Transcranial direct stimulation clinical trials

Investigators will address these questions in a two-part randomized double blind exploratory clinical trial. For this part of the study, investigators will determine relationships between target engagement and clinical outcomes mood and functional sub-constructs of cognitive control and emotion negativity bias, and whether imaging markers at baseline predict changes in antidepressant response.

One hundred people with depression 50 in each group will be randomized to receive either HD-tDCS or sham-tDCS for a total of 12 sessions each lasting 20 minutes occurring on consecutive weekdays. At the first and last session, subjects will receive minutes of active or sham HD-tDCS in the MRI scanner, which will allow investigators to map tDCS currents, and track changes in regional cerebral blood flow rCBF pre-to- post treatment using completely non-invasive methods.

At the first and last session and mid-way through the trial, participants will also complete a series of clinical ratings and neurocognitive tests. This proposal is a prospective, single-center, dose-escalation safety, tolerability, feasibility and potential efficacy study of transcranial direct current stimulation tDCS in acute stroke patients with substantial salvageable penumbra due to a large vessel occlusion who are ineligible for intravenous thrombolysis and endovascular therapy.

This proposal is a prospective, single-center, dose-escalation safety, tolerability, feasibility and potential efficacy study of transcranial direct current stimulation tDCS in acute stroke patients with substantial salvageable penumbra due to a large vessel occlusion before and after endovascular therapy.

Last updated: November 5, Transcranial Direct Current Stimulation clinical trials at University of California Health 5 research studies open to eligible people. Diffusion tensor imaging DTI focuses on the white matter fibers, revealing the neural connectivity between brain areas. Finally, voxel-based morphometry VBM is a computational analysis of morphological images that makes inferences about brain activity based on the differences of brain tissue concentration among areas.

For tDCS, these methods present the advantage of high spatial resolution; allowing to assess subtle changes in the stimulated area. For instance, one study used VBM to assess neuroplastic changes after five days of TMS over the superior temporal cortex; showing macroscopic gray matter changes in the region Even though, the reliability of some methods of MRI are currently under dispute Finally, there is a wide range of blood measurements used in neuropsychiatry research for surrogate outcomes One biomarker under intensive investigation is the brain-derived neurotrophic factor BDNF.

This marker plays an important role in synaptogenesis and neuroplasticity and is thus believed to be linked with some neuropsychiatric disorders — for instance, BDNF serum levels are low in depressed patients and increase after antidepressant treatment Additional biomarkers used in neuropsychiatry include inflammatory proteins such as interleucin-1, interleucin-6 and TNF-alpha ; hypothalamic-pituitary-adrenal activity, which is measured by serum and salivary cortisol ; and oxidative stress proteins such as nitric oxide and other neuroinflammatory protein markers , As neither the full spectrum of clinical efficacy nor the mechanism of action of tDCS are completely described, outcome measures for tDCS trials ideally will inform both about tDCS clinical potency and about the biology of tDCS.

With respect to clinical data, the common accepted behavioral outcomes might be insensitive to subtle changes in neurologic function. This is particularly relevant for tDCS as it has a modest perhaps subclinical neuromodulatory and behavioral effect, particularly for single exposures. Among these are changes in normal function that may be affected by tDCS. For example, an investigator testing tDCS effects on chronic pain might add a battery of motor tasks to see whether there is any subtle loss of normal function with treatment.

Similarly, an investigator applying tDCS for treatment of epilepsy may add a questionnaire to assess mood. To date, the common feature in tDCS trials appears to be its capacity to produce a lasting change in regional cortical excitability. Given these data, outcome measures aimed to capture the extent to which tDCS induces synaptic plasticity may also be useful additions to ongoing trials. That is, one could ask whether tDCS improved the symptom in question, and in parallel ask whether an LTP-type or LTD-type change in regional cortical excitability has occurred.

If so, then perhaps in future trials, the tDCS effect may be augmented by the addition of appropriate pharmacologic agents or behavioral tasks that facilitate synaptic plasticity. As an example, in future trials in which cathodal tDCS may be applied over an epileptic seizure focus, whether LTD-type suppression has occurred over the stimulated area can be determined within hours of tDCS.

However to find out whether seizures are reduced in frequency may take days to weeks. Thus subjects can be stratified into groups that have or have not undergone regional LTD, and clinical outcomes can be evaluated separately for subjects that did and did not experience regional depotentiation. This subclassification of subjects in an epilepsy trial would potentially reduce confounding results from subjects where tDCS was not biologically effective at the time it was administered.

Additionally, investigators would be wise to bear in mind the potential pitfall of choosing outcome scales that are not sufficiently sensitive to capture a relatively modest clinical tDCS effect. Thus, if tDCS strongly changes a component of a larger clinical scale, further research can be stimulated, even if negative results were found initially.

