Anales de la RANM

128 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 NEUROTHERAPEUTICS FOR ADHD Katya Rubia An RANM. 2021;138(02): 124- 131 compared to sham (n = 9) (36). A parallel, semi-blind randomised, active and sham-controlled study found significant improvements in ADHD symptoms in 43 ADHD adults after 15 sessions over 3 weeks of 18 Hz-rTMS of both DLPFC and IFC -combined with a short cognitive training session before and after stimulation- and a 1-month follow-up maintenance session (37). No significant effects were observed on other clinical, cognitive and EEG measures, but EEG measures under the stimulation area correlated with clinical symptom improvements. In children with ADHD, the first, open label tolera- bility and safety trial (N = 10) showed fewer teacher- rated inattention and parent-rated hyperactivity/ impulsivity symptoms one week after treatment compared to baseline after five daily sessions of 1Hz-rTMS over left DLPFC (38). The second pediatric study in 60 children with ADHD found that 30 daily sessions of 25min of 10Hz rTMS over right DLPFC over 6 weeks combined with Atomoxetine, compared to Atomoxetine (1.2mg/kg) alone of rTMS alone, significantly improved ADHD symptoms but not other clinical or cognitive measures, in which all groups improved (39). Both pediatric studies did not include a sham condition, however, and hence placebo effects cannot be excluded for the improve- ments within groups. With respect to safety, one study using rTMS observed a seizure in one patient after 3 sessions (37), but the majority of studies reported no side effects or serious adverse events other than related to transient itching or headache under the stimulation site. In conclusion, at the current state of the art, there is relatively little evidence that several sessions of rTMS improve ADHD symptoms or cognition. However, studies were relatively underpowered and conducted relatively few session numbers of rTMS with only 2 studies in children without a placebo condition. Transcranial direct current stimulation (tDCS) In tDCS, scalp electrodes apply a weak, relatively painless and persistent direct electric current to underlying brain regions with the current passing between a positively charged anode and a negati- vely charged cathode. The electrical currents lead to increase (anodal stimulation) or decrease (cathodal stimulation) of the excitability of neurons via the generation of subthreshold alterations of neuron membrane potentials that modify spontaneous discharge rates; this can increase or decrease cortical function and synaptic strength. tDCS compared to TMS is much easier to apply, cheaper and less painful and hence more suitable for children. Side effects are minimal and typically transient such as itching and reddening of the scalp site of stimulation in some people (33). Currents are typically applied for 20min in one session, which can be combined with a cognitive paradigm, which can boost the effect (33). The majority of tDCS studies (12 out of 18), unlike the rTMS studies, were conducted in children rather than adults with ADHD, presumably due to the high tolerability and low side effect profile. The majority of studies applied 1-5 sessions of about 20 minutes of tDCS in children or adults with ADHD, with the exception of our study which applied 15 sessions. Only 4 studies tested for clinical symptoms, 3 studies after 5 sessions of tDCS of DLPFC and 1 study after 15 sessions of right IFC; two studies in 9 and 15 ADHD patients, respectively, found an improvement with real compared to sham tDCS on clinical inattention symptoms, which persisted 1 or 2 weeks later (40, 41). One study found an improve- ment with transcranial random noise stimulation (tRNS) of left DPFC and right IFC compared to tDCS of left DLPFC combined with cognitive training on ADHD symptoms in 19 patients (42). However, the largest study that tested 15 sessions of tDCS of right IFC in 50 ADHD patients found no improvement compared to sham in clinical symptoms and even an improvement with sham relative to tDCS (43). All other studies tested the effects of tDCS on a range of executive cognitive functions and found an improvement on some but not other functions (33) with little consistency in findings between studies, and few of them correcting for multiple testing. Two meta-analyses tested the effects of tDCS on cognitive performance in ADHD. The first meta-analysis included 10 studies in 201 children/adults with ADHD and found that 1-5 sessions of anodal tDCS over mainly left DLPFC significantly improved cognitive performance in inhibition measures (Hedges’ g = 0.12) and in n-back reaction times ( g = 0.66) (44). However, effect sizes were small and the meta-analysis likely overestimated statistical significance as it did not control for interdependency between measures, and included attention measures within the inhibi- tory measures (33). Our larger meta-analysis of 12 tDCS studies in a total of 232 children and adults with ADHD found that one to five sessions of anodal tDCS over mainly left DLPFC led to small and only 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) (33). In conclu- sion, the findings of the use of tDCS to improve ADHD symptoms and cognition are mixed, with only 5 studies testing for clinical effects and meta-analyses showing some positive results on improving cognition, with, however, very small effects sizes. Very few studies stimulated the right IFC. Most studies tested 1 session and found no significant cognitive improvements (33). We conducted the largest double-blind sham-controlled RCT in 50 children with ADHD where we tested the effects of 15 sessions of 20 min of right IFC stimulation combined with cognitive training in executive function tasks. We found that both groups improved in clinical symptoms and cognitive functions with significantly less improvement in the real versus sham tDCS in primary and secondary clinical outcome measures. There was also no superior effect of real versus sham tDCS on a large battery of executive functions. While side effects did not differ between groups, the real tDCS group had worse adverse events related to mood, sleep and appetite (43).