Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, Working Memory
Conditions
Keywords
TMS, memory, ADHD, healthy, MRI, ADD
Brief summary
This study uses different types of functional magnetic resonance imagining (fMRI) to generate individual transcranial magnetic stimulation (TMS) targets. During the TMS/fMRI imagining sessions, the investigators stimulate a target of either high or low regional controllability during a working memory task to investigate network responses and the impact of TMS on behavior.
Detailed description
This study involves up to 4 visits for patients with Attention Deficit Hyperactivity Disorder (ADHD) and 5 visits for non-symptomatic subjects. Visit 1 has both remote and in-person procedures. The remote part of visit 1 will consist of a consenting and extended screening visit. The in-person procedures of visit 1 will be scheduled for the same day as visit 2. Before visit 2, the investigators will demonstrate TMS to make sure participants can tolerate the stimulation. Visit 2 consists of an hour-long baseline MRI Scan along with an assessment session. The baseline MRI scan is used to find individualized TMS targets. The assessment session of visit 2 will be done over a video call. During the video call, the investigators will have the participant complete some computerized tasks and assessments. Visit 3 will be a 1-hour long TMS/fMRI session, where the participant will complete a working memory task twice while single pulse TMS is being delivered. In between the 2 rounds of the working memory task, the participant will receive 4 minutes of repetitive stimulation. Non-symptomatic subjects will have a fourth visit that mirrors visit 3. Visit 5 or Visit 4 for ADHD participants, will take place if behavioral task is available, otherwise study participation will be considered complete. During the optional visit, participants may complete behavioral tasks during an MRI scan. No TMS will be administered during the final visit. Participants will receive the compensation at the end of their participation. Payment may be given earlier if the participant withdraws from the study.
Interventions
PROCEDUREHigh controllability TMS target
Administer TMS to a brain regions with high regional controllability while the subject engages in a working memory task.
DEVICETranscranial Magnetic Stimulation (TMS)
Transcranial Magnetic Stimulation (TMS) is a non-invasive form of brain stimulation. TMS can influence activity in various brain regions, and it allows researchers to test or modify brain circuit communication.
Sponsors
National Institutes of Health (NIH)
National Institute of Mental Health (NIMH)
University of Pennsylvania
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Masking description
This study will use a single-blind design.
Intervention model description
All healthy participants will have TMS administered to both their high and low regional controllability targets, but the order is randomized and counterbalanced. ADHD participants will have TMS administered to only their high regional controllability target.
Eligibility
Sex/Gender
ALL
Age
18 Years to 28 Years
Healthy volunteers
Yes
Inclusion criteria
* 18-28 years old * Right-handed * No history of schizophrenia or bipolar disorder * No history of neurological illness * Healthy participants: no history of any mental illness * ADD/ADHD Participants; Diagnosed with ADD/ADHD * ADD/ADHD: Ability to refrain from stimulant medication within 24 hours of study sessions * For participants reporting daily use of more than 400mg caffeine/ day: willing to lower down to this level at least 1 week prior to screening visit and maintain throughout study visits
Exclusion criteria
* Unable to have an MRI scan * Unable to receive or tolerate TMS * Pregnant, nursing, or trying to become pregnant (self-attestation alone) * History of stoke, epilepsy, or brain scarring * Healthy participants: psychoactive medication use * Healthy participants: first degree relative with psychosis * ADHD participants: inability to refrain from stimulant medication within 23 hours of study sessions * Active suicidality or current suicidal risk as determined by the investigator * Any medication that interferes with fMRI recordings as per PI discretion * Otherwise determined by investigator to be unfit for study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Single TMS Pulses to a High vs. Low Regional Controllability Target on Working Memory Task Performance | Up to 3 weeks | Control participants complete two visits in which they undergo functional MRI interleaved with TMS