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Rubia, K. Neurotherapeutics for Attention Deficit/Hyperactivity Disorder. Encyclopedia. Available online: https://encyclopedia.pub/entry/21058 (accessed on 21 June 2024).
Rubia K. Neurotherapeutics for Attention Deficit/Hyperactivity Disorder. Encyclopedia. Available at: https://encyclopedia.pub/entry/21058. Accessed June 21, 2024.
Rubia, Katya. "Neurotherapeutics for Attention Deficit/Hyperactivity Disorder" Encyclopedia, https://encyclopedia.pub/entry/21058 (accessed June 21, 2024).
Rubia, K. (2022, March 25). Neurotherapeutics for Attention Deficit/Hyperactivity Disorder. In Encyclopedia. https://encyclopedia.pub/entry/21058
Rubia, Katya. "Neurotherapeutics for Attention Deficit/Hyperactivity Disorder." Encyclopedia. Web. 25 March, 2022.
Neurotherapeutics for Attention Deficit/Hyperactivity Disorder
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Attention-deficit/hyperactivity disorder (ADHD) is characterised by persisting and impairing symptoms of age-inappropriate inattention and/or hyperactivity/impulsivity (DSM-5). EEG-neurofeedback has been tested for about 45 years, with the latest meta-analyses of randomised controlled trials (RCT) showing small/medium effects compared to non-active controls only. Three small studies piloted neurofeedback of frontal activations in ADHD using functional magnetic resonance imaging or near-infrared spectroscopy, finding no superior effects over control conditions. Brain stimulation has been applied to ADHD using mostly repetitive transcranial magnetic and direct current stimulation (rTMS/tDCS). rTMS has shown mostly negative findings on improving cognition or symptoms. Meta-analyses of tDCS studies targeting mostly the dorsolateral prefrontal cortex show small effects on cognitive improvements with only two out of three studies showing clinical improvements. Trigeminal nerve stimulation has been shown to improve ADHD symptoms with medium effect in one RCT. Modern neurotherapeutics are attractive due to their relative safety and potential neuroplastic effects. However, they need to be thoroughly tested for clinical and cognitive efficacy across settings and beyond core symptoms and for their potential for individualised treatment.

attention deficit hyperactivity disorder (ADHD) functional magnetic resonance imaging (fMRI) neurofeedback EEG-neurofeedback fMRI-neurofeedback brain stimulation transcranial magnetic stimulation (TMS) transcranial direct current stimulation (tDCS) trigem

1. Introduction

Attention-deficit/hyperactivity disorder (ADHD) is characterised by persisting and impairing symptoms of age-inappropriate inattention and/or hyperactivity/impulsivity (DSM-5) (American Psychiatric Association, 2000) [1]. It is one of the most common childhood disorders with a worldwide prevalence of around 7% (Thomas et al., 2015) [2]. Problems persist into adulthood in a substantial proportion of cases, and they are associated with comorbidities and poor academic and social outcomes (Thomas et al., 2015) [2].
ADHD patients have deficits in higher-level cognitive functions necessary for mature adult goal-directed behaviours, in so-called “executive functions” (EF), that are mediated by late developing fronto-striato-parietal and fronto-cerebellar networks (Rubia, 2013) [3]. The most consistent deficits are in “cool” EF such as motor response inhibition, working memory, sustained attention, response variability and cognitive switching (Pievsky & McGrath, 2018; Rubia, 2011; Willcutt et al., 2008) [4][5][6], as well as in temporal processing, in particular in time discrimination and estimation tasks (Noreika et al., 2013; Rubia et al., 2009) [7][8]. However, impairment has also been found in so-called “hot” EF functions of motivation control and reward-related decision making, as measured in temporal discounting and gambling tasks. However, evidence for hot EF deficit has been more inconsistent than for cool EF [5][8][9] (Noreika et al., 2013; Plichta & Scheres, 2014; Willcutt et al., 2008), in line with the diagnostic criteria. Evidence for cognitive deficits is more consistent in children than adolescents or adults with ADHD [6][10] (Groen et al., 2013; Pievsky & McGrath, 2018). There is furthermore considerable heterogeneity in cognitive impairments, with over 30% of patients showing no EF impairments (Nigg et al., 2005; Roberts et al., 2017) [11][12].
The most successful treatment is with psychostimulant medication which enhances catecholamines in the brain, reaching an effect size of ~0.8, with about 70% of patients with ADHD responding to it [13] (Cortese et al., 2018). Functional magnetic resonance imaging (fMRI) studies have shown that stimulant medication increases the activation of inferior frontal and striatal regions and their interconnectivity and decreases activation in areas of the default mode network [14] (Rubia et al., 2014), both of which are likely responsible for improvements in cognitive functioning [15][16] (Coghill et al., 2014; Pievsky & McGrath, 2018). Second-line treatment is with noradrenaline transporter/receptor blockers, Atomoxetine and Guanfacine, which also enhance brain catecholamines with effect sizes of 0.56 and 0.67, respectively [13] (Cortese et al., 2018). Stimulant prescription has increased dramatically over the last decades worldwide, which is controversial due to abuse and diversion potential. Furthermore, stimulants commonly have adverse effects on sleep and appetite as well as causing irritability, nausea/vomiting, abdominal pain, headaches, labile mood and growth suppression, although they are typically non-serious and can be transient [13] (Cortese et al., 2018). Moreover, only 50% of patients tolerate it sufficiently, caution is indicated for certain comorbid conditions (such as cardiovascular malfunctions and sleep problems) and adherence can be poor, in particular in adolescence. Importantly, longer-term efficacy has not been demonstrated in meta-analyses, nor in observational or epidemiological studies [13][17] (Cortese et al., 2018; Swanson, 2019), although there is controversy (Coghill, 2019) [18].
While the efficacy of stimulant medication for treating ADHD was a chance finding, as it was originally used for other medical conditions such as bronchodilatation, headache, and blood pressure [19] (Connolly et al., 2015) and the first neurofeedback treatment in ADHD also used EEG conditioning developed for seizure control [20] (Lubar & Shouse, 1976), modern neurotherapeutics have the advantage that they can directly target the key brain function deficits that have been found in ADHD over the past decades. There has been substantial research on brain function differences in ADHD relative to healthy controls with electroencephalography (EEG) since the 1970s (e.g., Satterfield, 1973; Satterfield et al., 1973) [21][22] and with fMRI over the past 2.5 decades that have provided researchers with neurofunctional biomarkers that could be targeted with neurotherapeutics, such as neurofeedback or non-invasive brain stimulation techniques.

