or cathodal tDCS through 35 cm2 electrodes over M1 for 15 min. Transcranial magnetic stimulation was used to examine tDCS-generated cortical excitability effects. The M1 electrode-orientation was following the right-left longitudinal plane, or positioned with 45° deviation from the midsagittal plane. Coverage of underlying brain and electrical field orientation were also investigated. RESULTS: Cortical excitability modulation was observed only when the electrode was aligned with 45° angle, which covered a larger area of the motor cortex. CONCLUSION: an electrode angle-orientation of 45° induces superior neuroplastic effects of M1 due to a better alignment with the motor cortex.

Recent Trends in the Use of Electrical Neuromodulation in Parkinson's Disease.

PURPOSE OF REVIEW: This review aims to survey recent trends in electrical forms of neuromodulation, with a specific application to Parkinson's disease (PD). Emerging trends are identified, highlighting synergies in state-of-the-art neuromodulation strategies, with directions for future improvements in stimulation efficacy suggested. RECENT FINDINGS: Deep brain stimulation remains the most common and effective form of electrical stimulation for the treatment of PD. Evidence suggests that transcranial direct current stimulation (tDCS) most likely impacts the motor symptoms of the disease, with the most prominent results relating to rehabilitation. However, utility is limited due to its weak effects and high variability, with medication state a key confound for efficacy level. Recent innovations in transcranial alternating current stimulation (tACS) offer new areas for investigation. SUMMARY: Our understanding of the mechanistic foundations of electrical current stimulation is advancing and as it does so, trends emerge which steer future clinical trials towards greater efficacy.

Automatic skull segmentation from MR images for realistic volume conductor models of the head: Assessment of the state-of-the-art.

Anatomically realistic volume conductor models of the human head are important for accurate forward modeling of the electric field during transcranial brain stimulation (TBS), electro- (EEG) and magnetoencephalography (MEG). In particular, the skull compartment exerts a strong influence on the field distribution due to its low conductivity, suggesting the need to represent its geometry accurately. However, automatic skull reconstruction from structural magnetic resonance (MR) images is difficult, as compact bone has a very low signal in magnetic resonance imaging (MRI). Here, we evaluate three methods for skull segmentation, namely FSL BET2, the unified segmentation routine of SPM12 with extended spatial tissue priors, and the skullfinder tool of BrainSuite. To our knowledge, this study is the first to rigorously assess the accuracy of these state-of-the-art tools by comparison with CT-based skull segmentations on a group of ten subjects. We demonstrate several key factors that improve the segmentation quality, including the use of multi-contrast MRI data, the optimization of the MR sequences and the adaptation of the parameters of the segmentation methods. We conclude that FSL and SPM12 achieve better skull segmentations than BrainSuite. The former methods obtain reasonable results for the upper part of the skull when a combination of T1- and T2-weighted images is used as input. The SPM12-based results can be improved slightly further by means of simple morphological operations to fix local defects. In contrast to FSL BET2, the SPM12-based segmentation with extended spatial tissue priors and the BrainSuite-based segmentation provide coarse reconstructions of the vertebrae, enabling the construction of volume conductor models that include the neck. We exemplarily demonstrate that the extended models enable a more accurate estimation of the electric field distribution during transcranial direct current stimulation (tDCS) for montages that involve extraencephalic electrodes. The methods provided by FSL and SPM12 are integrated into pipelines for the automatic generation of realistic head models based on tetrahedral meshes, which are distributed as part of the open-source software package SimNIBS for field calculations for transcranial brain stimulation.

Transcranial Alternating Current Stimulation (tACS) Mechanisms and Protocols.

Perception, cognition and consciousness can be modulated as a function of oscillating neural activity, while ongoing neuronal dynamics are influenced by synaptic activity and membrane potential. Consequently, transcranial alternating current stimulation (tACS) may be used for neurological intervention. The advantageous features of tACS include the biphasic and sinusoidal tACS currents, the ability to entrain large neuronal populations, and subtle control over somatic effects. Through neuromodulation of phasic, neural activity, tACS is a powerful tool to investigate the neural correlates of cognition. The rapid development in this area requires clarity about best practices. Here we briefly introduce tACS and review the most compelling findings in the literature to provide a starting point for using tACS. We suggest that tACS protocols be based on functional brain mechanisms and appropriate control experiments, including active sham and condition blinding.

