الفهرس 
NEUROBIOLOGY AND BIOMARKERS OF ADHDOnly 14 pages are availabe for public view
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Abstract
SUMMARY AND CONCLUSION
A
ttention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder of childhood characterized by inattention and/or hyperactivity/impulsivity causing impairment in the child’s academic and social functioning. The worldwide ADHD prevalence was estimated to be 7.1% in children and adolescents, 7.2 % of children and adolescents in the United States , however the incidence is much higher, reaching 9.4–21.8% in Egypt. 3 Most patients with ADHD will continue to have attention problems as an adults and many have comorbidities and academic and social problems.
Extensive studies of MRI in ADHD have found proven evidence for underlying brain structure and function deficits. Structural deficits were in the form of reduction in the grey matter, the cortical thickness and the surface area in frontal, parietal and temporal areas, the basal ganglia and insula as well, in patients with ADHD.4 These areas are interconnected by a neurocircuits and thus regulate attention, thoughts, emotions and behavior.
In addition to the deficits in grey matter, abnormal white matter tracts in fronto-striatal, interhemispheric and fronto-cerebellar circuits have been proven, and dysregulation of these circuits is considered as the underlying cause of the symptoms of Inattention and hyperactivity. Especially, the fronto-striatal circuit, which mediates executive cognitive functions, associated with deficits in motor response inhibition, working memory, sustained attention, response variability and cognitive switching as well as organization, and planning. Furthermore, the fronto-striatal-motivation/limbic circuits causing symptoms of emotional dysregulation, demotivation, hyperactivity-impulsivity, delay aversion and aggression. The fronto-cerebellar circuits are associated with motor coordination deficits and problems with the timing and timeliness of behavior.
The first line treatment for ADHD is psychostimulant medication despite the fact it’s controversial due to their potential of abuse and that only 50% can tolerate it sufficiently, also their adverse effects, on sleep, appetite, irritability, nausea/vomiting, abdominal pain, headaches, labile mood and growth suppression, however they are typically non-serious and can be transient. Moreover, long term efficacy has not been proven by research, and alternative treatments, including behavioral therapies, cognitive training, neurofeedback or dietary interventions, have shown limited efficacy.
Noninvasive brain stimulation treatments, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), can modulate cortical excitability and brain network activity. TMS can be used diagnostically for cortical neurophysiology, while daily use of repetitive TMS or tDCS can induce long-lasting changes. Accordingly they are promising therapeutic tool as it can stimulate brain dysregulated neurocircuits that have been implicated in ADHD. Furthermore, they are safe, with minimal side effects, cheaper than long-term drug treatments and can induce neuroplasticity.
Accordingly, the current study is a randomized sham controlled clinical trial and was conducted between August 2019 to August 2021, on 60 children with ADHD recruited from the out-patient clinic institute of psychiatry Ain shams university, aiming to assess the effect of rTMS combined with atomoxetine (ATX) in the treatment of ADHD, and whether rTMS combined to Atomoxetine is better than atomoxetine alone in treating children with ADHD.
Of the 60 participants, 30 participants was allocated to rTMS group who received 15 sessions of rTMS over the right DLPC, in conjunction with Atomoxetine 1.2 mg/kg/day. The other 30 participants were allocated to Sham control group who received 15 sessions of sham rTMS and atomoxetine 1.2 mg/kg/day. All participants were drug naïve for stimulants and non-stimulants, all other medications were stopped 2 weeks before the beginning of the study. Atomoxetine was started at 0.5mg/kg/day and was titrated to 1.2 mg/kg/day after 3 days. All participants underwent assessments of severity of ADHD symptoms done at 3 points, before the beginning of treatment (Pre), after receiving 15 sessions of rTMS/Sham rTMS (Post)and on follow up 1 month after treatment (FU), using revised-conner’s parent rating scale long version, Children’s Global Assessment Scale and Clinical Global Impression. The scores Pre, post and follow up were compared to evaluate the improvement of clinical symptoms and the therapeutic effects among the 2 groups were also compared.
The results of the presented study showed that t3he two groups show significant improvemnt in the T scores of all CPRS subscales, CGI and CGAS. However, rTMS group had a significantly more improvement than sham group in Attention total, ADHD severity, CGI and CGAS after rTMS and continued to the follow up after 1 month. Regarding Hyperactivity/impulsivity and social problems, rTMS group showed more significant improvement than sham group post rTMS/Sham, but on follow up there was no significant difference between the 2 groups.
Conclusion
The current work showed that 5 session/ week for 3 weeks (total of 15 sessions) of high frequency (10 Hz) repetitive transcranial magnetic stimulation directed to the right DLPFC and combined to atomoxetine is an efficatious treatment strategy for children with ADHD. Also, the combined treatment is superior to Atomoxetine in improving inattentive symptoms and overall ADHD symptoms severity in children with ADHD. However, further research is needed to validate our findings and to explore the optimum combination treatment protocol for children with ADHD.
STRENGTHS
T
his study among very few other that assess the therapeutic role of repetitive transcranial magnetic stimulation in children with ADHD. To date only six studies were carried out, 4 of them were conducted on adults and only 2 on children without including control group and with a small sample size. This study has several strengths points. The first is that it’s a randomized sham-controlled study, the inclusion of a control group (Sham group) gave a strength to this work which was not applied in other studies. Secondly, large sample size relative to other studies and being a pilot study. Thirdly, assessing rTMS in combination to atomoxetine as an effective treatment strategy for children with ADHD. Fourthly, this study among others that may pave the way to recognize the efficacy of rTMS as relatively safe therapeutic tool for children with ADHD.
LIMITATIONS
T
his study explores the possible therapeutic role of repetitive transcranial magnetic stimulation and the effectiveness of combining Atomoxetine and rTMS in children with ADHD. However, this work has several limitations, firstly, the small sample size, so further studies should be conducted on larger sample in order to ensure the results, moreover the study included only drug naïve ADHD without comorbidities which is not representative to the broad spectrum of presentations of ADHD. Secondly, the absence of guidelines for combination therapy including the dose of atomoxetine and the stimulation protocol of rTMS. Thirdly, the absence of neuropsychological tests to measure cognitive functions to validate our results of clinical improvement of inattention, assessments of the hot and cold executive functions. Finally, the follow up period was relatively short, longer follow up periods up to 6 months to track the long-term effect of rTMS.
RECOMMENDATIONS
• Research recommendations:
- Further studies on the therapeutic effect of rTMS in children with ADHD in order to prove its efficacy and safety for treatment.
- Further studies to assess the optimum combination therapy including the dose of atomoxetine and the stimulation protocol of rTMS
- Further studies on rTMS as diagnostic procedure to identify the electrophysiological biomarkers of ADHD and other neuropsychiatric disorders
- Studies on efficacy of rTMS in treating other neuropsychiatric disorders.
- Further studies on rTMS in children with ADHD conducted on larger samples from different catchment areas to be more representative to the community.
- Further studies on rTMS in children with ADHD with its broad comorbidities.
- Further studies on rTMS in children with ADHD and assess the improvement in the executive functions using Neuropsychological assessments.
• Clinical recommendations:
- Wider use of rTMS as a diagnostic and therapeutic procedure in different neuropsychiatric disorders
- The usage of neuropsychological tests for assessment of executive functions of children with ADHD at baseline and on follow ups
- The use of rTMS as a therapeutic tool for children with ADHD who didn’t show improvement or cant tolerate stimulants and/or nonstimulants.