Research progress of tDCS in the treatment of ADHD

Abstract

TDCS is one of the most widely used non-invasive neuromodulation techniques, which changes the excitability of local cortical tissue by applying weak continuous direct current to the scalp, effectively improves the attention and concentration of ADHD children, and improves the impulse disorder of patients, but related research is still in its infancy. Based on a review of a large number of existing literatures and an analysis of the pathogenesis and principle of ADHD, this paper summarized the research on tDCS in the treatment of ADHD in recent years from the aspects of treatment mechanism, safety and stimulation parameters, and simply compared the application of tDCS with other non-traumatic neuromodulation techniques in the treatment of ADHD. The future development direction of this technology is further discussed.

Introduction

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders in child and adolescent psychiatry. In the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the symptoms defined by ADHD are divided into inattention and hyperactivity/impulsiveness. The 11th edition of the International Classification of Diseases (ICD-11) distinguishes five subtypes of ADHD that match DSM-5: ADHD with combined manifestations, ADHD with inattention as the main manifestation, ADHD with hyperactivity/impulsiveness as the main manifestation, and ADHD with other specific manifestations and ADHD without specific manifestations (Drechsler et al. 2020). ADHD is easily misdiagnosed because it is often complicated with learning disabilities and overlaps with slow cognitive rhythm and emotional disorder(Salvi et al. 2021) The prevalence rate of children and adolescents in the world is slightly different from that of adults, ranging from 5% to 7.2%(Bandeira et al. 2016) for children and from 1 to 10% for adults (Polanczyk et al. 2014, 2007; Schertz et al. 2022; Kian et al. 2022).; The prevalence rate in high-income countries is higher than that in low-income countries(Solmi et al. 2022; Faraone et al. 2006; Cénat et al. 2021), and the prevalence rate of boys is higher than that of girls, with a ratio of about 2-4: 1(Magnin and Maurs 2017; Davies 2014; Cabral et al. 2020). However, the male-female ratio of adult patients is close, with a ratio of about 1: 1(Abdelnour et al. 2022). This may be because most girls with ADHD do not have externalized behavior problems, which leads to insufficient diagnosis, so the prevalence rate of boys and girls needs further verification (Rucklidge 2010).Although there has been some remission, a large part of ADHD symptoms in childhood will continue into adulthood (张婕 et al. 2023) Some past studies tend to believe that adult ADHD is a continuation of childhood ADHD, but some recent studies believe that adult ADHD and child ADHD may have two different developmental paths. depending on the age of onset Not all adult ADHD develops from childhood ADHD(Thapar and Cooper 2016).Having ADHD as a child and continuing to this day is known as persistent attention deficit hyperactivity disorder (ADHD), and not having symptoms until adulthood is known as delayed ADHD (Caye et al. 2016). No matter what kind of adult ADHD, the high incidence of complications (Agnew-Blais et al. 2018) will lead to various social dysfunction, which will cause significant injuries and pains in the whole life cycle of patients, increase the risks of various crimes, suicides and teenage pregnancy, and bring heavy burdens to individuals, families and society, so ADHD and its treatment have attracted more and more attention from the society.

The treatment methods of ADHD include multimodal therapy, drug therapy, cognitive behavioral therapy, neuropsychological therapy and noninvasive brain stimulation (Drechsler et al. 2020). At present, the most successful clinical treatment is psychotropic drugs, but ADHD drugs usually have certain side effects and adverse reactions. The accumulated data show that ADHD drugs can cause serious adverse cardiovascular reactions and increase blood pressure. Stimulants have low efficacy in young children, are addictive and abused in adults, and the long-term treatment cost is too high. There is no randomized trial evidence to prove the long-term safety of drug therapy (Bjerkeli et al. 2018; Torres-Acosta et al. 2020; Rubia 2022) Cognitive behavioral therapy mostly needs to be combined with drug therapy in a repetitive way,and the operation is complicated, but the effect of neurofeedback therapy on attention is not significant, and the existing evidence can not support that neurofeedback is an effective treatment for ADHD (Cortese et al. 2016). The most effective evidence-based strategy for multimodal therapy to control the core symptoms of ADHD is the combination of stimulant drugs and behavioral therapy (BT) or cognitive behavioral therapy (CBT), as well as group-based parental psychological education, but there is no evidence to prove that multimodal therapy is obviously superior to drug therapy alone (Ogundele and Ayyash 2023). Due to the side effects and adverse reactions of ADHD drugs, the public has doubts about the management of ADHD,both parents and clinicians are reluctant to use ADHD medications and often prefer non-pharmacological treatments More and more research began to focus on the development of non-drug therapy. In recent years, non-invasive brain stimulation therapy has been increasingly applied to ADHD, the most prominent being repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Some evidence suggests that non-invasive brain stimulation therapy may provide an alternative to stimulant medications for ADHD (Westwood et al. 2021), and compared with rTMS, tDCS has higher safety and tolerance, which is more suitable for pediatrics. This paper aims to further elaborate the latest research progress of tDCS in the treatment of ADHD, and provide more evidence for the clinical intervention and treatment of tDCS in children with ADHD.

