Keywords

Introduction

Techniques for non-invasive modulation of brain function and plasticity have emerged as an important research and promising clinical tool during the last two decades. It allows directed, controlled and localized modulation of brain physiology, and thus is a powerful tool to expand our understanding of brain functions, including implications for psychological and behavioral processes in health and disease, and has as well therapeutic implications.

tDCS is one of these techniques which (re-)gained increasing popularity during the last years. In the 50s and 60s of the last century, tDCS studies in humans and animal models showed that tonic application of weak direct currents to the brain could alter cortical activity and plasticity, modulate cognitive functions, and might be able to improve clinical symptoms in psychiatric diseases (for an overview see Esmaeilpour et al. 2017; Nitsche et al. 2003). tDCS, in its modern form, was re-discovered circa 2000. A rapid expansion of interest in the technique was fueled by increased knowledge about the relevance of specific cortical activity states and neuroplasticity for a multitude of psychological and behavioral processes, including pathological alterations in neurological and psychiatric diseases. tDCS – similarly to repetitive transcranial magnetic stimulation – is able to interfere with these processes, and thus enhance our basic understanding of human brain physiology, including pathological alterations, and on this foundation might lead to innovative therapeutic approaches. Special advantages of tDCS as compared to other non-invasive brain stimulation tools are that it is a technically relatively uncomplicated tool, and that the weak subthreshold stimulus can be applied during task performance without necessarily disrupting spontaneous activity of cortical networks (Woods et al. 2016). Indeed, a central feature of tDCS is modulation of spontaneous activity of the brain (Bindman et al. 1964; Reato et al. 2010).

The number of studies published since 2000 involving tDCS has increased exponentially (Bikson et al. 2016; Woods et al. 2016), reflecting its promising profile as a research and clinical tool (Knotkova et al. 2014, 2015). tDCS is a clearly useful and successful interventional tool in the field of human and animal model brain research. Ongoing research and development has resulted in increasingly advanced technology with regard to tDCS hardware and software, and increasingly precise understanding of physiological, psychological and behavioral effects of tDCS in health and disease. In part due to the neuromodulatory state-dependent impact of the stimulation, compounded by the large potential stimulation parameter space, knowledge about tDCS effects remains incomplete – although equal or even more advanced as compared to related techniques. Nonetheless, continuing to enhance our understanding about tDCS effects is crucial to improve its application in basic and clinical studies.

Open Questions and Challenges

Below we discuss open questions and challenges which are important for the future development of tDCS, but also for the field of non-invasive brain stimulation in general.

Deeper Understanding of Neurophysiological Mechanisms, Co-variates and Confounding Factors

Few fields in neuromodulation, and indeed interventional neuropsychiatry, have comparable breadth and depth of neurophysiology studies as tDCS. The physiological foundations of neuromodulation with DCS span at least decades where polarity specific changes in excitability and plasticity were established (Bindman et al. 1964). Dozens of modern animal experiments have characterized the cellular effects of DCS on acute brain function and plasticity (Macedo et al. 2016; Pikhovych et al. 2016; Rahman et al. 2015). The modern foundations of tDCS are notable based on human neuro-physiological recordings (Nitsche and Paulus 2000) – not, as the case for many other interventions, on serendipitous clinical findings. The core human neurophysiological findings with tDCS have been replicated, even as a more subtle dose response emerges. Ironically, those unfamiliar with the literature have attributed the richness in dose-response emerging from ongoing human and animal studies as suggesting a challenge to the foundations of the field (For example, they conflate studies showing that tDCS applied to subjects specifically a rest vs subject specifically engaged in a task produces different outcomes, to claim tDCS therefore has no “net” effect). This is the opposite of the case; rather this richness in dose-response and mechanism is expected given the complexity of brain function (and disease). That DCS can change brain function is unequivocal- the question is rather where are the more promising indications and how should interventions be optimized.

