Anales de la RANM

127 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 movie as feedback. Eighteen participants learned to self-upregulate the rIFC, while 13 participants self-upregulated a control region, the left parahip- pocampal gyrus. In both groups, activation of their respective target regions increased progressively across the 11 fMRI-neurofeedback runs. However, only the rIFC-neurofeedback group showed a transfer effect (self-regulation without feedback, as a proxy of transfer to real life) that correlated with reduced ADHD symptoms. There were no group differences in ADHD symptom improvements after the treatment, but both groups improved. However, only the rIFC-neurofeedback group showed a large ADHD symptom reduction at 11 months follow-up, with an effect size of almost 1, compared to an only trend-level reduction in the left parahippocampal gyrus-neurofeedback group. Only the rIFC-neurofe- edback group also showed trend-level improvement in a sustained attention task. The rIFC-neurofeedback group also showed increased functional connec- tivity between the rIFC and the ACC and caudate, and a decrease in functional connectivity between the rIFC and regions of the posterior default mode network. These connectivity findings suggest that not only the targeted region improved in activation but entire networks that are connected to this region (rIFC) (27). To assess the effects of fMRI-neurofee- dback on brain function in ADHD, the participants also performed a motor response inhibition fMRI task before and after treatment. The rIFC-neurofe- edback relative to the left parahippocampal gyrus- neurofeedback group showed increased activa- tion after compared to before neurofeedback in the rIFC and parietal regions during inhibition (26) and increased activation in left-hemispheric IFC/insula and striatal regions during performance monitoring, which correlated with ADHD symptom improve- ments and better performance (28). The increase of activation in IFC and striatal regions were similar to those we observed previously with stimulant medication (29), suggesting that fMRI-neurofe- edback of the rIFC has similar brain upregulation effects. Last, there were no group differences in side effects or adverse events. However, when we tested neurofeedback learning capacity, we found that only 48% of patients learned successfully to upregulate their target region with fMRI-neurofeedback -which is similar to the EEG-neurofeedback literature (30). The best predictors of fMRI-neurofeedback learning were not clinical or cognitive data but enhanced fronto-striatal activation in the fMRI Stop task at baseline (30). The only pilot study that tested NIRS-Neurofee- dback trained upregulation of the left DLPFC in 11 hourly sessions over 4 weeks in 9 ADHD children and compared it with EEG-Neurofeedback (N=9) and electromyography-Neurofeedback (N=9). Only NIRS-Neurofeedback showed significant improve- ments in clinical ADHD symptoms and in perfor- mance in inhibition and attention functions, which was, however, not superior to EEG- or electromyo- graphy-Neurofeedback (31). In conclusion, fMRI-Neurofeedback and NIRS-Neurofeedback research is still very new and only 2 small studies have been conducted. Some of the within-group improvement findings of these small proof of concept studies are promising. However, there is a need for larger, double-blind, placebo-controlled randomised controlled trials to more thoroughly assess the potential efficacy of these neurotherapies in ADHD. Brain stimulation Non-invasive brain stimulation therapies, specifi- cally repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and trigeminal nerve stimulation (TNS) have been applied to ADHD only very recently, over the past decade. These stimulation techni- ques are thought to 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 brain plasticity (32). In fact, studies in healthy adults and in different patient popula- tions have shown up to 1 year longer-term cognitive effects after stimulation with rTMS or tDCS (33). Furthermore, there is evidence that both techniques can lead to increased levels of catecholamines (33), which are known to be abnormal in ADHD (7). For rTMS and tDCS it seems 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 (33). Repetitive transcranial magnetic stimulation (rTMS) rTMS is a relatively safe non-invasive brain stimula- tion technique that uses brief, intense pulses of electric currents delivered to a coil placed on the subject’s head in order to generate an electric field in the brain via electromagnetic induction. Typically, high frequency rTMS promotes cortical excitability, while low frequency rTMS inhibits cortical excitabi- lity. rTMS has greater specificity in targeting neural regions than tDCS, but is more expensive and more painful, which makes it less suited for pediatric applications. Side effects are minor and transient, most commonly temporary scalp discomfort underneath the coil due to stimulation of the pericra- nial muscles and peripheral nerves (33). Six studies applied between 1-25 rTMS sessions of 20-30 min duration to ADHD, 4 of them in adults with ADHD. Two double-blind, sham-controlled crossover studies stimulated the right DLPFC. One session of 20Hz-rTMS relative to sham significantly improved overall self-rated ADHD symptoms and inattention in 13 ADHD adults but had no effect on hyperactivity (34). Another study showed that 10 daily sessions of 10Hz-rTMS relative to sham had no effect on self-rated clinical symptoms in 9 ADHD adults, nor on EEG measures or cognitive performance (35). A single-blind sham-controlled randomised study showed no effect on self-rated clinical or cognitive measures of sustained attention in 22 ADHD adolescents after 20 daily sessions over 4 weeks of 18Hz deep rTMS over bilateral DLPFC (n = 13)