Neurobiological Basis of ADHD

Although the etiology and pathogenesis of ADHD are not completely clear, the current consensus shows that it is caused by the accumulation of genetic and environmental factors (Thapar and Cooper 2016; Drechsler et al. 2020; Austerman 2015; Tripp and Wickens 2009). At present, neuroimaging of ADHD has found that there are structural or functional brain injuries in the neural circuits involved in behavioral perception and cognitive processes in ADHD patients, especially in the neural circuits of prefrontal lobe, striatum and cerebellum. Magnetic resonance imaging (MRI) found that the overall intracranial volume of children and adolescents with ADHD was smaller than that of the control group and other patients, and the local structure changed, and the volume of basal ganglia area decreased, although all the differences observed were relatively small (Hoogman et al. 2017, 2019; Li et al. 2021; Boedhoe et al. 2020). Many reports show that the striatum of ADHD patients is small, the difference of striatum structure between ADHD individuals and control groups decreases with age, and hyperactivity-impulsiveness symptoms also decrease, which may be the reason why the prevalence of ADHD in childhood is higher than that in adults, but it cannot explain why some patients' symptoms persist into adulthood.

Studies on cortical thickness and surface area found that the surface area of ADHD patients, especially in the frontal lobe, cingulate cortex and temporal lobe, was smaller than that of the control group (Lukito et al. 2020; Hoogman et al. 2019). The cortex of fusiform gyrus and temporal pole in children is thinner than that in the same age control group. There is no reliable difference between adolescents and adults with ADHD in these aspects (Albaugh et al. 2019). The change of cortical thickness in ADHD patients may be used as a substitute index for neuron density, cell structure and myelination in cortex (van Rooij et al. 2022; Cortese and Tessari 2017)Some studies have also found that subtle differences in cortical surface area are common only in children with ADHD, but not in adolescents and adults with ADHD (Hettwer et al. 2022), (Hoogman et al. 2019) Children and adults with ADHD show a decrease in the volume of basal ganglia, namely putamen, globus pallidus and caudate nucleus (Frodl and Skokauskas 2012; Albajara Sáenz et al. 2019). The asymmetry of brain structure and function is also considered as the potential mechanism of ADHD. According to the existing evidence, it can be inferred that the right hemisphere activity of ADHD patients decreases, thus allowing the brain dysfunction caused by the relatively dominant left hemisphere activity. A study analyzed the asymmetry of subcortical and cerebral cortex structure in as many as 1933 ADHD patients and 1829 unaffected controls. The results showed that the right hemisphere surface area of children was small, and there were some differences in the asymmetry of cortical thickness among different age groups. A recent study verified that the decrease of right frontal lobe excitability was related to ADHD cognitive impairment (Postema et al. 2021), (Chen et al. 2016).. Various functional magnetic resonance studies show that the results of functional magnetic resonance imaging can be used to distinguish healthy control group from ADHD patients. In 2019, a large-scale meta-analysis observed the dysfunction of nucleus pallidus and putamen in the fMRI experiment. Although this discovery was only reflected in male subjects, this result was the same as that of previous studies and was consistent with ADHD's frontotemporal pathway dysfunction model (Samea et al. 2019). The study of microstructure imaging found that some behavioral disorder symptoms of ADHD patients may be related to the damage of functional connection between brain regions caused by white matter (WM) microstructure abnormality. Some studies have found that the volume of whole brain gray matter (GM) and WM in ADHD patients is obviously reduced, and the total volume of WM, all four leaves and specific structures, such as corpus callosum (CC), are uniformly reduced, and the volume reduction of WM is even more obvious than that of GM. Compared with normal people, the most obvious difference in white matter of ADHD patients is located in the corpus callosum, extending to the right cingulate gyrus, right sagittal and left sensory layer, which may be the reason for the learning disorder of impulse and attention deficit in ADHD patients, and also shows that WM abnormality plays an important role in the pathophysiology of ADHD.It is not only an individual anomaly in each region, but also the connectivity between hemispheres is damaged. A study found that children with ADHD, especially girls, suffered more serious functional connection (FC) damage in the subfrontal nerve circuit. The distributed disconnection of large-scale brain connection network leads to the developmental delay of children with ADHD (Rosch et al. 2018; Castellanos and Proal 2012; Sripada et al. 2014; Qian et al. 2019; Zhang et al. 2020).Multiple studies have shown that people with ADHD (adults and children) have reduced frontal and frontostriatal perfusion compared to controls, with no sustained activation of the right lower frontal, dorsolateral prefrontal, and anterior cingulate cortex, as well as striatum, parietal, and cerebellar regions during cognitive control, time, and attention tasks. The severity of attention deficit and hyperactivity disorder in people with ADHD is inversely correlated with the degree of activation of these areas, which may be thought to be the reason why most children have ADHD (Cubillo et al. 2010, 2011; Westwood et al. 2023).