targeting a specific controllability region. Each visit involves administering single pulses of TMS while participants perform a working memory task (N-back), followed by a brief round of repetitive TMS (rTMS), and concluding with another set of single pulses while completing the N-back task. The targeted brain region is counterbalanced across visits, with one visit stimulating a high regional controllability target and the other stimulating a low regional controllability target. The effect of single-pulse TMS on N-back task performance will be assessed before rTMS administration using percent accuracy scores. Percent accuracy reflects the percentage of correct trials out of the total Nback trials, with higher scores indicating better task performance. |
| Effect of rTMS on Working Memory Task Performance | Pre- and post-TMS at visits 3 (approximately day 7) and 4 (approximately day 14) | Control participants complete two visits with functional MRI interleaved with TMS targeting a specific controllability region. Each visit includes single pulses of TMS during a working memory task (N-back), followed by a brief round of repetitive TMS (rTMS), and concluding with another set of single pulses while performing the N-back task. The targeted controllability region is counterbalanced, with one visit stimulating a high controllability target and the other a low controllability target. The effect of rTMS on N-back task performance will be assessed by comparing participants' percent accuracy scores before (pre-rTMS) and after (post-rTMS) rTMS. Percent accuracy, indicating the percentage of correct trials, will be analyzed for both high and low regional controllability targets across the visits. |
| Effect of rTMS to High vs. Low Controllability Target on Working Memory Task Performance | Up to 3 weeks | Control participants complete two visits where they undergo functional MRI interleaved with TMS targeting specific brain controllability regions. Each visit includes single pulses of TMS during a working memory task (N-back), followed by a brief round of repetitive TMS (rTMS), and concluding with another set of single pulses while performing the N-back task. The targeted brain region is counterbalanced across visits, with one visit stimulating a high controllability target and the other a low controllability target. In order to compare the effect of rTMS to high versus low controllability targets on working memory performance, we will assess the change in N-back task percent accuracy scores before (pre-rTMS) and after (post-rTMS) rTMS to both regions. A greater percent change (positive value) means improved task performance following rTMS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of rTMS on Working Memory Performance in Participants With ADHD | Pre- and post-TMS at visit 3 (approximately day 7) | Participants with ADHD complete a single visit where they undergo functional MRI interleaved with TMS to a high controllability region. During the visit, participants receive single pulses of TMS while performing the working memory task (N-back), followed by a brief round of repetitive TMS (rTMS), and concluding with another set of single pulses while completing the N-back task. The effect of rTMS on N-back task performance is assessed by comparing participants' percent accuracy scores before (pre-rTMS) and after (post-rTMS) rTMS. Percent accuracy reflects the percentage of correct trials out of the total number of N-back trials, with higher percent accuracy indicating better performance. |
Countries
United States
Participant flow
Pre-assignment details
Of the 68 participants screened for the study, 45 were enrolled and 23 did not start study procedures (13 screen failed, 4 withdrew from participation, and 6 lost to follow-up)
Participants by arm
| Arm | Count |
|---|---|
| Non-symptomatic Participants Non-symptomatic participants or those without any psychiatric history complete two visits involving functional MRI (fMRI) and TMS. Each visit targets a specific brain controllability region, with one visit focusing on a high controllability region and the other on a low controllability region. | 26 |
| ADHD Participants Participants diagnosed with ADHD or ADD complete one visit involving functional MRI (fMRI) and TMS. This visit focuses exclusively on a high controllability brain region. | 19 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Baseline MRI and Assessments | Lost to Follow-up | 0 | 0 | 4 |
| Baseline MRI and Assessments | Withdrawal by Subject | 2 | 0 | 0 |
| TMS/fMRI #1 | Physician Decision | 0 | 0 | 2 |