Indeed, tDCS arguably has a more specific and detailed neurophysiologic foundation than any other brain stimulation-derived neuromodulation intervention applied in humans, including those with relatively more progressive clinical deployment such as DBS and rTMS. For example, there is a rich literature on how co-variants (Fresnoza et al. 2014; Furuya et al. 2014; Labruna et al. 2016), such as brain system states influence tDCS outcomes – much of this work has been at the animal or human neurophysiological level, with extension to clinical intentions is ongoing (Strube et al. 2016). The challenge now is to integrate the rich data around tDCS mechanisms to develop hypotheses for the next generation of trials. Animal studies should focus not only on further elucidating mechanisms but on developing biophysically based hypotheses that can be used to formulate and test new tDCS interventions – for example “functional targeting” at the cellular level leading to task-specific tDCS effects (Bikson et al. 2013a, b; Kronberg et al. 2017). Efforts in human and pre-clinical studies must include further characterizing co-variants that lead to diversity in individual outcomes.

Evidence Supported by Advanced Neurophysiological and Neuroimaging Methods

Although basic mechanisms of tDCS have been explored in detail in animal and human studies, knowledge is still incomplete with regards to specific mechanisms and dynamics, which might however be relevant not only for our basic understanding of tDCS effects and neuroplasticity of the human brain, but also for the development of tailored stimulation protocols. Clinical neurophysiology and imaging have yielded multiple lines of evidence indicating the after-effects of stimulation depend on glutamatergic mechanisms, that alteration of GABA is involved, and that tDCS-induced plasticity is calcium-dependent (Nitsche et al. 2003; Stagg et al. 2009). At the same time, these studies have indicated that interactions among subject state, stimulation (intensity), and other factors (pharmacology) can engage distinct processes leading to qualitatively different outcomes of tDCS (Batsikadze et al. 2013; Nitsche et al. 2012). Here direct recordings from animal models, including slice preparations and single cell preparations, where background state can be directly titrated, and leveraging techniques like calcium imaging, voltage sensitive dye imaging, and optogenetics, are key to elucidate mechanisms. Animal studies will also allow isolation of the cellular targets of tDCS which could span different neuronal compartments (soma, dendrite, axon; Bikson et al. 2004; Kabakov et al. 2012; Kronberg et al. 2017; Lafon et al. 2017; Márquez-Ruiz et al. 2012; Rahman et al. 2013) as well as non-neuronal cell types (Gellner et al. 2016; Jackson et al. 2016; Rahman et al. 2013). For ongoing human research, specific MRI techniques, such as magnetic resonance spectroscopy, and positron emission tomography will help to clarify mechanisms further.

Beyond the regional cellular effects, network effects, i.e. presumably indirect effects of stimulation on remote, but functionally connected networks, have recently been identified (Polanía et al. 2011a, b, 2012), and might be of utmost relevance for the net functional effects of tDCS. Such multi-region effects reflect a combination of current spread to other brain regions (Dasilva et al. 2012; Kim et al. 2014; Seibt et al. 2015) and connectivity between regions determining outcomes (Rahman et al. 2017). Here respective mechanisms regarding the transmission of activity alterations, and the effect on distant hubs of respective networks are under-explored at present, but presumably relevant for development of targeted stimulation protocols. Animal models will allow direct recordings and modulations of respective remote effects, current flow models can address direct multi-region stimulation, and advanced functional imaging approaches in humans are also suited to clarify these application-relevant effects of stimulation.

Relevance of Modeling in Interaction with Physiological and Cognitive Mechanisms

Just as our understanding of tDCS has benefited from applying the most advanced and extensive neurophysiological and imaging characterization, computational models of tDCS have been among the most advanced in any neuromodulation field. For example models of tDCS were the first to include gyri-level precision (Datta et al. 2009), have been continuously enhanced over a decade (Datta et al. 2012; Lee et al. 2017; Opitz et al. 2015; Saturnino et al. 2015), and have been subject to extensive direct validation (Datta et al. 2012, 2013; Huang et al. 2017; Opitz et al. 2016). While state-of-the-art modeling work does not imply major questions on dosimetry do not remain, these modeling tools continue to inform rigorous hypothesis driven tDCS trials. While current flow patterns through the brain are well understood and validated, one major challenge is linking details of regional current flow with biophysical models that relate this current flow, through a particular brain region in a particular state, with resulting changes in function, and ultimately behavior. Most prior and ongoing modeling work has relied on the quasi-uniform assumption (Bikson et al. 2012) which is ambivalent to brain region or brain state. Work along these lines is ongoing (Reato et al. 2013), and is broadly referred to computational neurostimulation (Bestmann 2015), but remains a challenging frontier for tDCS as is requires a comprehensive understanding of both neuromodulation mechanisms and the underlying brain function (cognition or disease state) that is the functional target of stimulation.

