Transcranial direct-current stimulation

Transcranial direct-current stimulation

tDCS administration. Anodal (b) and cathodal (c) electrodes with 35-cm2 size are put on F3 and right supraorbital region, respectively. A head strap is used (d) for convenience and reproducibility, and a rubber band (e) for reducing resistance.
MeSH D065908

Transcranial direct current stimulation (tDCS) is a form of neurostimulation that uses constant, low current delivered to the brain area of interest via electrodes on the scalp. It was originally developed to help patients with brain injuries or psychiatric conditions like major depressive disorder. tDCS appears to have some potential for treating depression.[1][2] However, there is no good evidence that it is useful for cognitive enhancement in healthy people,[3][4] memory deficits in Parkinson's disease and Alzheimer's disease,[5] schizophrenia,[6] non-neuropathic pain,[7] nor improving upper limb function after stroke.[8][9]

Medical use

tDCS appears to be somewhat effective for depression.[2]

Safety

The adverse effects associated with tDCS appear to be mostly limited to headaches and itchiness and redness at the site of stimulation.[10] When applied following established safety protocols, transcranial direct current stimulation is widely regarded as a safe method of brain stimulation. Safety protocols limit the current, duration, and frequency of stimulation, thereby limiting the effects and risk.

Safety protocol

There has been much work done in the last 10 years to develop a safety protocol for administering transcranial direct current stimulation. Many studies have been conducted to determine the optimal time of stimulation and current used as well as steps to take in order to reduce or eliminate the side effects felt by the person receiving the stimulation. Present safety guidelines on the research and medical fields treat daily stimulation up to 60 min and up to 4 mA as safe.[11] However, the tolerability of every day application for more than 10 sessions per two weeks remains unclear.

Studies have been completed to determine the current density at which overt brain damage occurs in rats. It was found that in cathodal stimulation, a current density of 142.9 A/m2 delivering a charge density of 52400 C/m2 or higher caused a brain lesion in the rat. This is over two orders of magnitude from what is currently being used.[12][13][14]

There is no strict limitation on the duration of stimulation set at this point but a stimulation time of 20 minutes is considered the ideal time. The longer the stimulation duration, the longer the observed effects of the stimulation persist once the stimulation has ended. A stimulation length of 10 minutes results in observed effects lasting for up to an hour.[15]

It is generally encouraged to wait at least 48 hours to a week before repeating the stimulation. Also, it is advised to warn the person receiving the stimulation of the possible after effects of the tDCS stimulation.[15]

These studies indicate that transcranial direct current stimulation is safe in a single session. However, no studies have evaluated the long-term safety of repeated sessions of stimulation.

Side effects of stimulation

There are a few minor side effects including skin irritation, a phosphene at the start of stimulation, nausea, headache, dizziness, and itching under the electrode.[16] Nausea most commonly occurs when the electrodes are placed above the mastoid for stimulation of the vestibular system. A phosphene is a brief flash of light that can occur if an electrode is placed near the eye.[15] A recent study of over 500 subjects using the currently accepted protocol reported only a slight skin irritation and a phosphene as side effects.[12]

There are several ways to reduce the skin irritation felt during stimulation. Electrodes may be prepared with saline solution and the skin prepared with electrode cream. Also, ramping up (slowly increasing) the current can reduce the irritation.[17]

Risks

It is not advised to administer this stimulation to people susceptible to seizures, such as people with epilepsy. However, seizures do not seem to be a risk for healthy individuals.[15]

Mechanism of action

One of the aspects of tDCS is its ability to achieve cortical changes even after the stimulation is ended. The duration of this change depends on the length of stimulation as well as the intensity of stimulation. The effects of stimulation increase as the duration of stimulation increases or the strength of the current increases.[18] The way that the stimulation changes brain function is either by causing the neuron’s resting membrane potential to depolarize or hyperpolarize. When positive stimulation (anodal tDCS) is delivered, the current causes a depolarization of the resting membrane potential, which increases neuronal excitability and allows for more spontaneous cell firing. When negative stimulation (cathodal tDCS) is delivered, the current causes a hyperpolarization of the resting membrane potential. This decreases neuron excitability due to the decreased spontaneous cell firing.[15][19]