As the brain is under intensive development during childhood and adolescence — particularly the prefrontal cortex , intensive research is currently being made to explore how cognition, emotion, behavior and other functions evolve. Having neuromodulatory properties, tDCS would be an interesting tool to explore which brain areas are particularly important in each stage of development both in healthy and pathological conditions, such as epilepsy, cerebral palsy, autism and mental deficiency.

However because of its potential to induce neuroplastic changes, tDCS should be used carefully especially during important phases of brain development associated with intensive plasticity and also other processes such as synaptic pruning. A further step would be using tDCS for treating neuropsychiatric disorders in children, but this has not been tested yet.

In a review of TMS studies in children, no adverse effects were reported, but its use is still limited for some reasons, including lack of established safety guidelines Notwithstanding, tDCS is a promising tool for children neurology and psychiatry. TDCS is a putative candidate for adjuvant therapy for a range of neuropsychiatric conditions. Studies regarding tDCS ethics reveals its ability to induce changes in behavior such as in moral judgment , deception , and decision-making For instance, one recent study showed tDCS affected utilitarian behavior.

Similarly to other studies in tDCS, the polarity-dependent effects resulted in a selfish vs. Although the effects were short-lasting volunteers were not exposed to daily stimulation , the targeted area is similar than used in studies exploring the long-lasting tDCS effects.

Therefore, the ethical concern is whether tDCS could induce maladaptive behavior changes, and if so, to what intensity and extent of time. Diverse tDCS studies on healthy subjects have shown positive changes in attention and memory 23 , 24 , From the scope of neuroethics, the issue is whether tDCS enhances cognition in healthy subjects. Can tDCS be used to boost performance in specific situations e.

Another issue is thatthe cognitive effects described increased attention and memory from tDCS are in some aspects similar to amphetamines. As a tDCS device is easily built and inexpensive contrary to TMS , it could also be used for non-research and non-therapeutic objectives by lay people.

In fact, there are online videos in popular web sites such as Youtube explaining how to build and use a tDCS device Although it should be underscored that all the enhancement effects were present for a short period of time, it is possible that prolonged daily stimulation could increase the time span of such effects, thus inducing maladaptive changes.

On the other hand other legal substances such as caffeine are also frequently used as cognitive boosters. In fact, because applications in these fields are currently in the research stage, fixed protocols and safety guidelines are yet to be defined. Research and development of any new devices provides an opportunity for brain science and clinical care to advance, and also challenges the medical and wider communities to address potential dangers and complications, ethical and moral quandaries, and issues of healthcare economics and distributive justice.

For innovative neurotechnologies, these are major potential pitfalls to look out for. Intervening in the brain is always fraught with the potential for serious consequences. Despite these concerns, only by conducting carefully planned clinical and experimental studies can we provide the impetus to advance care for people with brain, emotional or psychological, or neuropsychiatric disorders.

The present paper addresses the main aspects of the clinical research of tDCS. This technique has a wide range of potential applications and can be used to explore the basic aspects of neurosciences as well as for the treatment of neuropsychiatric disorders. However, such characteristics also bring challenges regarding clinical design, neuroethics and legal issues. In this paper, we aimed to provide an overview of transcranial direct current stimulation in clinical research; thereby providing knowledge for conducting proper clinical trials using this promising approach.

We are thankful to Erin Connors for copyediting this manuscript. The first meeting was held in Milan, Italy in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Michael A. Dylan J. National Center for Biotechnology Information , U. Brain Stimul. Author manuscript; available in PMC Jul 1. Andre Russowsky Brunoni , Michael A. Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Brain Stimul. See other articles in PMC that cite the published article. Abstract Background Transcranial direct current stimulation tDCS is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity.

Methods We convened a workgroup of researchers in the field to review, discuss and provide updates and key challenges of neuromodulation use for clinical research. Keywords: Transcranial direct current stimulation, brain stimulation, clinical research, physical medicine, neuropsychiatry, medical devices. Introduction The effects of uncontrolled electrical stimulation on the brain have been reported since the distant past.

The electrophysiology of transcranial direct current stimulation 2. Table 1 Pharmacological agents that interact with transcranial direct current stimulation effects on cortical excitability. L-Dopa Dopamine precursor For anodal: excitability turns into inhibition; For cathodal: effects are enhanced 33 Sulpiride D2-receptor blocker Abolishment of tDCS-induced plasticity Pergolide dopamine agonist agent Enhancement of the duration of cathodal tDCS effects , Amino acid metabolism Lorazepam GABA allosteric modulator Anodal effects are delayed, but then enhanced and prolonged.

D-cycloserine NMDA agonist agent Enhancement of the duration of anodal effects; no effects during cathodal stimulation Voltage-sensitive channel blockers Carbamazepine Voltage-sensitive sodium channel blocker Abolishment of the depolarizing effects of anodal tDCS.

Open in a separate window. Box 1 — Insight from tDCS studies on cognition. The clinical research of transcranial direct current stimulation 3. Table 2 Main issues in the clinical research of transcranial direct current stimulation and possible solutions to effectively handle them.