In addition to the above neuroimaging studies, there are some well-recognized hypotheses that norepinephrine, dopamine, serotonin and other neurotransmitters are closely related to the pathological mechanism of ADHD (Anas Sohail et al. 2021; Wankerl et al. 2014; Bari et al. 2009). Some literatures show that the decision-making and learning deficits of ADHD patients may be caused by the impairment of reward prediction error (RPEs) caused by the dysfunction of dopamine system, which may be related to the dopamine transfer deficit (DTD) of ADHD patients (Hauser et al. 2014; Sonuga-Barke and Fairchild 2012; Tripp and Wickens 2009) and dopamine reuptake inhibition is an evidence-based strategy for the treatment of this disease (Demirtas-Tatlidede et al. 2013).

Genetic studies have found that ADHD is highly heritable, and the discovery of the first genome-wide significant risk locus in 2019 further strengthened these hypotheses (Demontis et al. 2019). These findings provide guidelines and goals for the use of ADHD stimulants (Mechler et al. 2022).

Up to now, most researches on neurological relevance of ADHD are not unified, which may be related to the heterogeneity of clinical patients, but not only these individual studies, but also some meta-analyses of ADHD children/adults have inconsistent results (Müller et al. 2018; Samea et al. 2019).Most of the existing literature points out that almost all symptoms of ADHD patients involve the prefrontal cortex(Henri-Bhargava et al. 2018), not the whole frontal lobe abnormality (Jones and Graff-Radford 2021). because the prefrontal cortex is closely related to cognitive control (CC) and executive function(Salehinejad et al. 2020b), and the main symptoms of ADHD patients are attention deficit, hyperactivity and impulsiveness caused by severe EF and CC injuries. However, the poor control of inhibition caused by insufficient executive resources (that is, the model based on inhibition) and the defect of impulse control caused by excessive activity (that is, the model of motivation dysfunction) are important theories of ADHD pathophysiology (Rubia et al. 2021; Manganotti et al. 2022; Ismail et al. 2017; Jannati et al. 2023; Bandeira et al. 2021).In the past ten years, neuroimaging has found that human brains of almost all ages, especially those of developing children and adolescents, have extremely high plasticity [65-69],and tDCS can be adjusted by stimulating abnormal neurons in the prefrontal cortex to alleviate the symptoms of ADHD patients, which indicates that tDCS has potential long-term neuroplasticity effect, which is not available in drug therapy(Westwood et al. 2023).It can be seen that tDCS will become a good treatment choice, but the related treatment is still in its infancy, and there are still many challenges to be faced in the future(Cosmo et al. 2020)

Treatment of tDCS and ADHD

TDCS is a non-invasive neuromodulation technique, which changes the excitability of regional cortical tissue by applying weak continuous direct current to the scalp(Woodham et al. 2021).and has a long-lasting effect after stimulation. It is recognized as a simple method with low price and easy to carry(Bandeira et al. 2021) At present, relevant studies have been relatively systematic [69], but the mechanism of tDCS improving ADHD symptoms and cognitive function is not completely clear,which may be related to the reactivation of damaged neural circuits.The existing clinical research shows that tDCS therapy can effectively improve the attention and concentration of ADHD children and improve their impulsive disorder(Antal et al. 2022; 成梅 et al. 2018; Lavezzi et al. 2022; Lapenta et al. 2018).

