Transcranial Electrical Stimulation

Abstract

This paper discusses transcranial electrical stimulation (tES) techniques, including transcranial direct Current Stimulation-tDCS, transcranial Alternating Current Stimulation-tACS, transcranial Pulsed Current Stimulation-tPCS, and oscillatory transcranial Direct Current Stimulation-OtDCS, and transcranial Random Noise Stimulation-tRNS. We try to give explanations about each of these techniques. Also, we will discuss their uses in human regeneration, augmentation, and treatment. Our point of view, like the previous article, is to use these stimulations in the form of wearable technology, which is expected to be implemented soon.

Introduction

As discussed in the previous paper, various body organs have different electrical functions. The human brain, as a complex system, also has electrical activity. Not only, the brain oscillation has a different frequency, but also various types of these frequencies have a direct impact on cognitive functions. Many technologies have been developed in recent years that can be used to change the electrical activities of the brain. Also, many studies have shown that different types of transcranial electrical stimulation can directly modulate brain oscillations.

Transcranial electrical stimulation (TES) is non-invasive neuromodulation in which low voltage constant or alternating currents are applied to the human brain via scalp electrodes. This technique can change the underlying structures of the brain. In this technology, weak currents can interact with neural processing, modify plasticity and accommodate brain networks, which in turn can change behavior. In tES we have two kinds of stimulating electrodes, cathode, which is carrying negative charge and anode, which is carrying positive charge.

We have various types of tES, which means that we can manipulate the brain in different ways. They include the transcranial direct Current Stimulation-tDCS, transcranial Alternating Current Stimulation-tACS, transcranial Pulsed Current Stimulation-tPCS, and oscillatory transcranial Direct Current Stimulation-OtDCS, and transcranial Random Noise Stimulation-tRNS. The basis of different technologies is to increase or decrease the function of the brain, which means to stimulate one part and sub-rest the other part.

Transcranial Direct-Current Stimulation (tDCS)

tDCS is a kind of non-invasive neuromodulation that uses low direct current Figure 1. It is a specific device that consists of a battery-powered current generator. It is applied via anodal and cathodal electrodes connecting to the human scalp. Applied over the motor cortex, anodal stimulation enhances, and cathodal stimulation inhibits cortical excitability [1] [2].

The voltage difference between these electrodes can create weak electrical currents that can cross the skull and induce membrane changes in cortical neurons. tDCS relies on the application of a weak direct current of 1–2 mA directly to the scalp through electrodes to induce regional changes in cortical excitability that can last up to a few hours after stimulation [3] [4]. This electrical field reaching the nervous tissues is low and cannot trigger neuronal action potentials. The probability of action potential discharge is assumed to be affected by the generated alterations in resting membrane potential, either towards depolarization (neurons below the anode) or hyperpolarization (neurons underneath the cathode). Furthermore, impacts on cortical excitability may endure longer than the duration of stimulation when enough charge is introduced into the brain (for example, through longer and repeated sessions). [5] [6] [7]

It is possible to adjust the behavioral and neurophysiological effects by changing the parameters, numbers and shape of the electrodes. For example, in tDCS, by changing the position of the electrodes, we will have changes in the intensity of the current and the size of the electrodes. Figure 2 shows different examples of electrode placement, which can be conventional tDCS and HD tDCS. Its normal type works in the form of 1*1, which means that two electrodes including a cathode and anode are placed on the head, which two electrodes can be placed in three different types: anodal, cathodal, or bi-hemispheric. In the anodal mode, the anode is placed on the target location, for example, M1 (the target location is usually determined by EEG) and the cathode is placed either in the supraorbital (SO) area of the opposite side or in an external location such as the shoulder. [9] [10]

HD (high-definition) tDCS (4*1 HD tDCS), in comparison, entails inserting five tiny gel-based disk electrodes into an electroencephalogram recording cap’s cover. Four cathodal electrodes are arranged in a ring-like pattern around an anode in the center. Due to fluctuating electrode impedance, stimulator devices should be current-controlled. [11]

