EEG Biomarkers for ADHD Stimulant Treatment
EEG Biomarkers for Pediatric ADHD Treatment Stratification
Pediatric attention deficit hyperactivity disorder (ADHD) affects up to 10% of children in the U.S. and more than 90% are prescribed stimulant medications according to clinical guidelines. The standard of care for pharmacological treatment of ADHD is a "trial-and-error" approach that requires frequent dose adjustments, side effects management, and communication among doctors, parents, and school personnel over weeks, months, and years. In the first year following prescription of stimulant medications, >50% of doctors are not able to conduct the recommended follow-up with their patients. Many patients stop taking medications or keep taking medications that do not work well, as a result.
This investigation will use a non-invasive brain imaging technique called EEG to look for activity in the brain that can predict which children with ADHD will respond well to two commonly prescribed stimulant medication groups, methylphenidate and amphetamines. Based on a previous study, it is expected that EEG signals can differentiate among children whose ADHD symptoms will get better on methylphenidate, and those whose ADHD symptoms will get better on amphetamines.
220 participants ages 7-11 with ADHD will be enrolled. Participants will not have autism or intellectual disabiltiy. They will not currently be taking psychiatric medications. Participants will not have not taken stimulant medications before or have tried stimulant medications >6 months or experienced an improvement in their ADHD symptoms by taking a stimulant medication before.
Study Participation Includes:
- Participant and caregiver complete a 3-hour visit at the Arnett Laboratory at 2 Brookline Place. During this visit, participants complete a brief IQ test and an EEG while their caregiver completes questionnaires and a clinical interview. The caregiver will give permission to request survey responses from the participant's teacher.
- The next day, the participant and caregiver will come back to the laboratory for a 1-hour visit. The participant will do another EEG while the caregiver fills out more surveys. The doctor will take the participant's vital signs and prescribe the medication.
- The participant will be randomly assigned to take either methylphenidate HCl or amphetamines every morning for 3 weeks. At the end of each week, the caregiver and teacher will fill out a questionnaire about the participant's behaviors and symptoms, including side effects.
- For one week, the participant will not take medications. They will come back into the lab for another EEG at the end of that week.
- The participant will then take the other medication every morning for 3 weeks. At the end of each week, the caregiver and teacher will fill out a questionnaire about the participant's behaviors and symptoms, including side effects.
- It will take participants about 7 weeks to complete this study. During this time, they will complete 3 in-person and 6 virtual study visits.
- The research funds will cover cost associated with the study. The participant's health insurer will not be billed for the medications or treatment. Medications will be provided through the research pharmacy.
- Participants will be given a report at the end of the study with details about the medication trials, symptom response, and any other findings. They will receive up to $270 for the completion of the study. Some travel-related costs will be covered by the study.
研究概览
详细说明
Pediatric attention deficit hyperactivity disorder (ADHD) affects up to 10% of children in the U.S. and more than 90% are prescribed stimulant medications according to clinical guidelines. The standard of care for pharmacological treatment of ADHD is a "trial-and-error" approach that requires frequent titration, side effects management, and communication among providers, parents, and school personnel over weeks, months, and years. This level of effort often exceeds the capacity of primary care providers, who manage treatment for the majority of affected children. In the first year following stimulant prescription, recommended routine follow-up occurs in <50% of cases treated in primary care. Consequently, suboptimal dosing and early discontinuation of stimulants are exceedingly common, with >75% pediatric ADHD patients showing suboptimal medication adherence in the first year.
The current proposal will utilize electroencephalography (EEG), a non-invasive, affordable brain measurement tool, to characterize predictive biomarkers for response to two commonly prescribed stimulant medication classes: methylphenidate (MPH) and amphetamines (AMP). Predictive biomarkers can be used to guide clinical decision making and treatment selection for pediatric ADHD, ultimately shortening the time from diagnosis to treatment optimization; reducing burden on clinicians, families, and teachers; and leading to better lifetime outcomes for children with ADHD. Thus far, behavioral- and genomic-based treatment biomarkers have not been successful for ADHD, and there is increasing demand by patients and providers to identify a solution.