| Washout (at Least 7 Days) | Lost to Follow-up | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Non-symptomatic Participants | ADHD Participants | Total |
|---|---|---|---|
| Age, Continuous | 22.96 years STANDARD_DEVIATION 2.89 | 22.68 years STANDARD_DEVIATION 1.86 | 22.84 years STANDARD_DEVIATION 2.49 |
| E-SWAN ADHD scale Hyperactive/Impulsive ADHD Subscale | -1.300 units on a scale STANDARD_DEVIATION 0.94 | 0.550 units on a scale STANDARD_DEVIATION 0.84 | -0.520 units on a scale STANDARD_DEVIATION 1.28 |
| E-SWAN ADHD scale Inattentive ADHD Subscale | -1.310 units on a scale STANDARD_DEVIATION 0.73 | 0.750 units on a scale STANDARD_DEVIATION 0.81 | -0.440 units on a scale STANDARD_DEVIATION 1.28 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 17 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 13 Participants | 28 Participants |
| Region of Enrollment United States | 26 participants | 19 participants | 45 participants |
| Sex: Female, Male Female | 18 Participants | 15 Participants | 33 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 19 |
| other Total, other adverse events | 0 / 26 | 2 / 19 |
| serious Total, serious adverse events | 0 / 26 | 0 / 19 |
Outcome results
Primary
Effect of rTMS on Working Memory Task Performance
Control participants complete two visits with functional MRI interleaved with TMS targeting a specific controllability region. Each visit includes single pulses of TMS during a working memory task (N-back), followed by a brief round of repetitive TMS (rTMS), and concluding with another set of single pulses while performing the N-back task. The targeted controllability region is counterbalanced, with one visit stimulating a high controllability target and the other a low controllability target. The effect of rTMS on N-back task performance will be assessed by comparing participants' percent accuracy scores before (pre-rTMS) and after (post-rTMS) rTMS. Percent accuracy, indicating the percentage of correct trials, will be analyzed for both high and low regional controllability targets across the visits.
Time frame: Pre- and post-TMS at visits 3 (approximately day 7) and 4 (approximately day 14)
Population: Of the 23 participants who completed all study procedures, 2 participant's data was unusable for this analysis for the percent change comparison and high controllability group. Only 1 participant was unusable for the low controllability group.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| TMS to a High Controllability Target in Non-Symptomatic Participants | Effect of rTMS on Working Memory Task Performance | Nback results Pre-rTMS | 79.71 percentage accuracy |
| TMS to a High Controllability Target in Non-Symptomatic Participants | Effect of rTMS on Working Memory Task Performance | Nback results Post-rTMS | 81.65 percentage accuracy |
| TMS to a Low Controllability Target in Non-Symptomatic Participants | Effect of rTMS on Working Memory Task Performance | Nback results Pre-rTMS | 78.39 percentage accuracy |
| TMS to a Low Controllability Target in Non-Symptomatic Participants | Effect of rTMS on Working Memory Task Performance | Nback results Post-rTMS | 84.75 percentage accuracy |
Comparison: Statistics are from 2-tailed t-test comparing pre-rTMS to post-rTMS 2-back accuracy scores for a high controllability TMS target. Alternative hypothesis: true mean is not equal to 0.p-value: 0.43t-test, 2 sided
Comparison: Statistics are from 2-tailed t-test comparing pre-rTMS and post-rTMS 2-back percent accuracy scores for a low controllability TMS target. Alternative hypothesis: true mean is not equal to 0.p-value: <0.04t-test, 2 sided
Primary
Effect of rTMS to High vs. Low Controllability Target on Working Memory Task Performance
Control participants complete two visits where they undergo functional MRI interleaved with TMS targeting specific brain controllability regions. Each visit includes single pulses of TMS during a working memory task (N-back), followed by a brief round of repetitive TMS (rTMS), and concluding with another set of single pulses while performing the N-back task. The targeted brain region is counterbalanced across visits, with one visit stimulating a high controllability target and the other a low controllability target. In order to compare the effect of rTMS to high versus low controllability targets on working memory performance, we will assess the change in N-back task percent accuracy scores before (pre-rTMS) and after (post-rTMS) rTMS to both regions. A greater percent change (positive value) means improved task performance following rTMS.