There are two different kinds of tDCS, transcranial mechanism and transcutaneous mechanism Figure 3A. As mentioned, tDCS is used for currents between 1-2 milliamps. These currents pass through the scalp, skull, and cerebrospinal fluid to reach the cerebral cortex. As a result, when the electric field reaches the cortex, it decreases by 0.5V/m. This field is weak for initiating action potentials in cortical neurons, but it can cause subthreshold membrane polarization in neurons, which changes cortical excitability and synaptic plasticity. This is the tDCS transcranial mechanism as described earlier. Now there is another type that can exert its effects through environmental pathways. This type is called the tDCS transcutaneous mechanism, which actually conducts the skin through stronger electric fields of about 20 V/m. This field is strong enough to initiate action potentials in peripheral nerves. As a result, peripheral nerve stimulation activates a large number of other brainstem and limbic structures, such as the locus coeruleus, amygdala, and hippocampus. Norepinephrine is released once the locus coeruleus is activated, and this hormone alters behavior by raising synaptic plasticity and cortical excitability.  Figure 3B [12] [13] [14]

Application of tDCS

Despite the limitations that tDCS has, research is being done on it for numerous of the illnesses. In this paragraph we will have a brief information about the tDCS application in verity of neuropsychiatric conditions [15].

Some paper illustrate that tDCS is a good method for treat major depression (MDD) [16], The dorsal and central neural systems in our brain regulate cognitive control and emotional evaluation, respectively. It is thought that depression is caused by a loss of activity in the connections between certain cortical areas and the limbic system. Impaired attention and other negative emotional reactions may result from reduced ventral system activity and increased dorsal system activity. Now, the research in paper [3] shows that using tDCS helps improve working memory and affective processing and, as a result, has proven the response rates of clinical depression. All of them are possible by connecting the electrodes over the dorsal region of the brain and boosting the activity of the left area. Also a few studies have been shows the effect of that on attention deficit and hyperactivity disorder (ADHD), bipolar disorder (BD), schizophrenia, obsessive compulsive disorder (OCD), and bipolar disorder (BD) [17]. Furthermore, in paper [18] they have used tDCS to improve cognitive functions such as language and memory attention. They show that [19] [20] decision-making in young and elderly participants have been improved with using tDCS. Also, variety of studies such as [21] [22] demonstrated that tDCS helps the improvement of long- term memory, working memory and learning in the healthy individuals. In systematic review [5] they have investigated 27 different trials of tDCS in people with epilepsy. They observed that tDCS has a direct impact on epilepsy. It has a significant decrease in clinical seizures. Fibromyalgia is a debilitating condition characterized by widespread chronic pain. It is believed to be caused by central nervous system dysfunction (CNS), but current treatments are largely ineffective. Transcranial Direct Current Stimulation (tDCS), a neuromodulation technique that targets the CNS, may offer a new line of therapy. [23]

Transcranial Alternating Current Stimulation (tACS)

As tDCS, it is a neuromodulatory technique, but the difference is that it applies oscillates to a sinusoidal current, waveform is shown in Figure 4. Transcranial Alternating Current Stimulation (tACS) passes this current through the electrodes to the brain. This technique can be used for treatment or boosting brain function. It allows to modulate brain oscillation directly [24]. Brain oscillations happen continuously in the brain and it has a direct impact on our feel, think, and it exactly related to the brain functions.

The alternating current changes continually between cathode and anode. Then, the current is going backwards and forwards between the two sides rather than being constant in direction. It does not have a fixed anode or cathode stimulation. The electrical current is continually changing direction between the two stimulating pads.

The two most important factors affecting the clinical application of tACS are the limited intensity of stimulation and the difficulty of accurately focusing the stimulating electric field.

The common transcranial electrical stimulation challenges are that the scalp will divert a significant portion of the current supplied during electrical stimulation, entirely passing the brain and reducing the intensity of the electric field in the target area. One of the methods suggested in paper [26] is optimizing the number of electrodes for increasing brain stimulation accuracy. As a matter of fact, the changes in the electrode and current properties have a significate effect on improving the degree of focus during stimulation . They [25] [12]define two different methods for optimization, the first one is high-definition electrical stimulation methods, and the second is interference modulation methods.