Building on our pilot data, this study will constitute a prospective, single-blind, double-baseline randomized MPH-AMP crossover trial with 220 treatment-naïve, 7-11-year-old children with ADHD. EEG will be collected prior to each medication arm, and treatment response will be determined using 3-week rapid titration protocols, consistent with our pilot study and other published trials. Trained clinicians will characterize each participant as a "responder" or "non-responder" for each medication.
EEG features with small to medium effect sizes that are predictive of positive response to MPH and AMP will be identified. Preliminary data suggest MPH and AMP will have distinct EEG predictive biomarkers. To further examine the translational potential of these results, test-retest reliability and classification agreement of biomarkers over 24 hours and 4 weeks will be estimated. Results of this study have potential to accelerate pediatric mental health treatment development and precision medicine care for ADHD.
研究类型
注册 (估计的)
阶段
- 第四阶段
联系人和位置
学习联系方式
- 姓名：Anne B Arnett, PhD
- 电话号码：617-919-7771
- 邮箱：ArnettLab@childrens.harvard.edu
学习地点
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Massachusetts
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Brookline、Massachusetts、美国、02445
- Boston Children's Hospital at Two Brookline Place
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接触：
- Anne Arnett
- 电话号码：9788861658
- 邮箱：anne.arnett@childrens.harvard.edu
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参与标准
资格标准
适合学习的年龄
- 孩子
接受健康志愿者
描述
Inclusion Criteria:
- Ages 7:0 - 10:11 (years:months)
- Has a diagnosis of ADHD or being evaluated for ADHD
- Stimulant naïve or previously trialed stimulant medications for < 6 months without achieving symptom remission, per caregiver report and/or medical chart review (if available)
- CGI-Severity rating of 4 "Moderately ill" through 6 "Severely ill."
- Willing and able to comply with study procedures
Exclusion Criteria:
- Use of stimulants or other psychotropic medications within 7 days before Eligibility Visit
- History of severe side effects to stimulants (suicidality, complete loss of appetite, cardiopulmonary complications) per caregiver report or medical chart review, determined by the study MD
- Intellectual disability or IQ < 75 per medical chart review or performance on standardized cognitive testing during the Eligibility Visit
- Diagnosis of Autism spectrum disorder (ASD) per medical chart review or caregiver report
- Fetal alcohol exposure per medical chart review or caregiver report
- Current suicidal ideation per caregiver or child report on CSSRS
- Non-febrile seizures per caregiver report or medical chart review
- Cardiopulmonary conditions, pregnancy or other medical conditions that contraindicate psychostimulant use per determination by the study MD
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：随机化
- 介入模型：交叉作业
- 屏蔽：四人间
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
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实验性的：Methylphenidate HCl then Mixed Amphetamines
Participants in the first Arm will complete a 3-week titration of Methylphenidate HCl (Quillivant XR, 25mg/5mL).
Doses will be increased at the end of each week using the following schedule: week 1 2mL; week 2 4mL; week 3 6mL.
If intolerable side effects develop, the dose will be reduced to the previously tolerated level or the medication will be discontinued if no tolerable therapeutic dose can be identified.
Next, participants will complete a 1-week no-medication washout (range = 5-14 days allowed to accomodate participant schedules).
Lastly, participants will complete a 3-week titration of Mixed Amphetamines (Dyanavel XR, 2.5mg/1mL).
Doses will be increased at the end of each week using the following schedule: week 1 2mL; week 2 3mL; week 3 4mL.
If intolerable side effects develop, the dose will be reduced to the previously tolerated level or the medication will be discontinued if no tolerable therapeutic dose can be identified.
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3-week titration of liquid Quillivant XR
3-week titration of liquid Dyanavel XR
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实验性的：Mixed Amphetamines then Methylphenidate HCl
Participants in the second Arm will complete a 3-week titration of Mixed Amphetamines (Dyanavel XR, 2.5mg/1mL).
