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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
90
Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that uses magnetic fields to stimulate nerve cells in the brain. By placing a coil on the scalp, TMS generates magnetic pulses that induce electrical currents in specific brain regions. This can alter brain activity and potentially influence behavior and symptoms of various neurological and psychiatric conditions. PAS involves the use of transcranial magnetic stimulation (TMS) at a low and high frequency to stimulate the prefrontal cortex at different areas of the brain. The goal is to assess its effects on cortical arousal and ADHD symptoms. Participants will receive daily sessions of this stimulation for three weeks, with the stimulation designed to influence brain activity and potentially alleviate symptoms of ADHD.
Ben Gurion University of the Negev
Beersheba, Israel
RECRUITINGChange in ADHD Symptoms Assessed by the Conners' Adult ADHD Rating Scale (CAARS)
This measure evaluates the change in ADHD symptom severity using the Conners' Adult ADHD Rating Scale (CAARS), a standardized and validated assessment tool. The CAARS provides subscale scores (e.g., Inattention, Hyperactivity-Impulsivity, ADHD Index) on a scale ranging from 0 to 100, with higher scores indicating greater symptom severity. Change will be assessed by comparing scores obtained at baseline (pre-treatment) and following the intervention (post-treatment), as well as at 1-month and 2-month follow-up visits.
Time frame: Pre-treatment (baseline) and post-treatment assessments at the end of the 3-week treatment phase, with follow-up assessments at 1 month and 2 months after treatment to evaluate sustained symptom improvement.
Change in Cognitive Control Assessed by Stroop Task Performance
This measure assesses changes in participants' cognitive control by comparing pre-treatment and post-treatment performance on the Stroop Task. Performance is evaluated based on reaction time (milliseconds) and accuracy (% correct responses) in congruent and incongruent trials. Lower reaction times and higher accuracy typically indicate better cognitive control, but outcome-neutral interpretation will be used to assess change.
Time frame: Pre-treatment (baseline) and post-treatment (immediately after the 3-week treatment phase). Additional assessments may be conducted during follow-up sessions at 1 month and 2 months after treatment.
Change in Working Memory Assessed by N-back Task Performance
This measure evaluates working memory by comparing participants' pre-treatment and post-treatment performance on the N-back task (2-back condition). Performance is quantified by reaction time (milliseconds) and accuracy (% correct target detections). Lower reaction times and higher accuracy reflect stronger working memory performance, but results will be analyzed in a directionally neutral manner.
Time frame: Pre-treatment (baseline) and post-treatment (immediately after the 3-week treatment phase). Additional assessments may be conducted during follow-up sessions at 1 month and 2 months after treatment.
Change in EEG Power Spectral Density Across Frequency Bands
This outcome assesses changes in EEG power spectral density (PSD) in the delta (0.5-4 Hz), theta (4-7 Hz), alpha (8-12 Hz), and beta (13-30 Hz) frequency bands during resting-state EEG. PSD will be calculated using Fourier-based spectral analysis and reported in microvolts squared per hertz (µV²/Hz) at frontal and motor cortex sites.
Time frame: Baseline (pre/post Session 1), end of treatment (pre/post Session 15), and at 1-month and 2-month follow-ups. EEG is recorded during rest, cognitive tasks, TMS, TEP, and post-treatment rest at each time point.
Change in Raw EEG Voltage
This outcome measures the overall amplitude of raw EEG signals recorded at rest. Changes in baseline EEG voltage levels will be evaluated across treatment sessions and follow-ups to assess general cortical excitability. Unit of Measure: Microvolts (µV).
Time frame: Baseline (pre/post Session 1), end of treatment (pre/post Session 15), and at 1-month and 2-month follow-ups. EEG is recorded during rest, cognitive tasks, TMS, TEP, and post-treatment rest at each time point.
Long-Term Change in ADHD Symptoms Assessed at Follow-Up by Conners' Adult ADHD Rating Scale (CAARS)
This outcome assesses the persistence of treatment-related changes in ADHD symptoms using the Conners' Adult ADHD Rating Scale (CAARS). The CAARS includes multiple subscale scores (e.g., Inattention, Hyperactivity-Impulsivity) ranging from 0 to 100, with higher scores indicating greater symptom severity. Scores will be compared between post-treatment and follow-up time points to evaluate sustained changes. Unit of Measure: CAARS Subscale Score (0-100).
Time frame: Assessed during follow-up sessions at 1 month and 2 months after the end of the 3-week treatment phase to evaluate the persistence of treatment effects.
Long-Term Change in Cognitive Control Assessed at Follow-Up by Stroop Task Performance
This outcome evaluates long-term effects of TMS on cognitive control using the Stroop Task. Performance will be measured by reaction time (milliseconds) and accuracy (% correct responses) during congruent and incongruent trials. Comparisons will be made between post-treatment and follow-up time points to assess sustained changes in executive function. Unit of Measure: Milliseconds (reaction time), Percent correct (% accuracy).
Time frame: Assessed during follow-up sessions at 1 month and 2 months after the end of the 3-week treatment phase to evaluate the persistence of treatment effects.
Long-Term Change in Working Memory Assessed at Follow-Up by N-back Task Performance
This outcome evaluates the persistence of treatment-related changes in working memory using the 2-back condition of the N-back Task. Performance will be assessed based on reaction time (milliseconds) and accuracy (% correct target detections). Results from post-treatment and follow-up assessments will be compared. Unit of Measure: Milliseconds (reaction time), Percent correct (% accuracy).
Time frame: Assessed during follow-up sessions at 1 month and 2 months after the end of the 3-week treatment phase to evaluate the persistence of treatment effects.
Change in Amplitude of TMS-Evoked Potential (TEP) Components
This outcome assesses the amplitude of specific TMS-evoked potential (TEP) components (e.g., P30, N45, N100) extracted from EEG data recorded during TMS stimulation sessions. These components reflect cortical excitability and inhibition. Unit of Measure: Microvolts (µV).
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Time frame: Baseline (pre/post Session 1), end of treatment (pre/post Session 15), and at 1-month and 2-month follow-ups. EEG is recorded during rest, cognitive tasks, TMS, TEP, and post-treatment rest at each time point.
Change in Variance of TMS-Evoked Potentials (TEPs)
This outcome quantifies the trial-by-trial variability of TEP responses to assess consistency of cortical reactivity. Variance in EEG response to TMS will be calculated for each major TEP component. Unit of Measure: Microvolts squared (µV²).
Time frame: Baseline (pre/post Session 1), end of treatment (pre/post Session 15), and at 1-month and 2-month follow-ups. EEG is recorded during rest, cognitive tasks, TMS, TEP, and post-treatment rest at each time point.
Change in EEG Frequency Characteristics
This outcome tracks shifts in peak and dominant frequency within delta, theta, alpha, and beta bands during resting EEG. It provides insight into general neurophysiological state and functional changes over time. Unit of Measure: Hertz (Hz).
Time frame: Baseline (pre/post Session 1), end of treatment (pre/post Session 15), and at 1-month and 2-month follow-ups. EEG is recorded during rest, cognitive tasks, TMS, TEP, and post-treatment rest at each time point.