In the first method for increasing the focus, replace the large electrodes with some small electrodes in order to boost the focusing effect Figure 5b. For another method, the mode of stimulation changes, which means that in this method, the specific waveform created at the point of the brain through the mutual interference of two or more electrode signals to meet the requirements of non-invasive deep brain stimulation [27] [28]. This method can be divided into five different ways, as shown in Figure 5, and each of them has a different and separate application. Figure 5c shows the phase-shifted tACS, in which two blue and one black region are for anodes and cathode, respectively, and the anode electrodes are only various in the phase. Figure 5D shows the amplitude modulation tACS (AM-tACS). The difference between this method with phase-shift tACS is the difference in the frequency of stimulus signals. According to the AM-tACS, a low-frequency envelope is created by the interference of two sine waves with differing frequencies. In Figure 5E, the shape of TI stimulation is shown.

Compared with AM-tACS, return electrodes in this method are separate, and their frequency is about kHz. Studies have shown that this stimulation method can stimulate the brain’s deep part without affecting the cerebral cortex. The ability of this method has been confirmed in vivo experiments. In this method, in fact, two high-frequency signals interfere and create a low-frequency electrical signal, which is the signal that affects the neurons of the brain. Figure 5F demonstrates Intersectional Short Pulse Stimulation. This method, compared to the previous methods, we do not add brain areas for stimulation, and what happens is that the stimulation signals of different phases are used at the same point at different times. Multiple pairs of electrodes are used to alternately transmit the stimulation current, and the surface layer of the brain is stimulated discontinuously in time, the schematic diagram of these methods are shown in Figure 6.

As a result, by using these methods, it is possible to improve factors such as the limited intensity of stimulation and the difficulty of accurately focusing the stimulus, which is one of the important and effective factors in the clinical applications of tACS. [29]

The application of tACS is to treat brain disease and boost brain function. Depression, Parkinson’s, tumor retardation, motor performance, cognitive enhancement is some of area that tACS can have an effect on them. In following we bring up examples for different kinds of tACS [30].  It illustrates the effect of HD-tACS on 24 persons. In this study, they put the electrodes on P3 and P4 with the intensity of 10Hz and 20 Hz for 20 min; the main outcome was increasing the alpha activity in the parietal lobe. The experience in 7 humans was done in 2020 [31], they have used AM-tACS for 4.5 minutes. The location of the parameter was over CPz, and below Oz, the parameter of the stimulation was 2mA, 500 Hz carrier, and 10 Hz envelope signal, and the main outcome of this research was SASS (Stimulation Artifact Source Separation, SASS) can be used to establish adaptive (closed-loop) AM-tACS. In paper [27] they have used the Temporally interfering stimulation Figure 7, the experience was done on mouse with the 2kHz/2.01 kHz and 125 µA, for 20 minutes. They understood, by altering the currents delivered to a set of immobile electrodes, we can directly evoke different motor patterns in living mice.

Other study was done with the intersectional short pulse stimulation with the 3 mm posterior from Bregma and 2 mm lateral of the midline. They have used 10, 100, and 1000 Hz frequency with different amplitudes 10, 20, 50, 100, and 200 µA. The outcome of the study was, when high-intensity current is injected into the brain, the charge density and sensation on the scalp surface are relatively low [28].

This article [29]  states that tACS can be used for neurological intervention. While continuous neuronal dynamics are impacted by synaptic activity and membrane potential, perception, cognition, and consciousness can all be affected by oscillating neural activity.

Distinct types of cognitive functions are linked to different frequencies of brain oscillations. This connection has been supported by research including intracranial stimulation, pharmacological interventions, and lesion studies. The advent of new non-invasive brain stimulation techniques, such as transcranial alternating current stimulation (tACS), makes it possible to modulate brain oscillations directly. A growing number of studies on the sensory, motor, and even higher cognitive processing demonstrate the effectiveness of tACS in modulating persistent rhythmic activity in the human brain, which in turn affects behavior. Interestingly, it has been shown that the oscillation phase also plays an important role in addition to amplitude and frequency. These studies have shown a causal relationship between brain oscillations with a specific frequency and a specific cognitive process. Therefore, when brain oscillations are manipulated, the cognitive function associated with it is also changed. Animal studies have shown that sinus currents can entrain endogenous brain oscillations [24].