2. Neurotherapeutics in ADHD

One of the most revolutionary findings of the last decade of neuroimaging has been the discovery of high brain plasticity, in particular in childhood/adolescence when the brain is still developing [23][24] (Jancke, 2009; Rapoport & Gogtay, 2008), but also in mid and older adulthood [25][26] (Draganski et al., 2004; Draganski & May, 2008). Even a few weeks or months of training of a particular skill in mid and older adults, for example, juggling [25][26] (Draganski et al., 2004; Draganski & May, 2008), learning for an exam [27] (Draganski et al., 2006) or learning to meditate [28] (Dodich et al., 2019) can change the structure of the brain. These insights into the brain’s neuroplastic potential make novel neuromodulation treatments, such as non-invasive brain stimulation or neurofeedback, attractive clinical interventions [29][30] (Rubia, 2018, Ashkan et al., 2013). This is even more relevant to early stages of disorders in young people where it is likely to be most effective [31] (Anderson et al., 2011), with evidence showing that children and adolescents show accelerated neural plasticity compared to adults after brain stimulation [32] (Brunoni et al., 2012).
The establishment of neurofunctional biomarkers for ADHD with EEG and fMRI studies over the past decades has made it possible to target these biomarkers using neurotherapeutics. Given the evidence for electrophysiological and neuroimaging functional deficits in ADHD, it seems plausible that treatments that try to reverse these underlying brain function deficits could potentially be promising, given that they are targeting the key neurobiological abnormalities associated with the disorder. EEG-NF has already been applied to ADHD for over 45 years with relatively inconsistent findings. fMRI or NIRS-neurofeedback is still very much in its infancy with too few and underpowered applications to provide a clear insight on potential efficacy. There has been an exponentially increasing number of non-invasive brain stimulation studies over the past 10 years. Studies have, however, been relatively small numbered with very heterogenous study designs. Consequently, findings have been inconsistent with respect to improving cognition, with very little evidence so far on improving clinical behaviour. 

2.1. Neurofeedback

Neurofeedback (NF) is an operant conditioning procedure that, by trial and error, teaches participants to volitionally self-regulate specific regions or networks through real-time audio or visual feedback of their brain activation, which can be represented on a PC. For children, this can be gamified in an attractive way. Given that ADHD is typified by poor self-control [33] (Schachar et al., 1993), and enhancing brain-self-control is the target of NF, ADHD is the psychiatric disorder where NF has been most applied, using electrophysiological neurofeedback (EEG-NF).

2.1.1. EEG-NF

EEG-NF trains self-regulation of oscillatory or task-related EEG-markers associated with ADHD, such as increased theta and TBR linked to compromised activation; decreased sensorimotor rhythm (SMR) related to impaired state regulation and sleep; and attenuated task-related slow cortical potentials (SCP) such as the CNV correlated with impaired preparation and activation (standard protocols) [34] (Arns et al., 2014).
Despite the fact that EEG-NF has been used to treat ADHD for 45 years, the majority of the studies had important methodological shortcomings like the lack of an appropriate control condition, randomisation, unblinded outcome measures, non-standardized feedback methods, limited or no reporting of self-regulation and appropriate learning. During the last two decades, large improvements have been made to address these major drawbacks, resulting, for example, in a very recent consensus publication on the reporting and experimental design of neurofeedback studies [35] (Ros et al., 2020).

Meta-Analyses of EEG-NF

During the last decade, a large number of meta-analyses were published which scrutinize the clinical efficacy of EEG-NF in ADHD. The first meta-analysis based on ten controlled studies reported large effect sizes in favour of EEG-NF when parents rated the clinical outcome of inattention or for impulsivity measured in tests, as well as non-inferiority compared to the gold standard of stimulant medication treatment; it therefore recommended EEG-NF as “efficacious and specific”, which means that the treatment has been shown to be statistically superior to credible sham therapy in at least two independent studies [36] (Arns et al., 2009) (for updated, more stringent criteria, see Arns et al., 2020) [37].
More than ten years and more than ten meta-analyses later [34][36][38][39][40][41][42][43][44][45][46] (Arns et al., 2009, 2014; Cortese et al., 2016; Van Doren et al., 2019; Micoulaud-Franchi et al., 2014; Riesco-Matías et al., 2021; Sonuga-Barke et al., 2013; Yan, et al., 2019; Lambez et al., 2020; Bussalb et al., 2019; Hodgson et al., 2014), the latest comprehensive meta-analysis to date reported significant albeit small to medium effect sizes and inferiority compared to stimulants [41] (Riesco-Matías et al., 2021). This drop of more than half of the effect size (for a historical/chronological viewpoint, see Figure 1) is interesting and probably related to the growing research using stricter control conditions and improved scientific standards for EEG-NF studies, which will be discussed in the following.
Figure 1. Effect sizes (ES) in meta-analyses of EEG neurofeedback studies for effects on global ADHD symptoms by year of publication. MPROX: ratings by parents/proximal raters; PBLIND: ratings by probably blinded raters. * Studies that used a standard protocol.
The first meta-analysis [36] (Arns et al., 2009) included non-randomised studies which are considered a weak experimental design to determine clinical efficacy [47] (Norris & Atkins, 2005), whereas randomised controlled trials (RCT) are considered gold-standard in clinical research. The following meta-analysis [48] (Sonuga-Barke et al., 2013) addressed this issue by including only RCTs, together with the inclusion of blinding criteria of the clinical outcome, such as ADHD core symptoms. These authors introduced the term of “probably blinded” raters, which refers to the assessment, most often by teachers, who probably do not know to which treatment the patient was allocated. These two new requisites blunted the clinical effect which still remained significant for unblinded raters (such as parents) with medium effect sizes but was reduced to a trend-level for the probably blinded raters. Following these new insights, the recommendation to consider EEG-NF in ADHD as efficacious and specific was ameliorated.
One year later, Micoulaud-Franchi et al. [40] (Micoulaud-Franchi et al., 2014) updated Sonuga-Barke’s meta-analysis of 2013 [42] (Sonuga-Barke et al., 2013), including the subdomains of the core ADHD symptoms, i.e., inattention, hyperactivity and impulsivity. When evaluating the core symptom domains separately, a significant effect emerged also for the probably blinded raters, but only for the inattention subdomain.
Subsequently, two years later, an update of Sonuga-Barke’s meta-analysis was published by the same group [38] (Cortese et al., 2016) on behalf of the European ADHD guidelines group, incrementing the analysis from 8 to 13 RCTs with parent-ratings and from 4 to 8 RCTs with probably blinded ratings. This updated meta-analysis resulted in insignificant findings for all probably blinded ratings, including inattention, but still showed a significant medium effect size for parents’ ratings. The discrepancy regarding the blinded findings in the subdomain of inattention in Micoulaud-Franchi [40] (Micoulaud-Franchi et al., 2014) appears due to selecting different blinded outcomes in the same studies.
The meta-analysis of Cortese [38] (Cortese et al., 2016) also reported an exploratory sensitivity analysis including only three EEG-NF studies that used standard protocols [34] (Arns et al., 2014), where the effects on ADHD symptoms became also significant for probably blinded raters, but subsequent large standard NF trials [49][50] (i.e., Arnold et al., 2020; Strehl et al., 2017) could not substantiate this. Importantly, Bussalb et al. [51] (Bussalb et al., 2019) in their meta-analysis systematically evaluated further factors which influenced the efficacy of NF. They concluded that the intensity of NF but not the treatment duration was associated with higher efficacy, teachers were less sensitive to patients’ symptoms and suggested that NF needs to be evaluated with placebo-controlled interventions.
As can be observed from this, progress has been made to enhance the quality and certainty of the consideration and evaluation of the efficacy of EEG-NF in ADHD. Neurofeedback should be considered an umbrella term since there exist a large number of different training modalities that are only limited by the available technology (such as Coherence training, asymmetry feedback, etc). This issue is of paramount importance and a standardization should be aimed for. To date, the already mentioned standard protocols fulfil these criteria and so far, very recently, a few larger studies were published.
The latest comprehensive meta-analysis [41] (Riesco-Matías et al., 2021) addressed an additional important point, which is the selection of an adequate control group, and compared EEG-NF vs. non-active control groups (waiting-list controls, treatment as usual) and active control groups. The main findings showed superiority of EEG-NF compared to non-active control groups for parent ratings and for the inattention subdomain rated by probably blinded raters, resembling the findings of Micoulaud-Franchi et al. [40] (Micoulaud-Franchi et al., 2014). However, when EEG-NF was compared with an active control condition, such as pharmacotherapy, EEG-NF was no longer superior. These findings underline the importance of considering active elements in control conditions, and the need to grade these active elements consistently across Neurofeedback and other neurotherapies studies. The recent consensus statement on evidence-based ADHD treatments excluded studies and meta-analyses with non-active or heterogeneous controls such as waiting control or treatment as usual [52] (Faraone et al., 2021). However, this approach may underestimate some genuine NF-effects in real life settings that are also detectable by blinded raters or are slower to develop.