Introduction to tDCS technology

As early as the 1960s, studies have reported that weak direct current (DC) stimulation changes the mental state of normal people and improves the symptoms of psychiatric patients(Liebetanz et al. 2002). In recent 20 years or so, tDCS, as a non-invasive brain stimulation technique suitable for human beings, has been reintroduced for its short-term and long-term effects on cortical excitability and neuroplasticity (Santos Ferreira et al. 2019). At present, tDCS has been studied for the management of ADHD(Woods et al. 2016; Hameed et al. 2017),or it can be used as a first-line treatment for major depression(Woodham et al. 2021; Aust et al. 2022; Zhou et al. 2020; Chase et al. 2020). Some evidence show that tDCS can effectively improve the conditions of obsessive-compulsive disorder, schizophrenia(Rapinesi et al. 2019; Cheng et al. 2022; Palm et al. 2020; Moffa et al. 2018) aphasia(de Aguiar et al. 2020), addiction(Lapenta et al. 2018; Sauvaget et al. 2015; Fregni et al. 2021) etc., and it can affect the gait adaptation, learning movement and cognitive function of healthy people by stimulating cerebellum. Of course, the evidence of its curative effect still needs further research and verification. In addition, a systematic review and meta-analysis of the influence of tDCS on object perception shows that tDCS can enhance the ability of object perception when it is targeted at frontal brain regions involving top-down attention (Lavezzi et al. 2022). However, tDCS did not have any effect on the perceptual integration of the right parietal cortex(Friehs et al. 2023).

Principles of action of tDCS in the treatment of ADHD

TDCS regulates nerve excitability and activity by providing low-intensity continuous direct current to cortical electrodes through two or more pads placed on the scalp (Lavezzi et al. 2022). There must be at least one anode electrode and one cathode electrode, and the current enters the human body through the anode and leaves through the cathode.

TDCS can't directly trigger the action potential in cortical neurons, but it can induce plasticity and affect spontaneous neural activity by causing the subthreshold polarity dependence of membrane potential to increase anode stimulation or decrease cathode stimulation. The mechanism of tDCS involves the use of cellular and molecular mechanisms that depend on local and distant synaptic plasticity, that is, long-term enhancement mediated by GABA and glutamate, which may be the reason for the long-term impact (Demirtas-Tatlidede et al. 2013).and the real advantage of tDCS over stimulants. The short-term effect of tDCS is thought to occur through the non-synaptic mechanism of resting membrane potential depolarization (Yamada and Sumiyoshi 2021). Some people speculate that the activation of neurons will not only change the membrane potential and discharge rate, but also reduce the membrane resistance. These effects depend on the stimulated active shooting range, its projection area, the surrounding structure at rest and the surrounding changes of transmitter system. In addition, because almost all tissues and cells are sensitive to electric fields, tDCS may also cause changes in non-neuronal tissues in the brain, which may be related to other therapeutic effects of tDCS (Lefaucheur et al. 2017). Some indirect evidence shows that tDCS can affect norepinephrine (Adelhöfer et al. 2019; Mishima et al. 2019; Dippel et al. 2017).Anode tDCS may interact with dopaminergic system and affect cognitive flexibility (Fonteneau et al. 2018; Meyer et al. 2019; Borwick et al. 2020). But some of these evidence come from animal experiments, and the research in human body has not been systematically explored.

It is generally believed that in bipolar montage, positively charged anode increases cortical excitability through neuron depolarization (Rubia et al. 2021; Cosmo et al. 2020) while negatively charged cathode reduces cortical excitability by inducing hyperpolarization (Breitling et al. 2016; Antal et al. 2022; Nitsche and Paulus 2011), thus changing spontaneous discharge rate, increasing or decreasing synaptic strength and cortical function. However, some studies believe that the effect of cathode tDCS has not been fully explored at present. TDCS cathode may not necessarily inhibit the excitability of motor cortex (Salehinejad et al. 2020c; Friehs and Frings 2019; Mosayebi Samani et al. 2019), but several conditions may change it, for example, the direction of axon can specify the excitability and inhibition of electric field, and the increase of stimulation intensity and duration can also transform the inhibition induced by tDCS of primary motor cortex cathode into excitation (Dadgar et al. 2022).It has also been found that acute selective serotonin reuptake inhibitor (SSRI) can increase and prolong the promotion duration induced by anode tDCS after intervention, thus transforming the inhibition induced by cathode tDCS into promotion, thus enhancing the clinical therapeutic effect of tDCS (Kuo et al. 2016; Melo et al. 2021; Nitsche et al. 2009).