Doses will be increased at the end of each week using the following schedule: week 1 2mL; week 2 3mL; week 3 4mL.
If intolerable side effects develop, the dose will be reduced to the previously tolerated level or the medication will be discontinued if no tolerable therapeutic dose can be identified.
Next, participants will complete a 1-week no-medication washout (range = 5-14 days allowed to accomodate participant schedules).
Lastly, participants will complete a 3-week titration of Methylphenidate HCl (Quillivant XR, 25mg/5mL).
Doses will be increased at the end of each week using the following schedule: week 1 2mL; week 2 4mL; week 3 6mL.
If intolerable side effects develop, the dose will be reduced to the previously tolerated level or the medication will be discontinued if no tolerable therapeutic dose can be identified.
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3-week titration of liquid Quillivant XR
3-week titration of liquid Dyanavel XR
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研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
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Medication A Clinical Global Impressions - Improvement Scale (CGI-I)
大体时间：Week 3 Virtual Visit (Day 22)
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Clinician rating of participant ADHD symptom improvement on medication A. The Clinical Global Impressions - Improvement Scale (CGI-I) is rated by a trained study clinician on a scale of 1-7, with scores of 1 ("very much improved") and 2 ("much improved") corresponding to clinically significant symptom improvement.
Scores of 3-7 will indicate no improvement or worsening of symptoms.
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Week 3 Virtual Visit (Day 22)
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Medication B Clinical Global Impressions - Improvement Scale (CGI-I)
大体时间：End of Study Virtual Visit (Day 50)
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Clinician rating of participant ADHD symptom improvement on medication B. The Clinical Global Impressions - Improvement Scale (CGI-I) is rated by a trained study clinician on a scale of 1-7, with scores of 1 ("very much improved") and 2 ("much improved") corresponding to clinically significant symptom improvement.
Scores of 3-7 will indicate no improvement or worsening of symptoms.
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End of Study Virtual Visit (Day 50)
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Frontal Theta Beta Ratio
大体时间：Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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Theta-Beta Ratio (TBR): TBR will be calculated from periodic resting EEG.
Periodic power isolates the oscillatory component of the EEG by subtracting the aperiodic power spectra from the total power.
Periodic power is extracted with the Fitting Oscillations and One-Over-f (FOOOF) MATLAB toolbox which parametrizes resting state EEG data into aperiodic and periodic components.
Resting spectral power values will be averaged over theta (4-6 Hz) and beta (13-30 Hz) frequencies across midline electrode clusters (frontal: Fz, F3, F4; central: Cz, C3, C4; parietal: Pz, P3, P4; occipital: Oz, O1, O2).
Our primary analyses will focus on frontal TBR during the Lights-Off Resting condition.
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Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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Aperiodic Dynamics
大体时间：Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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Aperiodic Dynamics: The aperiodic exponent for lights-off and lights-on resting conditions will be averaged across midline electrode clusters FOOOF MATLAB toolbox.
Aperiodic dynamic values will be computed for each participant as the difference between lights-on and lights-off exponent, divided by the lights-off resting exponent, as in prior publications.
Thus, higher scores will indicate greater exponents in the lights-on experiment.
Primary analyses will use the central electrode cluster.
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Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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P100 Visual Evoked Potential Amplitude
大体时间：Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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VEP P100 Amplitudes.
The P100 VEP component will be derived from a passive pattern-reversal visual evoked potential (VEP) task that includes 200 500ms trials of a black and white checkerboard reversal over 3 minutes.
P100 amplitudes will be averaged over an occipital electrode cluster (Oz, O1, O2) from approximately 75-150ms and extracted for each trial.
Primary analyses will focus on mean VEP amplitude over trials.
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Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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Vanderbilt Rating Scales
大体时间：Baseline, Medication A Week 1, Medication A Week 2, Medication A Week 3, Crossover Week 4, Medication B Week 5, Medication B Week 6, End of Study Week 7
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The Vanderbilt Rating Scales include 18 items corresonding to DSM-5 ADHD symptoms.