2.2. Brain Stimulation

Non-invasive brain stimulation therapies, most prominently rTMS and tDCS, have only over the past decade been applied to ADHD. These stimulation techniques affect cellular and molecular mechanisms involved in use-dependent local and distant synaptic plasticity, i.e., GABA and glutamate-mediated long-term potentiation, which may lead to longer-term effects [53] (Demirtas-Tatlidede et al., 2013). In fact, several studies in healthy populations and patient groups have shown longer-term cognitive effects of up to 1 year after stimulation [54][55] (Ruf et al., 2017, Katz et al., 2017). With high relevance to ADHD, positron emission tomography (PET) studies have shown that anodal frontal tDCS can release neurotransmitters such as dopamine [56][57][58] (Fonteneau et al., 2018; Meyer et al., 2019 Borwick et al., 2020), which furthermore correlated with better attention [59] (Fukai et al., 2019), with some indirect evidence for effects on noradrenaline [60][61] (Adelhöfer et al., 2019; Mishima et al., 2019). Similarly, rTMS over prefrontal regions in animals and humans has been shown to induce changes to neurotransmitter systems including alterations to serotonin, striatal dopamine release and metabolite levels, as well as to the release and concentrations of striatal glutamate [62][63] (Moretti et al., 2020; Poh et al., 2019). It has furthermore been shown that the combination with cognitive training which can prime the areas to be stimulated with a cognitive task is more effective than stimulation alone, due to the synergistic effects of functional targeting (Cramer et al., 2011; Kuo & Nitsche, 2012; Ziemann & Siebner, 2008) [62][63][64][65][66].