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.

Brain stimulation in Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disorder which is associated with severe disturbances of motor function, especially choreatic movements, cognitive decline and psychiatric symptoms. Various brain stimulation methods have been used to study brain function in patients with HD. Moreover, brain stimulation has evolved as an alternative or additive treatment option, besides current symptomatic medical treatment. This article summarizes the results of brain stimulation to better understand the characteristics of cortical excitability and plasticity in HD and gives a perspective on the therapeutic role for noninvasive and invasive neuromodulatory brain stimulation methods.

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.

[Transcranial alternating current stimulation. Entrainment and function control of neuronal networks]. / Transkranielle Wechselstromstimulation. Entrainment und Funktionssteuerung neuronaler Netzwerke.

Transcranial alternating current stimulation (tACS) is a new technique for the modulation of oscillatory brain activity as measured in the electroencephalogram (EEG). In contrast to well-established stimulation techniques, such as transcranial direct current stimulation and transcranial magnetic stimulation, tACS applies a sinusoidal alternating current at a specific frequency. This enables the modulation of the amplitude and frequency of endogenous brain oscillations as well as related cognitive processes. Therefore, the use of tACS has the possibility to evaluate well-known correlations between brain oscillations and cognitive processes in terms of causality. Such causal relationships have been documented in numerous neurocognitive studies on sensory, motor and perceptual processes; however, the clinical application of tACS is still in its infancy. In principle, any pathology that can reliably be connected with brain oscillations of a defined frequency is treatable. A current main focus of clinical research is on symptoms of Parkinson's disease and to a lesser degree, tinnitus. For an effective application of tACS it is important to choose the electrode positions as well as the frequency, intensity and duration of the stimulation in a theory-based and symptom-related manner. A successful therapeutic intervention requires the persistence of the tACS effect after stimulation has ceased. A mechanism that offers not only an explanation to the origin of persistent tACS effects but is also of high therapeutic benefit is neural plasticity. Therefore, one current focus of research aims at a better understanding of tACS after effects.

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.

Patterned Brain Stimulation, What a Framework with Rhythmic and Noisy Components Might Tell Us about Recovery Maximization.

Brain stimulation is having remarkable impact on clinical neurology. Brain stimulation can modulate neuronal activity in functionally segregated circumscribed regions of the human brain. Polarity, frequency, and noise specific stimulation can induce specific manipulations on neural activity. In contrast to neocortical stimulation, deep-brain stimulation has become a tool that can dramatically improve the impact clinicians can possibly have on movement disorders. In contrast, neocortical brain stimulation is proving to be remarkably susceptible to intrinsic brain-states. Although evidence is accumulating that brain stimulation can facilitate recovery processes in patients with cerebral stroke, the high variability of results impedes successful clinical implementation. Interestingly, recent data in healthy subjects suggests that brain-state dependent patterned stimulation might help resolve some of the intrinsic variability found in previous studies. In parallel, other studies suggest that noisy "stochastic resonance" (SR)-like processes are a non-negligible component in non-invasive brain stimulation studies. The hypothesis developed in this manuscript is that stimulation patterning with noisy and oscillatory components will help patients recover from stroke related deficits more reliably. To address this hypothesis we focus on two factors common to both neural computation (intrinsic variables) as well as brain stimulation (extrinsic variables): noise and oscillation. We review diverse theoretical and experimental evidence that demonstrates that subject-function specific brain-states are associated with specific oscillatory activity patterns. These states are transient and can be maintained by noisy processes. The resulting control procedures can resemble homeostatic or SR processes. In this context we try to extend awareness for inter-individual differences and the use of individualized stimulation in the recovery maximization of stroke patients.