Insight into Relations between tDCS Neurophysiological Effects and Changes in Functional Outcomes

Importantly, neurophysiological effects of tDCS build the foundation for generating hypotheses about functional outcomes , e.g. long term potentiation-like effects of facilitatory tDCS protocols are the rationale for presuming that these improve learning and memory formation, while facilitatory tDCS is applied in depression and other diseases to enhance activity of pathologically hypo-active areas. Increasingly sophisticated physiological insight may thus improve efficacy of tDCS interventions. For example, it was shown that combination of tDCS with serotonin reuptake inhibitors enhances LTP-like effects (Nitsche et al. 2009), and in accordance with these physiological results, combination of both techniques improved therapeutic efficacy in major depression, where compromised LTP is discussed to play a critical role (Brunoni et al. 2013).

While relying on general associations between physiology and functional outcomes to formulate mechanism hypotheses for tDCS interventions, it is important to not draw an oversimplified picture. Many neurophysiological parameters which are applicable for use in human experiments for exploring the effects of tDCS or the physiological derivates of cognitive processes have a resolution which is not sufficient to depict cognition-relevant physiology specifically. Motor evoked potentials, but also EEG and other functional imaging measures do not only monitor neurons or neuronal connections relevant for a specific process, but larger domains. Functional connectivity measures might be more specific, but systematic evaluations which physiological parameters are most closely related to psychological and behavioral functions are largely missing. It is thus not surprising that the association between physiological effects of brain stimulation tools and performance alterations is weak in some cases (López-Alonso et al. 2015). Identification of parameters showing potential to connect physiology and functions more closely is however of major relevance to tailor stimulation approaches best suited to improve functions, and to monitor interventions based on a rationale foundation. This will also pave the ground for fine-tuned individualized and also closed-loop stimulation approaches, which are potentially relevant future strategies to optimize stimulation effects.

Factors Playing a Role in Responsiveness/Non-responsiveness to tDCS

Even when at the group level replicable neurophysiological and cognitive changes are observed, neuromodulatory plasticity-inducing protocols, such as tDCS, but also rTMS, and PAS, show inter- and intraindividual variability, due to various sources (Ridding and Ziemann 2010). This variability is an intrinsic feature of neuromodulatory interventions, which have trait- and state-dependent effects. For basic studies, this variability is not only a source of noise, but can be exploited to learn more about determinants of human brain physiology. For applied studies, however, especially with regard to neuroenhancement and clinical treatment of patients, a reduction of variability – including enhancement of the proportion of responders – is relevant for intervention effectiveness. Numerous factors which affect the impact of tDCS on brain physiology, psychological factors, and behavior, have already been proposed and demonstrated, such as pharmacology, genetic polymorphisms, sex, age, handedness, head size, sensitivity to TMS, and strategic aspects of task performance. Other factors might emerge with ongoing research. Furthermore, task and performance characteristics, as well as technical aspects of stimulation and monitoring effects can affect tDCS outcomes (Woods et al. 2016). Identification of relevant factors will be likely relevant to pre-determine if e.g. a therapeutic intervention is promising or not in a specific patient/volunteer, but will also help to install an environment optimally suited for successful intervention. One problematic aspect might be however the multitude of factors able to influence stimulation-based neuromodulation, and that these factors are likely interacting. Therefore, one future challenge will be to identify relatively simple and feasible biomarkers, which are allowing to foresee efficacy, and adapt stimulation protocols individually.