Transcranial Pulsed Current Stimulation (tPCS)

transcranial pulsed current stimulation is a non-invasive technique to modulate oscillatory neural activity. This technique can modulate the rhythmic activity of the brain. This method causes reversible excitability changes in the human cortex. In tPCS we have two additional parameters which are “pulse duration (PD)” and “inter-pulse interval (IPI),”. In this method the tDCS interrupt. Actually, as you can see in Figure 8 instead of a continuous flow of direct current as in tDCS, the current flows in unidirectional pulses that are spaced apart by an IPI. This technique involves anodal tDCS (a-tDCS), which depolarizes the resting membrane potential and increases excitability by placing an anode over the targeted brain region. On the other hand, cathodal tDCS (c-tDCS), which applies cathode over the targeted region of the brain, hyperpolarizes the resting membrane potential and reduces excitability [32].

In comparison with tDCS which regulate the neuronal excitability by tonic depolarization of the resting membrane potential, tPCS, regulates neuronal excitability through a combination of tonic and phasic effects. Sometime when the direct current converts to pulse current it will have the number of benefits. For instance in paper [33] they shows that tPCS is a novel technique to boost corticospinal excitability.

It can be said that tPCS exert their effects not only by polarity-dependently modulating the motor cortex’s basal activity, but also by inducing voltage-carrying proteins in the membrane of M1 neurons through the on-off nature of the pulses. The physiological mechanisms underlying these effects, however, have not yet been identified. The activation of the cortex in this method can be different and influence by variation of the size and position of electrodes over the head. Also, in [34] brig up the anatomy of the region, intensity and frequency of the pulse, output waveforms (monophasic vs. biphasic) and the intervals between the pulses are significant too. As it shows in Figure 8 tPCS can be divided to inter-pulse intervals and long intervals.

This method is well-established for boosting brain performance in both healthy individuals and patients with neurological problems. It has been engaged in several significant discoveries in the field of human cortical function [35] [36] [37]. Furthermore, the direction of corticospinal excitability (CSE) changes depends on the polarity of the active electrode. A recent systematic review and meta-analysis of the efficacy of a-tDCS in healthy individuals and people with stroke indicated a-tDCS effectively enhances CSE and motor performance [38]  Paper [34] shows a-tPCS can be used as a method to deliver cranial stimulation to modulate M1 regions, also an efficient method for neuroplasticity research. In this article [36], also they showed that tPCS can be used as a tool to investigate human brain fluctuations. It is a tool to investigate the clinical neuroplasticity for modulation of corticospinal excitability. Using monophasic anodal and cathodal tPCS at theta and gamma frequencies, they illustrate the ability of stimulation to modulate brain activity.

Transcranial Random Noise Stimulation (tRNS)

tRNS (Transcranial random noise stimulation) is a specific type of tACS which introduce in 2008 in paper [39]  In tRNS, a modest electrical current oscillates at random frequencies to electrically stimulate the brain in a non-invasive manner. Its frequency spectrum ranges from 0.1 to 640 Hz and is separated into two groups: If-tRNS (low frequency) between 0.1 and 100 Hz, and hf-tRNS (high frequency) between 101 and 640 Hz. Waveform is shown in Figure 9.

The modulation effects in this technique include the high frequency band. Many research shows that it is an effective method for cognitive, motor and sensory tasks. For instance, this paper illustrates the research of sensory or perceptual processing in which hf-tRNS can enhance the perception of face expression of emotions and can improve visual detection or discrimination. And also, research on cognitive ability shows that use of hf-tRNS for boosting the arithmetic skills and calculation. By the way, it can be used for Parkinson’s disease by reducing motor cortex excitability, decreasing the depressive symptoms and treatment schizophrenia. It also has a hopeful effect on increasing the perceptual and motor learning. In this study [33], it was shown that using tRNS can improve pain and cognitive impairment that is common in patients with multiple sclerosis (MS). The results of this experiment showed that the use of tRNS is useful in modulating pain and it becomes more evident with the use of long-term stimulation.