Neuroplasticity refers to the ability of the brain to change throughout life based on experiences. The way that transcranial direct current stimulation functions could be due to the plasticity concepts of long term potentiation (LTP) and long term depression (LTD) since the two share some basic similarities. Long term potentiation is strengthening of the connection between two neurons while long term depression is weakening of the connection between two neurons. These effects are achieved mainly through an alteration of synaptic transmission ability. LTP enhances transmission and LTD hinders transmission. Likewise, tDCS stimulation involves the alteration of synaptic transmission ability through modifications of intracellular cAMP and calcium levels, as well as glial activation.[20] Also, both LTP, LTD, and the effects of tDCS are protein synthesis dependent. It is for these reasons that LTP and LTD are proposed mechanisms of the function of tDCS.[15][19]

Operation

Transcranial direct current stimulation works by sending constant, low direct current through the electrodes. When these electrodes are placed in the region of interest, the current induces intracerebral current flow. This current flow then either increases or decreases the neuronal excitability in the specific area being stimulated based on which type of stimulation is being used. This change of neuronal excitability leads to alteration of brain function, which can be used in various therapies as well as to provide more information about the functioning of the human brain.[15]

Parts

Transcranial direct current stimulation is a relatively simple technique requiring only a few parts. These include two electrodes and a battery-powered device that delivers constant current. Control software can also be used in experiments that require multiple sessions with differing stimulation types so that neither the person receiving the stimulation nor the experimenter knows which type is being administered. Each device has an anodal, positively charged electrode and a cathodal, negative electrode. Current is "conventionally" described as flowing from the positive anode, through the intervening conducting tissue, to the cathode, creating a circuit. Note that in traditional electric circuits constructed from metal wires, current flow is created by the motion of negatively charged electrons, which actually flow from cathode to anode. However, in biological systems, such as the head, current is usually created by the flow of ions, which may be positively or negatively charged—positive ions will flow towards the cathode; negative ions will flow toward the anode. The device may control the current as well as the duration of stimulation.[21]

Setup

To set up the tDCS device, the electrodes and the skin need to be prepared. This ensures a low resistance connection between the skin and the electrode. The careful placement of the electrodes is crucial to successful tDCS technique. The electrode pads come in various sizes with benefits to each size. A smaller sized electrode achieves a more focused stimulation of a site while a larger electrode ensures that the entirety of the region of interest is being stimulated.[22] If the electrode is placed incorrectly, a different site or more sites than intended may be stimulated resulting in faulty results.[15] One of the electrodes is placed over the region of interest and the other electrode, the reference electrode, is placed in another location in order to complete the circuit. This reference electrode is usually placed on the neck or shoulder of the opposite side of the body than the region of interest. Since the region of interest may be small, it is often useful to locate this region before placing the electrode by using a brain imaging technique such as fMRI or PET.[15] Once the electrodes are placed correctly, the stimulation can be started. Many devices have a built-in capability that allows the current to be "ramped up" or increased gradually until the necessary current is reached. This decreases the amount of stimulation effects felt by the person receiving the tDCS.[17] After the stimulation has been started, the current will continue for the amount of time set on the device and then will automatically be shut off. Recently a new approach has been introduced where instead of using two large pads, multiple (more than two) smaller sized gel electrodes are used to target specific cortical structures. This new approach is called High Definition tDCS (HD-tDCS).[22][23] In a pilot study, HD-tDCS was found to have greater and longer lasting motor cortex excitability changes than sponge tDCS.[24]

Types of stimulation

There are three different types of stimulation: anodal, cathodal, and sham. The anodal stimulation is positive (V+) stimulation that increases the neuronal excitability of the area being stimulated. Cathodal (V-) stimulation decreases the neuronal excitability of the area being stimulated. Cathodal stimulation can treat psychological disorders that are caused by the hyper-activity of an area of the brain.[25] Sham stimulation is used as a control in experiments. Sham stimulation emits a brief current but then remains off for the remainder of the stimulation time. With sham stimulation, the person receiving the tDCS does not know that they are not receiving prolonged stimulation. By comparing the results in subjects exposed to sham stimulation with the results of subjects exposed to anodal or cathodal stimulation, researchers can see how much of an effect is caused by the current stimulation, rather than by the placebo effect.

