Finding Alternatives to Standard Treatment for Attention-Deficit Hyperactivity Disorder (FAST-ADHD)

Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by poor attention, impulsivity, hyperactivity and emotional-motivational dysregulation. Here, we will test if repetitive transcranial magnetic stimulation (rTMS) can reduce the symptoms of ADHD.

Background & Rationale Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by poor attention, impulsivity, hyperactivity and emotional-motivational dysregulation. It has an estimated prevalence of 5% in children. Usually, ADHD in children is treated with stimulant medications, such as methylphenidate. However, these pharmacotherapy treatments have numerous unwanted side effects, including sleep disturbances, appetite changes, and emotional lability, and do not prove to be effective in every case. A promising and alternative option for reducing ADHD symptoms is non-invasive brain stimulation. Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive brain stimulation which involves the application of a magnetic field to the skull to change the behaviour and function of underlying brain areas. In turn, rTMS leads to positive long-term changes in neurochemical activity, and while studies are limited, some have shown that rTMS can reduce ADHD symptoms in adolescents with ADHD. In two separate neuroimaging studies, our team has shown that cortical thickness of the right superior frontal gyrus (r-SFG) is different in children with ADHD compared to those without (unpublished). Intriguingly, thinner r-SFG was associated with increased inattention and hyperactive behaviour, as measured by the Conners-3 Parent Rating Scale. Another recent study, in adults with ADHD, showed that high frequency rTMS to the right prefrontal cortex (which shares cortical space with the r-SFG) reduced ADHD symptoms. Moreover, studies have shown hypoactivity of the right superior frontal gyrus in individuals with ADHD. Therefore, in keeping with our findings, the primary aim of this study is to use rTMS to stimulate the r-SFG in children and adolescents with ADHD, hypothesizing that stimulating the r-SFG will lead to a reduction in ADHD symptoms. Parts of the superior frontal gyrus are anatomically and functionally connected to the cognitive control network. In line with this, cognitive control impairments are prevalent in individuals with ADHD. Participants will be randomly assigned to receive 4 weeks of active or sham (non-active) rTMS. Active and sham rTMS look and sound the same; the difference is that sham rTMS has no magnetic field emitted from the TMS coil, thereby acting as a placebo condition. Research Question & Objectives Furthermore, this study will examine brain chemistry before and after rTMS treatment as we recently showed that children with ADHD have decreased concentrations of glutamate in their right prefrontal cortex compared to typically developing children. This previous study also showed that gamma-Aminobutyric acid (GABA) concentrations in the supplementary motor area (part of the superior frontal gyrus) were significantly higher in children with ADHD compared to typically developing controls. Thus, as the secondary aim, we will examine the impact of rTMS on the participant's neurobiology (i.e. brain chemistry (e.g. glutamate/GABA concentrations)). Finally, most studies only investigate the effects of treatment on ADHD symptom severity and do not look further at the effects on everyday functioning. The core symptoms of ADHD (hyperactivity and inattentiveness) are biologically and functionally intertwined with downstream effects on overall daily functioning including academic success and peer relationships. Therefore, the third exploratory aim of this study is to investigate the behavioural outcomes of rTMS on several aspects of cognitive functioning and academic performance, and quality of life of children with ADHD. Methods Design: Sham-TMS controlled trial. (Sham rTMS vs Active rTMS) Primary Outcome: To examine the effect of active rTMS over the right superior frontal gyrus on ADHD symptoms, as measured by the Conners-3 Parent Rating Scale. Secondary Outcomes: To examine the impact of rTMS treatment on the neurobiology (glutamate and GABA concentrations) of the right superior frontal gyrus. Outline: Baseline Assessment (MRI Scan, assessment scales, neuropsychological testing) rTMS intervention: 5 x week for 4 weeks. Active repetitive TMS parameters will be intensity 120% resting motor threshold (RMT), 40 pulses over 4 seconds (frequency 10Hz), inter-trial interval of 26 seconds, 75 trains, 3000 pulses/session to the right superior frontal gyrus, duration of 37.5 minutes per session. For sham rTMS, set-up, duration, and sound (i.e. clicking sound) will be the same, but no magnetic field will be emitted from the rTMS coil. Post-intervention Assessment (MRI Scan, assessment scales, neuropsychological testing).

Participants and staff measuring outcomes will be blinded to whether the participant is receiving active or sham rTMS.

Active repetitive TMS parameters will be intensity 120% resting motor threshold (RMT), 40 pulses over 4 seconds (frequency 10Hz), inter-trial interval of 26 seconds, 75 trains, 3000 pulses/session to the right superior frontal gyrus, duration of 37.5 minutes per session.

For sham rTMS, set-up, duration, and sound (i.e. clicking sound) will be the same, but no magnetic field will be emitted from the rTMS coil.

Inclusion Criteria: Diagnosis of ADHD 8-16 years old IQ greater than 80 English fluency (to enable consent/assent) If on medication, must have been on the same type and dosage for at least 3 months. Exclusion Criteria: Diagnosis of mania, psychosis, or bipolar disorder Impediments to TMS or MRI (i.e. metal implants in body) Prior electroconvulsive therapy or vagus nerve stimulation Prior diagnosis of post-concussive syndrome Diagnosis of Autism Spectrum Disorder.

If we do make individual participant data (IPD) available to other researchers it will be in keeping with local provincial laws on health information privacy. Data (if available) will be provided upon request.