tDCS treatment parameters and safety

Most tDCS are studied in children with ADHD, which is also related to the high safety and tolerance of tDCS in pediatrics (Bikson et al. 2016), because tDCS are easier to apply, lower in cost, less in side effects and pain, and more suitable for pediatric applications (Rubia et al. 2021)The survey on parents' acceptance of tDCS in the treatment of ADHD shows that parents' acceptance and support of tDCS are very high after learning that tDCS is relatively safe, and they are eager to determine the curative effect of this treatment and put it into the treatment of ADHD (Buchanan et al. 2022).

In the treatment of tDCS in normal people and ADHD people, the side effects in children are almost the same as those in adults, and most of them are mild and transient side effects, such as itching, burning sensation, tingling (Rubia et al. 2021; Allenby et al. 2018; Salehinejad et al. 2020a; Westwood et al. 2023), skin redness, headache, loss of appetite, etc. (Leffa et al. 2022; Schertz et al. 2022). The most common adverse performance is skin reaction. Although skin problems will disappear after the end of tDCS, it is still a relatively simple but very important consideration for tDCS technology to minimize skin reaction caused by stimulation. Some rare serious adverse reactions include mania or hypomania in a few depressed patients after using tDCS, suicide in a depressed patient (Loo et al. 2010) and epilepsy recurrence in an epileptic child (Ekici 2015), but there is no definite evidence to show whether the above serious adverse reactions are caused by tDCS or accidental. A small sample study found that ADHD patients felt mild "shock" during tDCS (Salehinejad et al. 2020b). One study reported that an adult subject assigned to the intervention group refused to participate after the first stimulation because of a dramatic change in mood, feeling sad, depressed, and nervous. This negative effect began to accumulate five hours after stimulation and continued in milder forms into the next day. The study found no other reasons for this deterioration, but high-frequency rTMS has similar side effects and is already used to treat depression. (Cachoeira et al. 2017). This suggests that tDCS may have some more incidental side effects.

At present, there are no reports of serious adverse reactions and irreversible injuries related to tDCS in the treatment of ADHD patients(Antal et al. 2017; Bikson et al. 2016).The existing evidence shows that tDCS is safe to treat ADHD in adults and children, but the safety of tDCS needs to be further verified because of too little data collected. Therefore, although tDCS can enhance the cognitive function of healthy people, However, because enhancing one cognitive function, i.e., producing neural gain, may result in neural loss, i.e., a "cognitive cost" in exchange for "cognitive improvement "(Colzato et al. 2021; Sanches et al. 2020). the use of tDCS as an" enhancer "to enhance certain functions in healthy children and adolescents is not recommended. The current safety research supports the combination of tDCS and other treatments to improve the therapeutic effect of ADHD.

Since the safety of tDCS is also related to the stimulation parameters, systematic testing is needed to determine the optimal stimulation parameters, including the optimal stimulation current and current density, stimulation duration and stimulation times, stimulation area and frequency (Matsumoto and Ugawa 2017).At present, tDCS in human body only involves fixed continuous direct current, the current is 0.1-4 mA, the typical current intensity is 1-2 mA, the duration is 4 s-40 min, the typical duration is 10-30 min, and the conventional charge limit is 7.2 C. Children usually use intensity less than 1 mA, but related reports show that no serious adverse reactions have been found when using intensity of 2 mA for children (Bikson et al. 2016) A recent systematic review shows that children and adolescents (5-17 years old) in tDCS application, within the range of 0.5-2 mA for 10-20 min, up to 20 times, tDCS seems to be safe and tolerable (Buchanan et al. 2023). At present, there are relatively few safety experiments in children, and children should not be treated as miniature adults to reduce the stimulation parameters, because children have thinner skulls and less cortical spinal fluid, and it is uncertain whether tDCS will affect children's neurological development, so the safety of tDCS application in children still needs further verification.

In addition to stimulation intensity and time, electrode size is also an important parameter affecting tDCS effect. At present, 35cm2 and 25cm2 are most commonly used in adults and children. Studies have shown that smaller electrodes can generate current density at brain level with lower current intensity and higher focus, so this is closely related to the application of tDCS in children with smaller head size. One study reported that the larger electrode may cause more excitability of motor cortex than the smaller electrode, but other studies did not find this difference (Salehinejad et al. 2020b).