2.2.1. Repetitive Transcranial Magnetic Stimulation (rTMS)

rTMS is a non-invasive and relatively safe brain stimulation technique that uses brief, intense pulses of electric current delivered to a coil placed on the subject’s head in order to generate an electric field in the brain via electromagnetic induction. A commonly used figure-8 coil can provide relatively focal stimulation of approximately 5 mm3. The induced electrical current triggers action potentials in the brain via current flowing parallel to the surface of the coil and thus modulates the neural transmembrane potentials and therefore neural activity. The magnitude of the stimulation is inversely related to the distance from the coil. The effect differs depending on the stimulation intensity and duration; number of stimulation pulses and their frequency per second; and coil orientation. In general, based on motor studies, high frequency (>5 Hz) rTMS promotes cortical excitability, while low frequency (1 Hz) rTMS inhibits cortical excitability [67] (Lefaucheur et al., 2014).
Longer-term clinical improvements with rTMS have been demonstrated in several psychiatric disorders [68][69] (Janicak & Dokucu, 2015; Mehta et al., 2019), supporting its neuroplastic potential. Relative to tDCS, rTMS has greater specificity in targeting neural regions [70] (Parkin et al., 2015), but is more expensive. The most common side effects are transient scalp discomfort underneath the coil due to stimulation of the pericranial muscles and peripheral nerves [71] (Rossi et al., 2009).
The majority (four out of six) of rTMS studies were conducted in adults with ADHD. Two double-blind, sham-controlled crossover studies targeted the right DLPFC. In 13 ADHD adults, one session of 20 Hz-rTMS relative to sham significantly improved overall self-rated ADHD symptoms and inattention but had no effect on hyperactivity, mood or anxiety scores [72] (Bloch, 2012). In nine ADHD adults, 10 daily sessions of 10 Hz-rTMS relative to sham showed no effect on self-rated clinical symptoms, nor on EEG or EF measures [73] (Weaver et al., 2012). In a single-blind, sham-controlled, randomised study in 22 ADHD adolescents, 20 daily sessions over 4 weeks of 18 Hz deep rTMS over bilateral DLPFC (n = 13) compared to sham (n = 9) showed no effect on self-rated clinical or cognitive measures of sustained attention [74] (Paz et al., 2018). A parallel, semi-blind, randomised, active and sham-controlled study in 43 young adults with ADHD tested 15 sessions of 18 Hz-rTMS over 3 weeks and a 1-month follow-up maintenance session over the right prefrontal cortex, targeting both DLPFC and IFC. Stimulation was combined with a short cognitive training session targeting the right prefrontal cortex, which was conducted before and after stimulation. While patients were blind, researchers were only blind for the sham and real but not the active stimulation control condition, which was an off-target focal stimulation 5–6 cm away from the DLPFC or IFC and which did not target DLPFC or IFC [75] (Alyagon et al., 2020). The DLPFC/IFC stimulation compared to the other conditions showed significant improvements in the primary clinical outcome measure, which was self-rated ADHD symptoms, with an effect size of 0.96 versus sham and 0.68 versus the active control stimulation, and there was only a significant improvement in the hyperactivity/impulsiveness in the self-rated subscales. Superiority of real versus control conditions was no longer significant at follow-up a month later. There were no significant effects on depression ratings, behavioural executive functions (as measured on the BRIEF) or cognitive inhibition measures except for a trend of improving Stroop task performance relative to sham but not active control, which was correlated with the clinical changes in the DLPFC/IFC stimulation group. EEG measures showed a negative correlation between alpha activity and a positive correlation between low gamma activity under the stimulation area with clinical symptom improvements in the DLPFC/IFC stimulation group.
Two studies were conducted in children with ADHD. An open label tolerability and safety trial in 10 children with ADHD without a sham condition showed fewer teacher-rated inattention and parent-rated hyperactivity/impulsivity symptoms one week after five daily sessions of 1 Hz-rTMS over left DLPFC compared to baseline [76] (Gómez et al., 2014). A larger study randomised 60 children with ADHD into either 30 daily 25 min sessions of 10 Hz rTMS over right DLPFC, Atomoxetine (1.2 mg/kg) or combined treatment over 6 weeks. The combined treatment group compared to the individual treatment groups improved significantly post- relative to pre-treatment in inattention and hyperactivity/impulsiveness, but not in oppositional defiant behaviours, nor in cognitive measures of working memory, sustained attention and reward-based decision making. All groups improved in these clinical and cognitive measures [77] (Cao et al., 2018). However, without a sham condition, placebo or practice effects cannot be ruled out in both studies (Table 1).
Table 1. Clinical and cognitive effects of sham-controlled rTMS studies.
Stimulation Protocol Outcome Measures (Bold/Underlined = Improvement)
Study Design N Age Target Sessions Frequency Duration Clinical Cognitive
Children
Cao et al., 2020
[77]
Single-blind, randomised, parallel (2 active controls: ATX, ATX-rTMS; no sham) 64 (~20 each) 6–13 R DLPFC a 20 18 Hz (100% MT) 2000 pulses (4 s on, 26 s off) SNAP-IV CPT; WISC; IGT
Gomez et al., 2014
[76]
Open label 10 7–12 L DLPFC 5 1 Hz (90% MT) 1500 pulses (on, off n/r) DSM-IV ADHD symptom checklist (hyperactivity/imp., inattention) n/t
Adults
Bloch et al., 2010
[72]
Single-blind, sham-controlled, randomised, crossover 13 NR (adults) R DLPFC a 1 20 Hz (100% MT) 1680 pulses (2 s on, 30 s off) PANAS (inattentiontotal score; mood, anxiety, hyperactivity); VAS (inattention, mood) b n/t
Paz et al., 2018
[74]
Double-blind, sham-controlled, randomised, parallel A: 13 S: 9 A: 32
S: 30
L DLPFC c 20 18 Hz (120% MT) 1980 pulses (2 s on, 20 s off) CAARS TOVA
Weaver et al., 2012
[73]
Single-blind, sham-controlled, randomised, crossover 9 18 R DLPFC a 10 10 Hz (100% MT) 2000 pulses (4 s on, 26 s off) CGI-I scale; ADHD-IV scale WAIS/WISC-IV; Connors CPT; DKEFS; Buschke Selective Reminding Test; Symbol Digit Coding test; Finger Oscillation tasks
Alyagon et al., 2020
[75]
Double-semi-blind, randomised, active and sham-controlled 52 (15, 14, 14) 21–46 R IFC & DLPFC 15 18 Hz (120% MT) 1440 pulses (2 s on, 20 s off) CAARS (global ADHD symptomshyperactivity/impulsiveness) (BAARS-IV (hyperactivity/impulsiveness), BRIEF-A, BDI) STROOP; STOP
Abbreviations: A, active; BAARS, Barkley Adult ADHD Rating Scale; BRIEF-A, Behavioural Rating Inventory for Executive Functioning; BDI, Beck Depression Inventory; CAARS, Conners’ Adult ADHD Rating Scale; CGI-I, Clinical Global Impression-Improvement Scale; DKEFS, Delis–Kaplan Executive Function System; DLPFC, dorsolateral prefrontal cortex; Hz, number of magnetic pulses per second; IGT, Iowa Gambling task; L, left; MT, motor threshold; n/t, not tested; PANAS, Positive and Negative Affect Schedule; R, right; S, sham; SNAP-IV: Clinical rating scale of the severity of ADHD; TOVA, Test of Variables of Attention; VAS, Visual analogue scales; WAIS, Wechsler Abbreviated Scale of Intelligence, selected subtests from the Wechsler Adult Intelligence Scale; WISC-IV, Wechsler Intelligence Scale for Children-IV; a 5 cm forward to MT point; b small change from baseline of 0.25 and 1.16 out of 5-point Likert scales; c 6 cm rostral to motor cortex.
With respect to safety, one study reported a seizure in one patient (who was excluded from the study) after three sessions [75] (Alyagon et al., 2020), while most other studies reported no or few side or adverse events other than transient headaches and scalp discomfort localised to the stimulation area.
In conclusion, rTMS is relatively safe. The majority of studies were conducted in relatively small samples, using few session numbers of rTMS, and two out of six studies did not include a sham condition, making it impossible to rule out placebo or practice effects. Based on the conducted studies so far, there is relatively little evidence that several sessions of rTMS improve ADHD symptoms or cognition, with the exception of one study in adults that used multisession rTMS and stimulated right DLPFC and IFC combined with cognitive training, which needs replication. More multisession sham-controlled RCTs in large patient numbers are needed, in particular in paediatric ADHD, to more thoroughly test TMS effects using different protocols.