Time frame: Up to 3 weeks
Population: Of the 23 participants who completed all study procedures, 2 participant's data was unusable for this analysis for the percent change comparison and high controllability group. Only 1 participant was unusable for the low controllability group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| TMS to a High Controllability Target in Non-Symptomatic Participants | Effect of rTMS to High vs. Low Controllability Target on Working Memory Task Performance | 1.94 percentage accuracy change |
| TMS to a Low Controllability Target in Non-Symptomatic Participants | Effect of rTMS to High vs. Low Controllability Target on Working Memory Task Performance | 6.36 percentage accuracy change |
Comparison: Statistics are from paired 2 tailed t-test comparing 2-back percent changes (Post-rTMS - pre-rTMS) scores for participant's high and low controllability target. Alternative hypothesis: true mean is not equal to 0.p-value: 0.27t-test, 2 sided
Primary
Effect of Single TMS Pulses to a High vs. Low Regional Controllability Target on Working Memory Task Performance
Control participants complete two visits in which they undergo functional MRI interleaved with TMS targeting a specific controllability region. Each visit involves administering single pulses of TMS while participants perform a working memory task (N-back), followed by a brief round of repetitive TMS (rTMS), and concluding with another set of single pulses while completing the N-back task. The targeted brain region is counterbalanced across visits, with one visit stimulating a high regional controllability target and the other stimulating a low regional controllability target. The effect of single-pulse TMS on N-back task performance will be assessed before rTMS administration using percent accuracy scores. Percent accuracy reflects the percentage of correct trials out of the total Nback trials, with higher scores indicating better task performance.
Time frame: Up to 3 weeks
Population: Of the 23 participants who completed all study procedures, 2 participants were unusable for this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| TMS to a High Controllability Target in Non-Symptomatic Participants | Effect of Single TMS Pulses to a High vs. Low Regional Controllability Target on Working Memory Task Performance | 79.71 percentage of accuracy |
| TMS to a Low Controllability Target in Non-Symptomatic Participants | Effect of Single TMS Pulses to a High vs. Low Regional Controllability Target on Working Memory Task Performance | 78.39 percentage of accuracy |
Comparison: Of the 23 participants who completed all study procedures, 2 participant's data was unusable for this analysis. Statistics are from paired 2 tailed t-test comparing pre-rTMS 2-back percent accuracy scores for participant's high and low controllability target.p-value: 0.66t-test, 2 sided
Secondary
Effect of rTMS on Working Memory Performance in Participants With ADHD
Participants with ADHD complete a single visit where they undergo functional MRI interleaved with TMS to a high controllability region. During the visit, participants receive single pulses of TMS while performing the working memory task (N-back), followed by a brief round of repetitive TMS (rTMS), and concluding with another set of single pulses while completing the N-back task. The effect of rTMS on N-back task performance is assessed by comparing participants' percent accuracy scores before (pre-rTMS) and after (post-rTMS) rTMS. Percent accuracy reflects the percentage of correct trials out of the total number of N-back trials, with higher percent accuracy indicating better performance.
Time frame: Pre- and post-TMS at visit 3 (approximately day 7)
Population: Of the 13 participants with ADHD that completed the study, 1 participant's data was unusable for this analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| TMS to a High Controllability Target in Non-Symptomatic Participants | Effect of rTMS on Working Memory Performance in Participants With ADHD | Nback results Pre-rTMS | 69.64 percentage of accuracy |
| TMS to a High Controllability Target in Non-Symptomatic Participants | Effect of rTMS on Working Memory Performance in Participants With ADHD | Nback results Post-rTMS | 81.18 percentage of accuracy |
Comparison: Statistics are from 2-tailed paired t-test comparing 2-back accuracy score before and after rTMS to a high controllability target. Alternative hypothesis: true mean is not equal to 0.p-value: <0.05t-test, 2 sided