Because Dorsolateral prefrontal cortex (DLPFC) is an important part of the prefrontal cortex to play a cognitive function, it is a commonly used target stimulation area for tDCS. Some evidence show that the Right inferior frontal gyrus (rIFG) anode tDCS can improve the response inhibition ability of ADHD patients, so this area is also one of the target areas for ADHD treatment (Buchanan et al. 2023).

tDCS clinical treatment

At present, most of the tDCS studies retrieved are conducted in children with ADHD, and only seven studies on adult ADHD patients have been retrieved. Some clinical evidence show that tDCS seems to improve the cognitive and behavioral functions of children and adults with ADHD, such as visual attention, inhibition control and working memory.

Studies have found that tDCS stimulation of the left dorsolateral prefrontal cortex (DLPFC) by tDCS improves the symptoms of inattention in children and adolescents (Guimarães et al. 2021); However, the anode tDCS in the right posterior parietal cortex (r-PPC) has no significant effect on the distraction and response inhibition of ADHD children. It may be that the activation of r-PPC improves the bottom-up attention control, but hinders the top-down attention control (Salehinejad et al. 2020a). A randomized controlled study, including 64 subjects, used home tDCS equipment for daily treatment. The results showed that the attention of adult ADHD patients who did not take stimulant drugs was improved after tDCS treatment (Leffa et al. 2022; Barham et al. 2022).A study on short-term application of tDCS in adult ADHD patients found that it improved their symptoms of inattention (Cachoeira et al. 2017).

In terms of improving impulse control, two studies found that stimulating the left DLFC with tDCS anode can adjust the cognitive control loop, enhance the activity of DLFC, improve the inhibition control of effective response inhibition, and relieve the impulse symptoms of adults and adolescents with ADHD (Allenby et al. 2018; Soltaninejad et al. 2019). However, a clinical study to evaluate the cognitive impact of tDCS on adult ADHD patients did not find that anodic tDCS stimulation could improve patient inhibition control (Cosmo et al. 2015).

TDCS anode in prefrontal cortex has been repeatedly proved to improve the working memory of ADHD patients (Soff et al. 2017), One study found that tDCS anode on the left DLPFC led to the increase of neuron activation and connection in the brain area further away from the stimulation area, thus improving the working memory (WM) of adolescent ADHD patients (Sotnikova et al. 2017). One study confirmed the regulatory effect of tDCS on the planning and working memory of a small group of adults with ADHD (Berger et al. 2021).\

Studies have proved that combining cognitive training with tDCS in cortical region to mediate the cognitive function under training can produce greater and lasting functional improvement (Bandeira et al. 2016; Dubreuil-Vall et al. 2021), and the symptoms of patients can be obviously improved after treatment (Demirtas-Tatlidede et al. 2013; Ditye et al. 2012). However, in 2022, a study on tDCS combined with cognitive training showed that using this scheme in children with ADHD DLPFC not show any other therapeutic benefits except cognitive training (Schertz et al. 2022).This situation may be related to the difference of research design, stimulation parameters and anode and cathode stimulation sites. In the future, we still need a larger sample, use a large number of local tDCS, and distinguish between those with and without cognitive training, so as to conduct more uniform design research and evaluate the clinical and cognitive benefits of tDCS with more convincing data (Rubia et al. 2021).

4 Comparison between tDCS and other non-invasive brain stimulation techniques (NIBS)

4.1 RTMS

RTMS and tDCS are two widely used non-invasive brain stimulation techniques (Finisguerra et al. 2019). RTMS is a non-invasive diagnosis and treatment technology (Bejenaru and Malhi 2022), which generates a short-term high-intensity magnetic field by passing a short-term strong pulse current through a magnetic coil to trigger stimulation. This magnetic field can stimulate or inhibit a small brain area under the coil, and most of the research is aimed at the motor cortex (Hallett 2007). Compared with tDCS, rTMS can directly trigger the action potential in cortical neurons, and the long-term lasting effect is usually mediated by increasing the cortical excitability of stimulated neurons. At present, the treatment of drug-resistant depression is the most mature clinical treatment technology of rTMS (Burke et al. 2019).At the same time, rTMS has also been developed and applied to the treatment of pain, movement disorders, stroke, drug addiction and other mental disorders (Lefaucheur et al. 2020). There is relatively little evidence that rTMS can obviously improve the hyperactivity disorder of adult ADHD patients, but the attention deficit disorder of patients has not been improved. Compared with tDCS, most rTMS studies are conducted in adults with ADHD, but the research in children with ADHD is limited. A study on adolescents and young people with ADHD found no difference between rTMS and sham control (Weaver et al. 2012). Most safety studies are conducted in adults, and the adverse reactions of children and adolescents are similar to those of adults(Rubia 2018). The most common adverse effect of rTMS is transient scalp discomfort below the coil due to stimulation of the pericranial muscles and peripheral nerves, while the most common adverse effect of tDCS is mild transient tingling, itching, and redness of the skin below the electrode(Doruk Camsari et al. 2018).