Patient-Tailored Protocols and Established Optimized “General Protocols” for Specific Populations

In part because tDCS experiments aim to achieve functional outcomes based on prior physiological evidence, most cognitive and behavioral interventions adapt a stimulation montage and use a single current/duration from prior work. Systematic tritration of protocols to identify optimal protocols to change performance or symptom-alleviation has been performed in a limited number of studies. This incremental and conservative approach to dose exploration is the general rule for all non-invasive brain stimulation protocols. For physiological effects of motor cortex stimulation - and other rather basic effects – several studies show how stimulation intensity, duration, and electrode position can alter – in a sometimes non-linear fashion – tDCS effects. These non-linearities of effects, which are an essential attribute of neuromodulation, are an important justification for additional indication-specific systematic titration studies. Importantly, since target areas differ with regard to many factors responsible for variability of effects, it will not be sufficient to perform these titration experiments for a single model area. Whereas for basic studies it might not be relevant in each case to receive optimally strong effects – think e.g. about the question of identification of the contribution of a target area to a specific cognitive process, where the presence or absence of tDCS impact on a function, and not its size, is the relevant information – this is crucial for patient studies. Here, similarly to pharmacological studies, systematic titration of dosage is required to identify the “optimal” protocols. In further accordance to pharmacological studies, this optimization can be performed at the group and the individual level. Definition at group level by systematic titration of protocol parameters is relatively easily done, but has not been performed in many studies so far. It is however crucial to be able to decide if tDCS (or any other brain stimulation technique) is able to successfully and relevantly treat specific symptoms. The second step will then be to develop patient-tailored protocols. This endeavor is more demanding, because individual titration would ideally require some biomarkers to foresee response, and inform the individualized protocol design, which are not yet available (see also above), and might include state and/or enduring parameters. Nevertheless, at least for therapeutic application, these optimizing approaches are of critical importance to evaluate the potential of this tool.

Stimulation Parameters and Safety

There are many challenges pertaining to tDCS parameters and safety. Examples include exploration of parameters out of the well-established range; support from modeling and neuroimaging, or building a pool of long-term safety data.

To date, tDCS human trials have been largely restricted to intensities between 1 and 2 mA for ~20 min, with one session daily for up to a few weeks. While this is an advantage as far as developing a rigorous record on tolerability and substrate for mechanisms (Woods et al. 2016), this represents a narrow range of potential dose. For example, what are the consequences of stimulation for several hours (as was done in early tDCS literature; Esmaeilpour et al. 2017)? So, while the reinforcement of testing of specific doses (even across diverse indications and populations) builds credibility and basis for ongoing work (Woods et al. 2016), at the same time we can expect that the optimal dose for any given indication has yet to be identified. As such, we expect that ongoing results from clinical trials, while often encouraging, to not reflect the maximal efficacy possible with tDCS (Brunoni et al. 2012). With any new dose, there is a need for vigilance in regards to safety, but we note that there have been no serious adverse effects thus far with controlled tDCS studies despite a wide range of subjects tested (e.g. including children, individuals with epilepsy) and that animal studies suggest a wide margin before theoretical risk of injury (Bikson et al. 2016). One perceived limit in regards to dose was skin tolerability but in the decade since 2 mA was first tested, new electrode technologies have been made available (Minhas et al. 2010) and early testing with higher current using modern techniques has proven to be well tolerated. Certainly compared to other neuromodulation techniques, such as rTMS, there has been little exploration of new dose space.

Challenges Related to Electrodes and Stimulator Technology

This area includes development toward user-friendly, easy-use solutions, as well as solutions suitable for adoption in clinical/hospital practices and solutions suitable for at-home use.

To date, a majority of tDCS trials continue to use electrode technology that is largely based on a design as tested circa 2000 (DaSilva et al. 2011; Nitsche and Paulus 2000). However, there is now increased emphasis on rigor and reproducibility in protocols even using these classic electrode approaches (Woods et al. 2016). New electrode technologies are being developed, often associated with new headgears or caps, which might have advantages with regard to easy and correct application of the intervention, including home use of patient populations (Kasschau et al. 2015; Woods et al. 2015). While in principle tDCS involves a basic control of current, approaches to further increase reliability and tolerability through adaptive stimulation have been proposed (Hahn et al. 2013), and then applied in susceptible populations (Gillick et al. 2015a, b) or for extended multi-session tDCS (Paneri et al. 2016).