History

Discovery

The basic design of tDCS, using direct current (DC) to stimulate the area of interest, has existed for over 100 years. There were a number of rudimentary experiments completed before the 19th century using this technique that tested animal and human electricity. Luigi Galvani and Alessandro Volta were two such researchers that utilized the technology of tDCS in their explorations of the source of animal cell electricity. It was due to these initial studies that tDCS was first brought into the clinical scene. In 1801, Giovanni Aldini (Galvani's nephew) started a study in which he successfully used the technique of direct current stimulation to improve the mood of melancholy patients.[26] Aldini gave a detailed account of his treatments of melancholy patient Luigi Lanzarini and also described the stunning result when he first tried the treatment on his own head:

First, the fluid took over a large part of my brain, which felt a strong shock, a sort of jolt against the inner surface of my skull. The effect increased further as I moved the electric arcs from one ear to the other. I felt a strong head stroke and I became insomniac for several days.[26]

Transition into modern scientific research

There was a brief rise of interest in transcranial direct current stimulation in the 1960s when studies by researcher D. J. Albert proved that the stimulation could affect brain function by changing the cortical excitability.[27]:49–64 He also discovered that positive and negative stimulation had different effects on the cortical excitability.[27]:65–77 It wasn’t until recently that interest in tDCS was reignited. This time, the rediscovery was fueled by an increase of interest and understanding of basic brain functioning, therapeutic application, as well as new brain stimulation and brain imaging techniques such as TMS and fMRI. Now, Transcranial direct current stimulation is beginning to be used more frequently as a brain stimulation technique because, with proper safety protocols, tDCS is safe for human use.[18][15]

Comparison to other devices

Transcranial electrical stimulation techniques. While tDCS uses constant current intensity, tRNS and tACS use oscillating current. The vertical axis represents the current intensity in milliamp (mA), while the horizontal axis illustrates the time-course.

TMS

While the tDCS method is gaining interest, the most commonly used method of brain stimulation is transcranial magnetic stimulation (TMS). This technique of brain stimulation utilizes an electric coil held above the region of interest on the scalp that uses rapidly changing magnetic fields to induce small electrical currents in the brain. There are two types of TMS: repetitive TMS and single pulse TMS. Both are used in research therapy but effects lasting longer than the stimulation period are only observed in repetitive TMS. Similar to tDCS, an increase or decrease in neuronal activity can be achieved using this technique, but the method of how this is induced is very different. Transcranial direct current stimulation has the two different directions of current that cause the different effects. Increased neuronal activity is induced in repetitive TMS by using a higher frequency and decreased neuronal activity is induced by using a lower frequency.

Both TMS and tDCS are painless and considered safe for human use. However TMS is more expensive, difficult to sham, and may need a trained coil holder, whilst tDCS is relatively easy to apply. Transcranial magnetic stimulation causes the neuron’s action potentials to fire, resulting in a stronger effect. Since tDCS only causes increased spontaneous cell firing, it does not have as big of an effect. One benefit of tDCS when compared to TMS is that due to the smaller effect, there is a much smaller chance of causing seizures in the person receiving the stimulation.[21]

Other types of stimulation

Variants related to tDCS include tACS, tPCS and transcranial random noise stimulation (tRNS),[28] a group of technologies commonly referred to as transcranial electrical stimulation, or TES.

Research

In 2016 European meta analysis has found level B evidence (probable efficacy) for fibromyalgia, depression and craving.[29]

A 2015 study that reviewed results from hundreds of tDCS experiments found that there was no statistically conclusive evidence to support any net cognitive effect, positive or negative, of single session tDCS in healthy populations - there is no evidence that tDC is useful for cognitive enhancement.[3] A second study by the same authors found there was little-to-no statistically reliable impact of tDCS on any neurophysiologic outcome.[4]

A few clinical trials have been conducted on the use of tDCS to ameliorate memory deficits in Parkinson's disease and Alzheimer's disease and healthy subjects, with mixed results.[5]