Relatively speaking, compared with rTMS, tDCS is more suitable for the treatment of ADHD children and has higher safety. Although rTMS is more specific to nerve regions, tDCS is cheaper, more portable, and easier to operate, so tDCS may have greater potential for clinical development.

4.2 tRNS

Transcranial random noise stimulation (tRNS) and tDCS belong to transcranial electrical stimulation (tES). Comparatively speaking, tDCS is the most studied tES type in ADHD. However, tRNS is a novel tES form, and its stimulation is transmitted through two electrodes, and the output of subthreshold signals may be enhanced through stochastic resonance. Although both tRNS and tDCS involve weak current passing through one or more electrodes placed on the scalp, cathode tDCS will reduce cortical excitability. Compared with tRNS, its sensitivity to cortical folding is reduced by using two excited electrodes, thus reducing the potential impact of anatomical differences between subjects (Dakwar-Kawar et al. 2023).

At present, tRNS have been proved to be effective in improving adult's cognitive function (Harty and Cohen Kadosh 2019). The latest evidence shows that the combination of tRNS and cognitive training (CT) can improve ADHD symptoms more effectively than tDCS, and the effect amount is equivalent to effective drug treatment (Dakwar-Kawar et al. 2023). The results of a randomized controlled trial among ADHD children show that tRNS have neuroplasticity, can obviously improve the clinical symptoms and working memory of ADHD children, and can have a long-term impact (Berger et al. 2021). When mental fatigue increases, compared with tDCS combined with CT, tRNS combined with CT can improve the processing speed more(Dakwar-Kawar et al. 2022), and the side effects such as tingling and itching of tRNS are less than tDCS (Berger et al. 2021).

Compared with tRNS, tDCS does not seem to have an advantage, but there are relatively few studies on tRNS, and more studies are needed to further verify its effectiveness in the future.

4.3 TNS

Trigeminal nerve stimulation (TNS) is the only non-drug treatment technology approved by the US Food and Drug Administration (FDA) to treat ADHD with minimal risk (Loo et al. 2021), and it is widely and successfully used to treat various neuropsychiatric diseases. TNS device usually consists of a programmable pulse generator, which transdermally transmits a small current through a self-adhesive supraorbital electrode to excite the forehead branch of the first (V1) or second (V2) branch of trigeminal nerve (i.e. supraorbital nerve and infraorbital nerve, respectively) (Mercante et al. 2023). At present, there is little research on TNS in the treatment of ADHD. Some experiments in children and adolescents with ADHD have proved that the therapeutic effect of TNS on ADHD may be similar to that of second-line non-stimulant drugs (McGough et al. 2015, 2019; Rubia 2021), and TNS has almost no side effects. At present, only temporary eye twitching and headache are found (Rubia et al. 2021).

TNS not only has high safety, but also seems to have higher curative effect than rTMS and tDCS in improving ADHD symptoms, and its price is cheaper than tDCS, and it is easy to operate, so it does not need professional operation training. But at the same time, the selection of TNS stimulation parameters mainly depends on the specific experience of equipment operators, and the consistency of stimulation parameters is not high. Coupled with the lack of basic knowledge of TNS' neurobiological effects, TNS still has great research space in regulating cognitive function(Rubia et al. 2021).