Parents and teachers will each complete the scales using an electronic form.
Items are rated on a scale of 0-3, with 0 = symptom never or rarely occurs, and 3 = symptom often or almost always occurs.
Total symptom severity is calculated as the sum of all 18 items; inattention symptom severity is calculated as the sum of items 1-9; hyperactivity/impulsivity symptom severity is calculated as the sum of items 10-18.
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Baseline, Medication A Week 1, Medication A Week 2, Medication A Week 3, Crossover Week 4, Medication B Week 5, Medication B Week 6, End of Study Week 7
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
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P100 Visual Evoked Potential Habituation
大体时间：Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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VEP P100 Amplitudes.
The P100 VEP component will be derived from a passive pattern-reversal visual evoked potential (VEP) task that includes 200 500ms trials of a black and white checkerboard reversal over 3 minutes.
P100 amplitudes will be averaged over an occipital electrode cluster (Oz, O1, O2) from approximately 75-150ms and extracted for each trial.
Secondary analyses will focus on P100 amplitude changes over trial, i.e. habituation coefficients.
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Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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Side Effects Rating Scale, Parent- and Teacher-Report
大体时间：Baseline, Medication A Week 1, Medication A Week 2, Medication A Week 3, Crossover Week 4, Medication B Week 5, Medication B Week 6, End of Study Week 7
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Adverse effects associated with stimulant treatment will be recorded by parents and teachers on a weekly basis on the Vanderbilt Follow-Up rating scales, which include an adapted version of the Pittsburgh Side Effects Rating Scale.
12 side effects symptoms are rated on a scale of 0 = not currently a problem to 3 = severe problem.
Side effects will be used for clinical decision making.
Secondary exploratory analysis will examine associations between EEG features and total severity of side effects by summing ratings from the 12 items.
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Baseline, Medication A Week 1, Medication A Week 2, Medication A Week 3, Crossover Week 4, Medication B Week 5, Medication B Week 6, End of Study Week 7
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EEG Coherence
大体时间：Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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EEG coherence will be derived from resting state EEG as well as ERP tasks.
Both global (i.e., long-range) and local (i.e., within region of interest) coherence will be examined in exploratory analyses.
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Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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N2 Event Related Potential Amplitude
大体时间：Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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The HAPPE+ER pipeline will be used to extract N2 amplitudes during the Go-NoGo task, by condition and electrode.
Mean amplitudes will be calculated for components across regions of interest, following visual inspection of temporal and topographic plots.
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Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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P300 Event Related Potential Amplitude
大体时间：Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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The HAPPE+ER pipeline will be used to extract P300 amplitudes during the Go-NoGo task, by condition and electrode.
Mean amplitudes will be calculated for components across regions of interest, following visual inspection of temporal and topographic plots.
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Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)
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合作者和调查者
研究记录日期
研究主要日期
学习开始 (估计的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
其他研究编号
- P00055002
计划个人参与者数据 (IPD)
计划共享个人参与者数据 (IPD)？
IPD 计划说明
All participants will be given the option to share their de-identified data with research or public registries at the time of informed consent. Data that includes video content (EEG .mff files; assessment videos) will not be shared for ethical reasons. Only de-identified data will be shared. Participants who do not consent to data sharing will still be eligible to participate in this study. All data projected during the study will be preserved by the PIs for the duration required by law in Massachusetts where the data are collected.
To facilitate interpretation of the data, relevant metadata, manual of operations, study protocols, and details regarding data collection tools will be shared and associated with relevant datasets.
Survey data, behavioral assessment scores, EEG and ERP measures will be made available in .csv or .txt format that do not require the use of specialized
IPD 共享时间框架
IPD 共享访问标准
IPD 共享支持信息类型
- 研究方案
- 树液
药物和器械信息、研究文件
研究美国 FDA 监管的药品
研究美国 FDA 监管的设备产品
在美国制造并从美国出口的产品
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