This study investigates the effects of high and low-frequency paired associative deep transcranial magnetic stimulation (dTMS) on adults with Attention Deficit Hyperactivity Disorder (ADHD). The study aims to explore whether targeting the prefrontal cortex with paired stimulation can improve symptoms of ADHD by balancing cortical arousal between the brain hemispheres. A total of 90 participants with ADHD will be recruited. Participants with ADHD will undergo three weeks of daily TMS treatment, while participants who receive a sham treatment will be included for baseline comparisons. The study will measure electrophysiological, cognitive, and clinical outcomes using a variety of assessments, including EEG, cognitive tests, and CAARS to evaluate the treatment's efficacy.

Introduction Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that uses magnetic fields to stimulate nerve cells in the brain, potentially altering brain activities and influencing behavior. It has been applied in both healthy individuals and patients to study brain activity, behavior, and therapeutic effects. TMS can be administered as single pulses or repetitive stimuli, with the latter showing lasting effects beyond the treatment session. High-frequency TMS is FDA-approved for treating major depressive disorder, obsessive-compulsive disorder, and smoking cessation.

ADHD is a neurodevelopmental disorder characterized by inattention, impulsivity, and hyperactivity. Neuroimaging studies have identified deficits in brain regions such as the prefrontal cortex, basal ganglia, and cerebellum in ADHD patients. Enhancing activity in these areas, particularly the prefrontal cortex, through high-frequency TMS has shown promise in reducing ADHD symptoms.

Research Question and Hypothesis The study aims to assess the effectiveness of paired associative stimulation (PAS) in treating ADHD. It hypothesizes that right-to-left prefrontal paired stimulation can enhance cortical arousal and provide symptom relief. The study includes two active treatment groups (high and low-frequency PAS) and a sham treatment group, with secondary goals to quantify short- and long-term changes in behavior, brain function, and structure.

Methods

Participants Total: 90 ADHD patients ADHD patients: Pre-screened by a psychiatrist; will undergo three weeks of treatment.

Healthy controls: Single session to measure brain activity and arousal.

Length of Experiment Recruitment duration: Approximately three years to recruit 90 ADHD subjects. Individual participation: Three weeks of treatment, with follow-up sessions at one and two months post-treatment.

Procedure Patient recruitment: Includes medical screening, consent, physical and neurological examinations, and psychological assessments.

Experimental Groups:

Group A: Low-frequency active PAS (30 ADHD subjects). Group B: High-frequency active PAS (30 ADHD subjects). Group C: Low-frequency sham PAS (30 ADHD subjects).

Daily Magnetic Therapy Phase 15 TMS treatments over three weeks for ADHD subjects, including cognitive exercises post-TMS. Data collection includes EEG recordings, cognitive tests, and brain response measurements before and after TMS.

Follow-up Phase Two sessions, four weeks apart, assessing treatment effectiveness and side effects through EEG and questionnaires.

Conclusion This study explores the potential of high and low-frequency paired associative dTMS in treating ADHD by targeting interhemispheric balance in the prefrontal cortex. The research will provide insights into the efficacy of PAS as an innovative treatment approach for ADHD.

Inclusion Criteria:

• Men and women aged 21-65.
• Aligned with the diagnosis of ADHD according to the criteria of the DSM-5.
• Participants taking medication for the treatment of attention deficit hyperactivity disorder will be asked, starting one week before the start of the treatment until the end, to take Ritalin IR 10mg (provided that the taking of the medication will be done at least 8 hours before the start of the treatment or at least one hour after it. This instruction is also valid for taking the medication on the days of the follow-up sessions (4 and 8 weeks from the end of the daily treatment phase). Ritalin is given as the only option because a drug with a short half-life is needed. The dose can be increased up to 20 mg per dose). The choice of this drug is to ensure that changes in brain function/activity are not the result of the Ritalin medication but of the research intervention.
• Give their written and oral consent to participate in the study.

Exclusion Criteria:

• Additional active psychiatric disorders in Axis I of the DSM-5.
• Antipsychotic treatment, antidepressants, or mood stabilizers.
• History of intolerance to TMS.
• Diagnosis of severe personality disorder according to the DSM-5.
• Current suicidal tendency.
• High and uncontrolled blood pressure.
• History of epilepsy, seizures or febrile seizures.
• History of epilepsy or seizures in first degree relatives.
• History of a head injury or major stroke that produced impairment.
• History of metal in the head (outside the oral cavity).
• History of surgery involving metal implants or a known history of metal particles in the eye, pacemakers, hearing aid implantation, use of neurostimulators, or any medical pump.
• History of drug or alcohol addiction.
• Inability to adequately communicate with the examiner.
• Participation in another medical study at the time of conducting the experiment or 3 months before it.
• Inability of the subject to sign a consent form.
• Pregnancy or not giving a commitment not to get pregnant during the study period or having sex without using contraceptives.