4.4 TUS

Transcranial ultrasound stimulation (TUS) is a new NIBS technology, which has the characteristics of non-invasive, high penetration and high spatial resolution. The existing evidence has proved that TUS can effectively regulate nervous system diseases, and its ultrasound can focus on cortex and deep brain structures, and induce lasting changes in cortical excitability (Samuel et al. 2022). The biggest advantage of TUS is that its spatial resolution has reached an unprecedented few cubic millimeters, which overcomes the serious limitations of other non-invasive technologies. It is a non-invasive tool to change neural circuits with great prospects in both humans and animals. At present, the research on TUS is still in the early and rapid growth stage. The existing evidence shows that TUS can change the short-term brain excitability and connectivity and induce long-term plasticity (Sarica et al. 2022). At present, there are no serious adverse reactions reported in the research on TUS, and the subjects only have some minor obstacles including headache, emotional deterioration, scalp fever and cognitive problems (Sarica et al. 2022). A study on TUS treatment of ADHD model rats for two weeks showed that TUS had an effective neuromodulation effect on ADHD (Wang et al. 2023), so it is possible for TUS to be put into clinical practice to improve the cognitive dysfunction of ADHD in the future.

Summary and prospect

In this paper, the development of tDCS in the treatment of ADHD is summarized and combed by collecting the existing literature, and the pathogenesis of ADHD and the treatment mechanism of tDCS are analyzed, and tDCS is simply compared with other NIBS technologies. TDCS has some advantages in treating ADHD, including simple operation, portability, low price, high safety and so on. The outstanding advantage is good long-term effect. However, some emerging NIBS technologies also have these advantages and are even better than tDCS, such as TRNs, tRNS,TNS,TUS. However, these studies are still in the initial stage. In comparison, tDCS and rTMS are still the most widely used NIBS technologies for treating ADHD, and related research has been more systematic. The treatment mechanism of tDCS is not completely clear, and the individual efficacy of existing stimulation schemes is very different, so the best treatment scheme can not be obtained yet. However, it is undeniable that tDCS research has brought positive effects to ADHD patients of all ages, and parents of ADHD children have a high degree of support for tDCS, so the therapeutic effect of tDCS can not be ignored.

At present, the use of tDCS in the treatment of ADHD is still in the development stage, and future research can be further carried out in the following aspects:

First, further verify the effectiveness of tDCS, improve safety and further determine the best stimulation parameters. At present, there are still few clinical trials of tDCS in the treatment of ADHD, and the experimental sample size is generally insufficient, the research design is inconsistent, and the research results are mixed. Therefore, in the future, more authoritative data should be used to prove that tDCS can play an effective role in children and adult ADHD patients, and further verify the causal relationship between the serious adverse reactions mentioned in this paper and tDCS, and reduce the occurrence of known common minor adverse reactions. And further determine the best stimulation parameters in children, and further measure the best stimulation current and current density, stimulation duration and times, stimulation area and frequency, so as to ensure that tDCS can be put into pediatric use more safely.

Second, further explore the pathogenesis of ADHD and the therapeutic mechanism of tDCS. At present, the pathogenesis of ADHD is still unclear, and the mechanism of tDCSd is still being explored. At present, there are only a few widely recognized hypotheses and unified conclusions about the pathogenesis of ADHD, and the clarity of tDCS treatment mechanism can also be used as definitive evidence to verify the effectiveness of treatment. Therefore, it is very necessary to further explore the pathogenesis of ADHD and the treatment mechanism of tDCS.

Third, further increase the tDCS research on adult ADHD patients. Up to now, a large number of researches on tDCS have been conducted in children and adolescents, and only seven researches have been conducted in adult ADHD patients. Therefore, it is urgent to increase the tDCS research on adult ADHD patients in the next stage to verify the effectiveness and safety of tDCS treatment in adult ADHD patients.

Fourth, tDCS should be combined with drug or non-drug treatment. The combination of tDCS with drugs or non-drugs, especially with cognitive therapy, is considered to be a very potential treatment method, which can enhance the therapeutic effect on ADHD patients while alleviating the side effects and increase the duration of the therapeutic effect. The recent experiment of combining tDCS with cognitive therapy is not ideal, so a large number of experiments are still needed to further verify the efficiency of combining tDCS with drugs or non-drugs in the future.

Fifth, further develop the research of tRNS,TNS,TUS and other technologies to alleviate and treat ADHD symptoms. These emerging NIBS technologies may be better than tDCS in all aspects, especially TUS technology, which has the advantages of high penetration and high spatial resolution that other NIBS technologies can't replace. This technology began to develop rapidly at the initial stage, and TUS is undoubtedly more potential than other technologies.

Funding

Our research was funded by Qilu Medical College.

Data availability

Data availability is not applicable to this article as no new data were created or analyzed in this study.

Declarations

Ethical approval

This is a review, ethics approval are not applicable.