As of 2014 there have been several small randomized clinical trials (RCT) in major depressive disorder (MDD); most found alleviation of depressive symptoms. There have been only two RCTs in treatment-resistant MDD; both were small, and one found an effect and the other did not.[30] One meta-analysis of the data focused on reduction in symptoms and found an effect compared to sham treatment, but another that was focused on relapse found no effect compared to sham.[30]

Research conducted as of 2013 in schizophrenia has found that while large effect sizes were initially found for symptom improvement, later and larger studies have found smaller effect sizes (see also section on use of tDCS in psychiatric disorders below). Studies have mostly concentrated on positive symptoms like auditory hallucinations; research on negative symptoms is lacking.[6]

Research conducted as of 2012 on the use of tDCS to treat pain, found that the research has been of low quality and cannot be used as a basis to recommend use of tDCS to treat pain.[7] In chronic pain following spinal cord injury, research is of high quality and has found tDCS to be ineffective.[31]

In stroke, research conducted as of 2014 has found that tDCS is not effective for improving upper limb function after stroke.[8][9] Research conducted as of 2015 suggests tDCS may be effective for improving post-stroke aphasia.[9][32] Research conducted as of 2013 suggests that tDCS may be effective for improve vision deficits following stroke.[9]

tDCS has also been studied in various psychiatric disorders such as depression,[33][34][35][36][37][38] and to reverse cognitive deficits in schizophrenia.[39] Some researchers are investigating potential applications such as the improvement of focus and concentration.[40] tDCS has also been studied in addiction.[41][42]

tDCS has also been used in neuroscience research, particularly to try to link specific brain regions to specific cognitive tasks[43] or psychological phenomena.[44] The cerebellum seems of particular interest in research, due to its high concentration of neurons, its location immediately below the skull, and its multiple reciprocal anatomical connections to motor and associative parts of the brain.[45] Although the exact mechanisms subserving cerebellar tDCS remain to be clarified, the number of studies applying tDCS over the cerebellum is exponentially growing. The majority of studies focus on the impact of cerebellar tDCS on motor, cognitive, and affective functions in healthy and patient populations, but some also employ tDCS over the cerebellum to study the functional connectivity of the cerebellum to other areas of the brain.[46]

Regulatory approvals

As of 2015, tDCS has not been approved for any use by the US FDA.[32] An FDA briefing document prepared in 2012 stated that "there is no regulation for therapeutic tDCS".[47] tDCS is a CE approved treatment for Major Depressive Disorder (MDD) in Europe.

See also

References

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  42. ↑ Jansen, JM; Daams, JG; Koeter, MW; Veltman, DJ; van den Brink, W; Goudriaan, AE (December 2013). "Effects of non-invasive neurostimulation on craving: A meta-analysis.". Neuroscience and biobehavioral reviews. 37 (10 Pt 2): 2472–80. PMID 23916527. doi:10.1016/j.neubiorev.2013.07.009.
  43. ↑ Harty S, Robertson IH, Miniussi C, Sheehy OC, Devine CA, McCreery S, O'Connell RG (Mar 2014). "Transcranial direct current stimulation over right dorsolateral prefrontal cortex enhances error awareness in older age.". J Neurosci. 34: 3646–52. PMID 24599463. doi:10.1523/JNEUROSCI.5308-13.2014.
  44. ↑ Grimaldi G, et al Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease. Neuroscientist. 2014 Nov 18. doi:10.1177/1073858414559409 PMID 25406224
  45. ↑ van Dun, Kim; Bodranghien, Florian C. A. A.; Mariën, Peter; Manto, Mario U. (2016-01-01). "tDCS of the Cerebellum: Where Do We Stand in 2016? Technical Issues and Critical Review of the Literature". Frontiers in Human Neuroscience. 10: 199. PMC 4862979 Freely accessible. PMID 27242469. doi:10.3389/fnhum.2016.00199.
  46. ↑ van Dun, Kim; Bodranghien, Florian; Manto, Mario; Mariën, Peter (2016-12-28). "Targeting the Cerebellum by Noninvasive Neurostimulation: a Review". The Cerebellum: 1–47. ISSN 1473-4222. doi:10.1007/s12311-016-0840-7.
  47. ↑ "FDA Executive Summary - Petitions to Request Change in Classification for Cranial Electrotherapy Stimulators" (PDF).
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