2.2.2. Transcranial Direct Current Stimulation (tDCS)

tDCS applies a weak continuous direct electric current to underlying brain regions via scalp electrodes with the electrical current passing between a positively charged anode and a negatively charged cathode. In general, currents induce plasticity by causing subthreshold polarity-dependent increases (anodal stimulation) or decreases (cathodal stimulation) in membrane potentials that modify spontaneous discharge rates and cortical excitability, thus increasing/decreasing cortical function and synaptic strength [30] (Ashkan et al., 2013). tDCS is much easier to apply and has lower financial costs than TMS. Furthermore, tDCS has the advantage of being less painful than TMS and hence is more suitable for paediatric applications. Side effects are minimal in children (and adults), typically involving transient itching and reddening of the scalp site of stimulation in some participants (Krishnan et al., 2015; Zewdie et al., 2020) [78][79].
Combining cognitive training with tDCS over a cortical area that mediates the cognitive function being trained [64] (Kuo & Nitsche, 2012) has been shown to yield larger and long-lasting functional improvements that modify the impaired system [66] (Cramer et al., 2011), presumably via a synergistic effect of training-induced and stimulation-induced plasticity [65] (Ziemann & Siebner, 2008). Combined effects of cognitive training with tDCS in other disorders and healthy subjects have been shown to last up to 6 months [80][81] (Boggio et al., 2012; Kuo et al., 2014) and 1 year (Katz et al., 2017) [55].
Functional neuroimaging studies have furthermore demonstrated modulation not only of the stimulation site but also of functionally interconnected (sub)cortical regions [82] (Polania et al., 2011), which makes them useful for targeting networks such as fronto-striatal systems in ADHD. Furthermore, relevant to ADHD, striatal dopamine [83] (Pogarell et al., 2007) and noradrenaline [61][84] (Kuo et al., 2017; Mishima et al., 2019) have been implicated in the mechanism of action, both of which are typically reduced in ADHD (Cortese et al., 2018) [13].
Unlike with rTMS, the majority of tDCS studies (12 out of 18) (see Table 2) have been conducted in children with ADHD, presumably due to the high tolerability and relatively low side effect profile of tDCS, which would make it a good treatment option if efficacious. The majority of studies used very small session numbers and tested cognitive effects only (see Table 2).
Two double-blind, sham-controlled, crossover studies applied single session stimulation over the DLPFC. In 15 adolescents with ADHD, anode-left/cathode-right tDCS over bilateral DLPFC improved WCST completion time, n-back reaction times and Stroop reaction times and commission errors to incongruent trials but had no effect on n-back accuracy or Go/No-Go task performance [85] (Nejati, Salehinejad et al., 2020). In 10 ADHD adolescents, anodal tDCS over the left dlPFC improved n-back accuracy and reaction times compared to both sham and cathodal tDCS; anodal and cathodal tDCS also improved WCST performance, but anodal tDCS led to greater improvement; cathodal tDCS also improved No-Go accuracy, potentially via interhemispheric inhibition increasing right prefrontal activation [85] (Nejati, Salehinejad et al., 2020), a region associated with motor response inhibition in children and adults [86][87][88] (Rubia et al., 2013; Rubia et al., 2003; Rubia et al., 2007). This last finding is in line with a single-blind, crossover study in 21 adolescents with ADHD, which found in a subsample of seven participants that, compared to sham, one session of anodal, but not cathodal, tDCS over the right IFC reduced commission errors (trend-level) and reaction time variability in an interference inhibition task (Breitling et al., 2016) [89].
Two single-blind, sham-controlled crossover studies stimulated left DLPFC or right IFC in 20 high school students with ADHD symptoms that were above cut-off on validated ADHD questionnaires. Single session anodal relative to cathodal tDCS over the left DLPFC improved Go accuracy while cathodal tDCS relative to anodal tDCS and sham improved No-Go accuracy in the Go/No-Go task, but there was no change in Stroop task performance [90] (Soltaninejad et al., 2019). Anodal tDCS over the rIFC relative to sham improved Go accuracy, but there were no changes in other Go/No-Go or Stroop task measures (Soltaninejad et al., 2015) [91].
A double-blind, sham-controlled RCT in 50 children with ADHD tested the effects of 15 sessions of 20 min of right IFC anodal tDCS combined with cognitive training in executive function tasks. The study found that both groups improved in clinical symptoms and cognitive functions, but the improvement in the real versus sham tDCS in primary and secondary clinical outcome measures was significantly less pronounced [92] (Westwood et al., 2021). Groups did not differ in a large battery of executive function cognitive outcome measures [92] (Westwood et al., 2021) nor in EEG measures within a smaller subsample of data collected from 26 participants only [93] (Westwood et al., 2021). Furthermore, the real tDCS group had worse adverse effects related to mood, sleep and appetite immediately after stimulation (Westwood et al., 2021) [93].
A double-blind crossover study applied five daily sessions of anodal or sham tDCS over left DLPFC in 15 adolescents with ADHD, but because of a carry-over and learning effects, only the first sessions were analysed, thus reducing the sample to seven to eight participants per condition [94] (Soff et al., 2017). Compared to sham, anodal tDCS improved parent-rated inattention and cognitive measures of attention (QbTest; which combines cognitive measures of hyperactivity, impulsiveness and inattention in a hybrid n-back/GNG task) one week but not immediately after the last stimulation session, while cognitive measures of hyperactivity on the QbTest were improved immediately after anodal tDCS and seven days later [94] (Soff et al., 2017). Analysis of 13 out of the 15 ADHD adolescents after a single session of anodal tDCS relative to sham showed reduced reaction time variability but increased errors on the QbTest, but this analysis included the carryover effect [95] (Sotnikova et al., 2017).
A double-blind, sham-controlled crossover study found that overnight slow-wave oscillatory anodal tDCS over left and right DLPFC, relative to sham, improved declarative memory in 12 ADHD children [96] (Prehn-Kristensen et al., 2014), reaction time and its intra-subject variability on Go trials in a Go/No-Go task in 14 ADHD children [97] (Munz et al., 2015) but had no effects on No-Go accuracy, alertness, digit-span or motor memory.
An open label trial in nine ADHD children found that five daily sessions of anodal tDCS to left DLPFC combined with a picture association cognitive training task reduced errors in attention (omission) and switch-task performance, but did not improve working memory, while parents, with one exception, reported improvements in some of their children’s behaviour [98] (Bandeira et al., 2016).
