Anales de la RANM

129 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 To conclude, there is large heterogeneity in tDCS studies with respect to study designs, stimulation parameters and site of stimulation which makes comparability between studies difficult. While relati- vely safe, the larger studies found no clinical effects with multi-session tDCS. Meta-analyses show small effects of improving cognition. However, larger and more homogeneously designed studies using a larger number of sessions of localised tDCS with and without cognitive training are needed to more thoroughly assess clinical and cognitive benefits. Trigeminal nerve stimulation (TNS) External trigeminal nerve stimulation (TNS) is another non-invasive intervention with minimal side effects. TNS transmits small electrical currents transcutaneously via a self-adhesive, supraorbital electrode to excite (trigger action potentials) the supratrochlear and supraorbital branches of the ophthalmic nerve (V1) located under the skin of the forehead. The supraorbital nerve is a branch of the first trigeminal division and has widespread connec- tions to the brain, in particular the reticular activa- tion system, locus coeruleus, brain stem, thalamic, frontal and cortical areas (45). It also has effects on dopamine and noradrenaline, which have effects on arousal and attention and been implicated in ADHD (7, 14). Two studies tested the efficacy of TNS in ADHD, which is typically applied every night for several weeks. An 8-week, open trial, pilot feasibi- lity study showed significant reduction in ADHD symptoms in 21 children with ADHD, in depression and in a scale that measures behavioural executive functions in daily life. There were also positive effects on selective attention and inhibitory control. The second study was a blinded, sham-controlled proof of concept study of 4 weeks of TNS in 62 children with ADHD. The active relative to the sham TNS group had a significant reduction in ADHD symptoms and trend-level differential improvement for anxiety but not for depression (46). Quantitative EEG data showed increased power in the active relative to the sham group in right frontal midline and inferior frontal regions after compared to before treatment, which furthermore correlated with improvements in ADHD symptoms. Findings suggest that right frontal upregu- lation mediates the clinical effects (47). Both trials showed that TNS was well tolerated with no serious adverse events and relatively minor and transient side effects such as headache or fatigue. Based on evidence from this small, underpowered proof of concept study, TNS is now the only brain stimulation technique that is approved for ADHD. More evidence is needed to demonstrate the efficacy of TNS for reducing ADHD symptoms and improving cognition. Modern neurotherapeutics is still in its infancy in the field of ADHD. Neurofeedback studies using higher spatially resolved neuroimaging techniques such as NIRS and fMRI have only recently been piloted in ADHD, showing feasibility in relatively small subject numbers, but without the power to demonstrate clinical or cognitive effects. Larger, sham-controlled studies that allow the identification of predictors of neurofeedback learning are necessary to establish whether NIRS or fMRI neurofeedback training has potential as a treatment for some individuals with ADHD. Several non-invasive brain stimulation studies with heterogeneous study designs have been conducted in small groups of ADHD children and adults, most of them using tDCS in either single or 5 sessions targeting mostly DLPFC with few studies targeting right IFC or other regions. Meta-analyses of tDCS effects mostly of DLPFC show small effect sizes for improving cognitive functions (33, 44). Only 5 studies have tested clinical effects with inconclusive findings. Larger sham-controlled studies are needed to further test the efficacy of tDCS on improving symptoms or cognitive functions. TNS seems to be promising so far in improving ADHD symptoms based on one sham-controlled study (47), but replication of findings in larger samples is necessary. For both neurofeedback and brain stimulation studies, far more knowledge is needed on the optimal stimulation protocols for different age and patient subpopulations (i.e., best stimula- tion/neurofeedback site, intensity of stimulation, duration of stimulation/ neurofeedback, frequency of sessions, electrode size, inter-electrode distance, etc). It is likely that brain stimulation combined with cognitive training has a larger potential to enhance brain plasticity in ADHD than brain stimulation alone. Interindividual baseline differences in brain activation are likely to affect learning of brain self-regulation or stimulation effects. Also, positive or negative side effects of regional fMRI-neurofeedback or stimulation on not self-regulated/non-stimulated regions such as neighbouring regions or homologue regions in the other hemisphere which may be indirectly downre- gulated needs to be better understood. In conclusion, the substantial knowledge acquired over 3 decades of fMRI imaging in ADHD has opened up treatment targets for neurotherapeu- tics which seem attractive for children with ADHD due to their safety and minimal side effects and their potential for longer-term neuroplastic effects, compared to medication treatments. However, neurotherapies need to be more thoroughly tested for their short- and longer-term efficacy, optimal “dose” effects (i.e., optimal target site; intensity of stimulation; frequency of stimulation/neurofee- dback sessions), potential costs that may accompany the benefits, and their potential for individua- lised treatment depending on clinical or cognitive ADHD subtypes. It is likely that different clinical or cognitive subgroups of ADHD patients will benefit from either neurofeedback, brain stimula- tion or medication with individualised protocols and establishing this knowledge will be crucial to the benefit of individual patients. CONCLUSIONS