The motor cortex is subjected to a random electrical oscillation spectrum using tRNS. For 60 minutes following stimulation, tRNS causes sustained excitability. This enhanced excitability appears to be caused by higher frequencies (100–640 Hz), which may be explained by the frequent opening of Na channels. Similar to tDCS, this technique is effective in treating conditions including depression [39].

The purpose of this article [40] is to review the existing research on electrical noise’s effects at the cellular, systemic, and behavioral levels and to explore how to apply this new technique to improve the human nervous system’s ability to operate cognitively and motorically. In this research, they examine how noise stimulation affects intracellular and animal models. They also look at the immediate online advantages of tRNS when administered to the sensory or motor cortex, as well as its offline effects. We tie these findings to research suggesting that one key cellular substrate for mediating these effects of tRNS may be the activation of voltage-gated sodium ion channels. In order to provide both (1) offline effects in the form of long-lasting increases in cortical excitability and (2) acute online noise benefits, tRNS may boost the efficiency of neuronal signal transmission and processing.

Oscillatory Transcranial Direct Current Stimulation (otDCS)

As mentioned earlier, frequency-modulated tDCS protocols can mimic natural neural rhythms that enhance physiological activity and affect memory functions. It was also mentioned in the previous section that standard tDCS uses a constant current intensity to form an electric field between anode and cathode electrodes to modulate the resting membrane potential and thereby affect the excitability of the cerebral cortex. However, oscillating tDCS (otDCS) protocols, in which the current oscillates around a specified value (positive or negative), have been developed. This technique, with the rhythmic change of the intensity of the current, in addition to the unspecified change of excitability, will bring certain natural neural rhythms. activity (such as gamma or theta rhythm) to enhance central nervous system functions that are assumed to be mediated by these oscillatory activities [41] [42].

Complex waveforms can be created by combining oscillations and DCs. In oscillatory tDCS (otDCS) the current is oscillating around a certain value (positive and negative), this method includes both AC and DC elements, which simultaneously modulate the potential and oscillatory activity of nerve membranes. [43] Figure 10 shows the waveform of OtDCS. It can be said that these current intensity changes can bring certain natural neural rhythms, in addition to unspecified changes in excitability. activity (such as gamma or theta rhythm) to enhance central nervous system functions that are assumed to be mediated by these oscillatory activities. More precisely, this approach can modulate oscillatory activity in two ways—both directly, through frequency-specific domain modulation (eg, the AC effect), and indirectly through DC effects on cortical excitability [44]. The endogenous rhythms of the cerebral cortex are effectively determined by these combined actions. Therefore, otDCS might be a practical way to improve corticospinal oscillatory connectivity [45]. And also, it worth mentioning that both of these effects have an impact on boosting the theta activity.

In this paragraph we assert some of the application of this technique. although, it needs more time for research. In this study, at first, they show that oscillatory tDCS [45]  [46]  can be used for modulation, furthermore, they investigate the effect of otDCS on improving memory by augmenting theta oscillations. In another research they demonstrate that otDCS boost the corticomuscular coherence and motor-evoked potentials (MEPs) [47].

This study [48] demonstrates that theta oscillatory modulated anodal tDCS improves associative memory (AM) and it does so more effectively than sham stimulation. Some participants responded more favorably to theta oscillatory tDCS than to tDCS, which may be related to their various physiological conditions.

The ability to recall and access a variety of connected experiences or pieces of information is known as associative memory (AM). With their convergent connections to the hippocampus, association regions of the parietal, frontal, and temporal cortex are key players in this process. Loss of associative memory is one of the most obvious symptoms of dementia and mild cognitive impairment as well as normal cognitive aging. Therefore, strengthening associative memory is one of the most important challenges in neurocognitive rehabilitation. [49] [50] [51]

Conclusion

The goal of transcranial electrical stimulation (tES) is to change brain function non-invasively by applying current to electrodes on the scalp. Due to the advancements in technology, various models of tES methods have been developed for various purposes such as augmentation, treatment, and regeneration. These methods include transcranial direct Current Stimulation-tDCS, transcranial Alternating Current Stimulation-tACS, transcranial Pulsed Current Stimulation-tPCS, and oscillatory transcranial Direct Current Stimulation-OtDCS, and transcranial Random Noise Stimulation-tRNS which can be used as wearables for various purposes shortly.