In a double-blind crossover study in 14 children and adolescents with ADHD, the right IFC was stimulated with either conventional tDCS, high definition tDCS (HD-tDCS) or sham while performing a working memory task with inhibitory elements which was repeated after stimulation as an outcome measure. HD-tDCS is a 4:1 small electrode array with one electrode encircled by four electrodes of the opposite polarity, which delivers a more spatially restricted and therefore focal stimulation that can reduce side effects from stimulating non-target brain regions. The study found that neither a single session of conventional anodal tDCS nor HD-tDCS over right IFC combined with working memory performance compared to sham had any effect on performance in the n-back task; however, ERP data from 10 participants in ADHD showed elevated N200 and P300 after the two tDCS conditions versus sham and a shift towards the values seen in a healthy control group (Breitling et al., 2020) [99].
One study applied one session of anodal tDCS over the right inferior (and some superior) parietal lobe in 17 ADHD children in a single-blind crossover study. In line with the role of inferior parietal lobe in orienting attention, anodal relative to sham tDCS improved performance in bottom-up orienting attention but deteriorated selective attention as measured in the Stroop interference reaction time and error effects and had no effect on alerting or top-down executive attention as measured in the shifting attention and Go/No-Go tasks (Salehinejad et al., 2020) [100].
One recent study tested effects of tDCS on reward-related decision making in ADHD [101] (Nejati, Sarraj Khorrami, et al., 2020). Twenty children with ADHD received tDCS in three separate sessions with either anodal tDCS over the left DLPFC and cathodal tDCS over right vmPFC; the reversed montage; or sham stimulation. Anodal tDCS over the right vmPFC, coupled with cathodal tDCS over the left DLPFC, reduced risky decision-making in the Balloon Analogue R Task but had no effect on the key impulsiveness outcome measure in the delay discounting task (k mean); it did have an effect on some conditions, but these were not corrected for multiple testing (Nejati, Sarraj Khorrami et al., 2020) [101].
Another recent study compared the clinical and cognitive effects of tDCS with tRNS in ADHD. Although similar to tDCS in terms of equipment and setup, tRNS applies an alternating current at random frequencies and/or intensities. The mechanisms by which tRNS influences brain activity are less known but are thought to be different than for tDCS [102] (Fertonani & Miniussi, 2017). The most prevalent explanation for tRNS is stochastic resonance, whereby the introduction of an appropriate level of random noise enhances the output of subthreshold signals; thus, the application of weak electric currents amounts to an introduction of neural noise [102] (Fertonani & Miniussi, 2017). Information processing at the neuronal level is sensitive to stochastic resonance [103] (McDonnell & Ward, 2011). The double-blind cross-over study compared five sessions of transcranial random noise stimulation (tRNS) over left DLPFC and right IFC with tDCS of left DLPFC combined with executive function training in 19 children with ADHD. Relative to tDCS, tRNS showed a clinical improvement in ADHD rating scale scores from baseline after treatment and one week later. Cognitively, tRNS compared to tDCS improved working memory, but only processing speed during sustained attention. An exploratory moderation analysis predicted a trend-level larger tRNS effect on the ADHD rating scale for those patients who showed the greatest improvement in working memory. tRNS yielded fewer reports of side effects, in line with the literature on adults showing that tRNS is a more comfortable neurostimulation method than tDCS (Berger et al., 2021) [104].
Only four studies have been conducted in adults with ADHD. In a double-blind parallel study in 60 adults, anodal tDCS over the left DLPFC compared to sham had no effect in two Go/No-Go tasks or a functional cortical network activity based on EEG recordings in a subsample of 50 patients [105] (Cosmo et al., 2015). One single-blind crossover study applied a single session of anodal tDCS over the left and right DLPFC in 20 undergraduate students with ADHD, which, compared to sham, improved in hyperactivity measures (i.e., multiple/random responses) in a sustained attention task but had no effect on omission errors or reaction times [106] (Jacoby et al., 2018). A double-blind crossover study in 37 adults with ADHD administered three sessions of visual working memory training combined with anodal tDCS of the left DLPFC and reported that compared to sham, anodal tDCS reduced commission errors in a sustained attention task immediately but not three days after the last stimulation, while there was no effect on omission errors, reaction times, stop task or visual working memory training performance [107] (Allenby et al., 2018). [107] One double-blind parallel study in 17 adults with ADHD found that tDCS of anodal right/cathode-left DLPFC (n = 9) versus sham (n = 8) improved inattention but not hyperactivity/impulsive symptoms immediately after five daily sessions of stimulation and at a 2-week follow-up, with total ADHD scores also improving at the 2-week follow-up, although group differences disappeared at the 4-week follow-up (Cachoeira et al., 2017) [108]. Finally, in a double-blind crossover study in 37 adults with ADHD, participants were asked to perform a Flanker (n = 18) or a stop task (n = 19) before and after receiving a single session of anodal tDCS over the left or right DLPFC relative to sham. In the Flanker task, left but not right DLPFC stimulation reduced reaction times on incongruent but not congruent trials compared to sham and right DLPFC stimulation. This was furthermore correlated with increased left and right P300 increase in EEG measures on incongruent trials after left and right DLPFC stimulation compared to sham, respectively and with reduced N200 amplitude after left compared to right DLPFC stimulation. In the stop task, there was no effect in inhibitory measures, but left DLPFC stimulation relative to sham increased Go reaction time, which was correlated with increased P200 amplitude during Go trials (Dubreuil-Vall et al., 2020) [109].
In conclusion, only 3 out of 17 tDCS studies tested clinical effects. Two studies found that tDCS of left DLPFC improved clinical inattention symptoms while one study foundthat tRNS compared to tDCS improved ADHD symptoms (see Table 2).