AEs are mild and transient at usual doses. Further research should actively investigate adverse effects; long-term follow-up; modeling studies. Dose- effect curve Higher doses, higher current densities and higher periods of stimulation seem to be associated with effects of larger magnitude and duration. Great between-subjects variability of effects; using higher doses is limited due to AEs; pharmacotherapy alters dose-effect curve; optimal parameters not yet defined.

Further research addressing pharmacological modification of tDCS effects; increasing duration span of tDCS to avoid skin damage; bayesian approaches and modeling studies to define optimal dose. Using multiple referral sources; specific neuromodulation ambulatories; building trust with volunteers and physicians lectures, web sites, explanatory videos Eligibility Sample should be homogeneous, especially in phase II studies.

Sources of heterogeneity are: concomitant use of medications, incorrect diagnosis of neuropsychiatric condition, wide spectrum of severity and refractoriness.

Stratification during randomization; post-hoc analysis controlling for severity, refractoriness and medications; drug washout. Attrition High attrition rates might lead to negative findings; especially if intention-to-treat analyses are performed. Daily visits to the research center and skin damage are specific issues related to dropout in tDCS trials. Careful explanation of study objectives and possible side effects; covering of transportation costs; flexible schedules; using run-in period to identify non-committers.

Methods Blinding Blinding is the strongest approach to minimize bias. Sham TDCS involves applying an electrical current for less than 30 seconds, as to mimic intial side effects.

Several studies suggested that the sham method is reliable, at least in healthy volunteers, with intermediate-high doses and in one-session studies. TDCS device can be turned off manually single-blinded, requiring another person to evaluate subjects or automatically double-blinded.

Further studies should explore whether this sham method is reliable in other contexts, e. Staff blinding should also be more carefully evaluated. Approach To induce long-lasting days to weeks effects, tDCS must be delivered continuously usually daily for 5 to 10 days Number of sessions and time period between stimulations are still undefined as well as the extent of such effects after the initial sessions.

Long follow-up of subjects months to years ; performing specific studies designed to evaluate cumulative changing in cortical excitability according to the number of stimulations and time period between them Control group In tDCS research, the control group might be either a sham-group or an active group in which polarities are inverted. The latter approach is an even more reliable blinding method than sham; although it can as well induce effects.

Studies exploring mechanisms of tDCS could have three groups; studies using tDCS as treatment should prefer using a sham group. Box 3 - Insights from tDCS studies for major depression. Table 3 Substitutive outcomes used in transcranial direct current stimulation research. Outcome Definition Pros Cons Neuropsychological tests Paper or computerized tests that explore cognitive performance. Non-expensive, relatively easy to apply, specific tests can be used according to the brain area under study.

Low signal-to-noise ratio, as performance depends on the rater, the subject's characteristics age, educational level ; learning effects, thus requiring a control group. Relatively non-specific. Strong temporal relationship i. Relatively non-specific measurement of several brain networks and medium to low spatial relationship.

Devices should be adapted to minimize electrical noise of tDCS. Transcranial Magnetic Stimulation TMS TMS used as a tool to index cortical excitability Relatively affordable and easy to apply, provide several measures of cortical excitability.

Measures obtained with TMS have considerable intra and inter-subject variability; usually applied over the motor cortex only. Good temporal relationship, able to index subclinical changes, can be used during "online" tDCS. Poor spatial resolution, invasive, PET is expensive and not always available requires a cyclotron. Not-invasive, excellent spatial and temporal resolution according to the method , specific.

Analyses are difficult and can yield false-positive results, expensive, not always available, tDCS devices and MRI cannot be used simultaneously. Minimally invasive, easy to perform, samples can be frozen and analyzed later, gives a quantitative measurement, sensible to change. Minimal spatial resolution brain metabolites are usually not specific of a particular area , low temporal resolution metabolites must cross the BBB , lack of important biological blood markers in neuropsychiatry.

Box 4 — Challenges for outcome measures in tDCS clinical research. The ethics of transcranial direct current stimulation TDCS is a putative candidate for adjuvant therapy for a range of neuropsychiatric conditions. Conclusion The present paper addresses the main aspects of the clinical research of tDCS.

Acknowledgments We are thankful to Erin Connors for copyediting this manuscript. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.

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Interhemispheric modulation induced by cortical stimulation and motor training. Tolerability will be evaluated using a standardized questionnaire. Follow-up assessments 1 and 6 months after the intervention will examine long-lasting effects. Discussion: The results of this study will provide insights into the changeability of social impairments in ASD by investigating social and emotional abilities on different modalities following repeated sessions of anodal tDCS with an intra-simulation training.

Furthermore, this trial will elucidate the tolerability and the potential of tDCS as a new treatment approach for ASD in adolescents. Keywords: autism spectrum disorder; clinical trial; neuromodulation; social cognition; transcranial DC stimulation.