Recently, the tDCS procedure and technical equipment have been adapted for a use by lay persons (patients and their family caregivers) at home. Fulfilling ethical and regulatory imperatives for human subject protection, the guidelines and recommendations for the at-home approach (Charvet et al. 2015) promote provisions for enhanced compliance & safety monitoring, as well as technical solutions for low-burden and easy-to-use tDCS application. This facilitates an access to tDCS trials and practice for patients with specific physical and/or cognitive constrains and enables valuable data-collection from specifically challenged patient populations. Following general tends in communication technologies, future developments in the at-home tDCS may include deeper integration of tDCS with telemedicine technologies.

Regulatory Issues

The regulatory status of tDCS continues to evolve. The official regulatory posture governing the use of tDCS evidently depends on jurisdiction. Current regulation in the EU supports the use of tDCS in the treatment of depression and pain. In most cases, the use of tDCS remains investigational or off-label therapy. In the United States, the prescribed use(s) of investigational devices remain highly regulated in compliance with FDA Quality Systems and/or IEC certification standards. When medical devices are used with the intent to treat (outside of the context of a clinical trial), FDA approval is not necessarily required. However, this does not, nor should it suggest cavalier use of tDCS in clinical contexts. Physicians remain obligated to obtain and employ the most current knowledge about the product (including if it is manufactured to medical device standards), and subject-specific dose and treatment profiles. Such knowledge should be based upon both scientific rationale and sound medical evidence (e.g.- clinical trials, reports of investigator-initiated research, empirical laboratory studies relevant to the focus and scope of intended use-in-practice, and evidence-based reviews). Patients should be fully informed of known effects, effectiveness, and limitations.

Education and Professional Competence

Skill development leading to tDCS competency that allows for consistent and safe application of tDCS requires comprehensive education and training. The competency-building process starts with a sufficient knowledge base covering all basic aspects of tDCS use and a core insight into current understanding of neural mechanisms underlying tDCS effects. This is followed by step-by-step training. As tES has not yet been integrated into medical practice, it is not included in formal medical graduate and postgraduate education. Availability of tES courses/workshops is growing, but they cannot substitute for comprehensive training. With the tDCS field quickly expanding, an implementation of medical-board accredited curricula into regular undergraduate and postgraduate education system is warranted. Well-trained tES personnel should be proficient in the following aspects of tES application (1) the theoretical background of tES, (2) principles and rationale of tES use in specific populations, (3) dose, target, and stimulation protocol determination, (4) selection of subjects, (5) safety evidence and safety precautions pertaining to tES delivery, (6) preparation and positioning of the electrodes, preparation and operating the tES unit, (7) outcome monitoring and recording, including recording and reporting adverse events (Knotkova et al. 2015; Woods et al. 2016).

Access to tDCS

In numerous controlled clinical trials, tDCS has been shown to be effective in reducing clinical symptoms that are refractory to other treatments (e.g. pharmacological agents, physical and/or cognitive therapy, etc.). However, because clinical trials are inherently restricted in scope, time, and geography, patient access to therapy in trials is often impractical or difficult. As well, for patients that have completed clinical trials, options for continuity of clinical care are at best limited (if not wholly unavailable), even if patients have proven to be highly responsive. In light of this, patients who may gain clinical benefit from tDCS treatment often are unable to access clinical venues for its safe and apt provision, increasing the burden of disease. If denied access to provision to tDCS under medical care, some patients will then seek alternative resources. Thus the current access of tDCS to patients is an important challenge for the field to address and it may not be ethical to ban access to therapy under any conditions until a definitive consensus on efficacy is reached by some organization.

Conclusions

Overall, tDCS holds great potential for research and clinical applications. However, hand in hand with the potential go multiple challenges, gaps in current knowledge, and unmet needs that together represent hurdles on the path toward further development of this promising technology. In specifics, the imminent needs include: further research supported by advanced neurophysiological and neuroimaging methods in order to bridge gaps in understanding the neurophysiological mechanisms of tDCS and relations to specific functional outcomes; optimization and standardization of stimulation protocols; building a pool of long-term safety data and an environment for data sharing; development toward user-friendly solutions; progress toward implementation of tDCS to clinical practice; initiatives supporting education and professional competence in tDCS use in research and clinical settings. Nonetheless, it is rewarding to see that the complex challenges in fact facilitate the development of the field, promote resource sharing and collaboration, and stimulate professional exchange in the broad tDCS community.