With respect to cognition, most studies found effects in the performance of some but not other tasks, with little consistency in findings between studies, and most studies did not correct for multiple testing (see Table 2). Two meta-analyses tested for consistent findings of tDCS on cognition in ADHD. A meta-analysis of 10 studies (201 children/adults with ADHD) found that one to five sessions of anodal tDCS over mainly left DLPFC significantly improved cognitive performance in inhibitory control measures (Hedges’ g = 0.12) and in n-back reaction times (g = 0.66) [110] (Salehinejad et al., 2019). However, effect sizes were small, and the meta-analysis likely overestimated statistical significance by not controlling for interdependency between measures and conflated inhibitory with non-inhibitory cognitive measures [111] (Westwood et al., 2021). Addressing these and other limitations, a larger meta-analysis of 12 tDCS studies (232 children/adults with ADHD) found that one to five sessions of anodal tDCS over mainly left DLPFC led to small, trend-level significant improvements in cognitive measures of inhibition (g = 0.21) and of processing speed (g = 0.14) but not of attention (g = 0.18) (Westwood et al., 2021) [111].
In conclusion, the findings of the use of tDCS to improve ADHD symptoms and cognition have been mixed, with some positive results on improving cognition, with, however, very small effects sizes observed in meta-analyses (see also Table 1). However, the comparability of results was hampered by the large heterogeneity in study designs, stimulation parameters and site of anodal and cathodal stimulation. Larger samples and more homogeneously designed studies using a larger number of sessions of localised tDCS with and without cognitive training are needed to more confidently assess clinical and cognitive benefits.
Importantly, for both TMS and tDCS but also tRNS or tACS, systematic testing is needed to identify the optimal stimulation parameters that can elicit reliable clinical or cognitive effects. Parameters that should be tested include optimal stimulation sites, frequency, duration, and superiority of stimulation effects combined with cognitive training. For tDCS, tRNS and tACS, studies should consider if effects depend on age, electrode size and inter-electrode distance, the focality of stimulation and antagonistic effects of cathodal stimulation on the desired effect of the anodal stimulation. Children, for example, have thinner skulls and less corticospinal fluid, which means potentiation of the effects of brain stimulation compared to adults and optimal dosages cannot be easily transferred from adult studies. For example, cathodal tDCS at 1 mA, which has excitability-diminishing effects in adults, has shown to have excitatory effects in children and adolescents when applied over the motor cortex [112] (Moliadze et al., 2015). Stronger intensity might be needed for deeper regions, such as IFC, as opposed to more superficial regions, such as DLPFC, which might explain the null findings in studies of stimulation of rIFC in ADHD (Salehinejad et al., 2020). Clear and evidenced dosage guidance is therefore paramount for paediatric studies, especially since stimulation intensity and duration are non-linear [113] (Lefaucheur et al., 2017) and neuroplasticity changes are strongest during childhood development [114] (Knudsen, 2004). Furthermore, hardly anything is known on the longer-term efficacy of tDCS/tRNS/tACS or TMS protocols in ADHD. In healthy volunteers, up to 1-year longer-term cognitive effects have been observed with tDCS combined with cognitive training [55] (Katz et al., 2017) and up to 1 month in other psychiatric disorders [115][116] (Kekic et al., 2016; Moffa et al., 2018) with evidence for longer-term effects also with TMS in other psychiatric disorders (Janicak & Dokucu, 2015; Mehta et al., 2019) [68][69].
Given that tDCS is thought to affect neuroplasticity [117][118] (Kim et al., 2014; Nitsche et al., 2008), potential longer-term efficacy could be the real advantage of tDCS over stimulant medication. There is furthermore potential to combine tDCS with pharmacological or non-pharmacological treatments, in particular with cognitive training, as mentioned above.
While direct side effects appear to be minor and transient for non-invasive brain stimulation, such as itching and tingling over the stimulation site [78][100] (Krishnan et al., 2015; Salehinejad et al., 2020), there are, however, important neuroethical concerns about potential unknown negative effects of localised brain stimulation on the still-developing brain. It has been suggested that the neural state at the time of stimulation (Silvanto et al., 2008) [119] or baseline cortical excitation-inhibition levels may influence stimulation effects [120] (Krause et al., 2013), with those with suboptimal basal neural states likely to benefit more than those who already have an optimal activation pattern. This would suggest that application in psychiatric patient groups like ADHD who have suboptimal activation patterns may be more justified than its application as cognitive enhancer in healthy children and adults [121] (Cohen-Kadosh et al., 2012). It is also possible that the stimulation of a particular region negatively affects the activation in other regions, which could then impair non-targeted functions.
Inter-individual differences in traits, which may be associated with differences in baseline neural states, have in fact shown to affect the benefits or costs of brain stimulation. For example, subjects with high mathematical anxiety benefited in their reaction time to mathematical tasks with tDCS over DLPFC, while those with low mathematical anxiety had an impairment in reaction time. Moreover, both groups became worse in an interference inhibition task [122] (Sarkar et al., 2014), which could possibly reflect a negative effect of tDCS of DLPFC on the neighbouring IFC region, which mediates interference inhibition. Similarly, prefrontal stimulation improved automaticity of learning but impaired numerical learning mediated by parietal regions, while parietal stimulation impaired automaticity of learning mediated by prefrontal regions and improved numerical learning [123] (Iuculano & Kadosh, 2013). Inter-individual differences in brain activation at baseline are hence likely to determine whether patients benefit or not from tDCS over a particular brain region, suggesting that future brain stimulation treatment should be individualised based on baseline brain and cognitive dysfunctions. This is particularly pertinent given that there is heterogeneity in cognitive dysfunction in ADHD (Nigg et al., 2005; Roberts et al., 2017) [11][12].
Findings of cognitive costs of tDCS on functions mediated by other brain regions are particularly worrying in paediatric applications where the brain is still developing and more plastic. It will therefore be crucial to assess potential costs on non-targeted cognitive functions which may occur via indirect down-stimulation of other brain regions that are interconnected with the stimulated site and that mediate these non-targeted functions. This knowledge will be crucial to understand the risk-benefit ratio of localised brain stimulation to the individual patient and to children in particular. These worries of effects on non-targeted brain regions also apply to the neurofeedback studies. Most ethical considerations have concluded that there are no ethical reasons against tDCS in children and adolescents who have a medical condition that is handicapping and where potential side effects can be outweighed by benefits, while use of tDCS as cognitive enhancer in healthy children and adolescents is not advised [121] (Cohen Kadosh et al., 2012). These benefits and risks, however, will still have to be established in ADHD as well as in other childhood disorders.
Table 2. Clinical and cognitive effects of sham-controlled tDCS studies.
  Stimulation Protocol Outcome Measures
(Bold/Underlined = Improvement; Cursive = Impairment)
Study Design n Mean Age Anode/Cathode mA Sessions Timing a Duration (mins) Clinical Cognitive
Children
† Bandeira et al., 2016
[98]
Open label 9 11 L DLPFC/R SOA 2 5 Online 28 Patient Global Impression of Improvement Visual Attention Test (OM); NEPSY-II-inhibition (Switch errors); Digit Span; Corsi Cubes
Breitling et al., 2016
[99]
Single-blind, sham-controlled, randomised, crossover 21 14 R IFC/L Cheek 1 1 Online 20 n/t Flanker (Incongruent trials: COM c,d & RTV ce
        L Cheek/R IFC 1 1 Online 20 n/t Flanker
Munz et al., 2015
[97]
Double-blind, sham-controlled, randomised, crossover 14 12 L DLPFC/R Cheek;
R DLPFC/L Cheek
0.25 1 Offline 25 (5 on, 1 off) n/t Go/No-Go (Go RT & RTV); Motor memory; Alertness
Nejati et al., 2020, Exp 1
[101]
Double-blind, sham-controlled, randomised, crossover 15 10 L DLPFC/R DLPFC 1 1 Offline 15 n/t Go/No-Go; N-back (Acc, RT); Stroop (Incongruent trials: COM & RT); WCST (Completion time)
Nejati et al., 2020, Exp 2
[101]
Double-blind, sham-controlled, randomised, crossover 10 9 L DLPFC/R SOA 1 1 Offline 15 n/t Go/No-Go; N-back (Acc cRTd; WCST (Total categories completedtotal & pers errorsd
        R SOA/L DLPFC 1 1 Offline 15 n/t Go/No-Go (No--Go acc) d; N-back; WCST (Total categories completedtotal & pers errors cd
Prehn-Kristensen et al., 2014
[96]
Double-blind, sham-controlled, randomised, parallel 12 12 L DLPFC/R Cheek; R DLPFC/L Cheek 0.25 1 Offline 25 (5 on, 1 off) n/t Declarative Memory (Acc); Alertness; Digit Span
Soff et al., 2017
[94]
Double-blind, sham-controlled, randomised, crossover 15 14 L DLPFC/Vertex 1 5 Online 20 FBB-ADHD(Inattention fg,h QbTest (Inattention fhyperactivity ig,h
Soltaninejad et al., 2019 [91] Single-blind, sham-controlled, randomised, crossover 20 16 L DLPFC/R SOA 1.5 1 Online 15 n/t Go/No-Go (Go Accc,d; Stroop
        R SOA/L DLPFC 1.5 1 Online 15 n/t Go/No-Go (NoGo Accc,j; Stroop
‡ Soltaninejad et al., 2015
[91]
Single-blind, sham-controlled, randomised, crossover 20 16 rIFC/L SOA 1 1 Online 15 n/t Go/No-Go (Go Acc); Stroop
Sotnikova et al., 2017
[95]
Double-blind, sham-controlled, randomised, crossover 13 14 L DLPFC/Vertex 1 1 Online 20 n/t QbTest (RTRTV kOMsAccl
Breitling et al., 2020
[99]
Double-blind, sham- and HD-tDCS controlled, randomised, crossover ADHD: 15HC: 15 13
(10–16)
R IFC/L SOA 1 3 with CT Online 20 n/t WM task; ERPs N200P300
Salehinejad et al., 2020
[100]
Single-blind, sham-controlled, randomised, cross-over 19 9
(8–12)
1 2 Online 23 n/t ANT (orienting); GNG; SAT; Stroop
† Westwood et al., 2021
[92]
Double-blind, sham-controlled, randomised, parallel 50 14 R IFC/L SOA 1 15 Online 20 ADHD-RS; Conners 3P GNG; Stop; Simon; WCST; CPT; MCT; time estimation; NIH WM; Verbal Fluency
Nejati et al., 2020
[101]
Double-blind, sham-controlled, randomised, cross-over 20 9 L DLPFC/R vmPFC
R DLPFC/L vmPFC
Sham
1 1 Online 20 n/t BARTCDDT (k20k10)
† Berger et al., 2021
[104]
Double-blind, active controlled, randomised, cross-over 19 7–12 L DLPFC (tDCS)/R SOA
L DLPFC/R IFC (tRNS)
0.75 5 Online 5 n/t ADHD-RS;
Working & short-term memory, Moxo-CPT
(all improved with tRNS vs. tDCS)
Adults
† Allenby et al., 2018
[107]
Double-blind, sham-controlled, randomised, crossover 37 32 L DLPFC/R SOA 2 3 Online 20 n/t Conners CPT (COM m); Stop Task
Cachoeira et al., 2017
[108]
Double-blind, sham-controlled, randomised, parallel A: 9
S: 8
A: 31
S: 34
R DLPFC/L DLPFC 2 5 Offline 20 ADHD Checklist (InattentionTotaln; SDS (after tDCS); ADHD total score 2 weeks None
Cosmo et al., 2015
[105]
Double-blind, sham-controlled, randomised, parallel A: 30
S: 30
A: 32
S: 33
LDLPFC/R DLPFC 1 1 Offline 20 n/t Go/No-Go
Jacoby et al., 2018
[106]
Single-blind, sham-controlled, randomised, crossover 20 23 L&R DLPFC/Cerebellum 1.8 1 Offline 20 n/t CPT (multi-button presses)
Dubreuil-Vall et al., 2020
[109]
Double-blind, sham-controlled, randomised, crossover 37 18–67 L DLPFC/R SOA
R DLPFC/R SOA
2 1 Offline 30 n/t Flanker (incongruent RTn = 18; L P300; L N200. Stop (go RTs); L P200n = 19
Flanker; Stop
Abbreviations: A, active; Acc, accuracy; ANT, attention networking task; BAART, Balloon analogue risk taking task; CDDT, chocolate delay discounting task; COMs, commission errors; Conners 3P, Conners-3 Parent Rating Scale; CPT, continuous performance task; DLPFC, dorsolateral prefrontal cortex; FBB-ADHD, parents’ version of a German adaptive Diagnostic checklist for ADHD; L, left; mA, milliamps; mins, minutes; n/t, not tested; OMs, omission errors; cM, contralateral mastoid relative the other electrode; SOA, contralateral supraorbital area relative the other electrode; IFC, inferior frontal cortex; MCT: Mackworth Clock Task; NIH-WM, NIH Toolbox List Sorting Working Memory Test; N200; negative ERP component; P300; positive ERP component; R, right; RT, reaction time; RTV, reaction time variability or standard deviation of reaction times; S, sham; SAT, switching attention task; SDS, Sheehan Disability Scale; SSRT, stop-signal reaction time; WCST, Wisconsin task-sorting task. a Timing refers to whether cognitive performance was during (online) or after (offline) stimulation; c Would likely not survive multiple comparison correction; d Comparisons between stimulation conditions based on post-hoc LSD tests, which do not correct for multiple comparisons; e Based on underpowered analysis focusing on the first session, with seven participants per condition; f Improvement only seen seven days after the fifth anodal tDCS session; g Did not survive correction for multiple comparisons; h Based on underpowered analysis focusing on the first five sessions, with seven/eight participants per condition; i Improvement seen immediately after the fifth anodal tDCS session and seven days later; j Significant in comparison to cathodal tDCS only; k Based on a crossover interaction. tDCS reduced RT and RTV in one out of four conditions (2-back tasks), but this did not survive correction for multiple comparisons; l Included carryover effect raised by Soff et al., (2017); m Significant only immediately after anodal tDCS, not significant three days later; n Inattention improved immediately after anodal tDCS and after two weeks, while total score improved only after two weeks. † combined stimulation with cognitive training; ‡ originally published written in Persian language but was translated for researchers by the lead author Dr Zahra Soltaninejad.

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