A Phase 1/2 interventional study of rTMS in Traumatic Brain Injury, sponsored by National Institute of Neurological Disorders and Stroke (NINDS). Completed at 1 site in United States. Open to participants aged 18 Years to 50 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-04-12.
Sponsored by National Institute of Neurological Disorders and Stroke (NINDS) · Phase 1/2, Interventional, and Treatment
Background:
Traumatic brain injury (TBI) damages the connections between brain cells. This can lead to problems like memory loss. Repetitive transcranial magnetic stimulation (rTMS) can help improve connections between brain areas in healthy people. Researchers want to see if it can be useful in patients with memory problems after TBI.
Objective:
To see how repetitive transcranial magnetic stimulation can be used to improve the connections between parts of the brain and whether this will lead to changes in memory.
Eligibility:
Adults 18-50 years old with TBI who can speak and write in English.
Healthy volunteers the same age and English ability.
Design:
Participants will be screened with a neurological exam and may have a urine pregnancy test.
Participants with TBI will have 7-15 visits. Healthy volunteers will have 2-8 visits.
At the visits, participants will have all or some of the following:
A week after the last visit, some participants will return for a memory test.
Objective: To use resting state functional connectivity (FC) as a biomarker of synaptic modulation by repetitive transcranial magnetic stimulation (rTMS) in paradigms intended to improve memory and learning. Ancillary outcomes include the effects of rTMS on the interaction between the explicit implicit memory systems.
Study population: Healthy adult volunteers
Design: The study contains two experiments. Experiment 1 is designed to establish the number of rTMS sessions required to produce a meaningful change in resting parieto-hippocampal FC in healthy subjects. Experiment 2 will replicate a prior experiment which used rTMS to enhance the explicit memory system in healthy subjects, and look for potential effects on the implicit system. This intervention will be contrasted with a negative control condition (vertex stimulation) in a between-groups design.
Outcome measures: The primary outcome measure is the change in FC produced by serially applied rTMS and improvement in explicit memory. We will explore whether enhancement of the explicit system has effects on resting state connectivity in the implicit system and whether white matter integrity predicts changes in FC in healthy subjects.
2,112 studies on the registry are indexed under Brain Injuries; 384 are open to participants now.
This study's enrollment of 68 is above the median of 48 across 1,331 interventional studies indexed under Brain Injuries.
Browse Brain Injuries studies →National Institute of Neurological Disorders and Stroke (NINDS) is the lead sponsor of 592 studies on the registry; 56 are open to participants now.
Of its 18 completed or terminated interventional studies of FDA-regulated products, 8 (44%) have results posted.
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Experiments 1 and 2:
Healthy individuals
Age 18-50 (inclusive)
English speaking and writing
Experiment 3:
Age 18-50 (inclusive)
English speaking and writing
History of mild to moderate TBI
Performance 1 standard deviation below age-adjusted population norms on the
CVLT-2 within the past year from the date of visit.
EXCLUSION CRITERIA:
Any current major neurological or psychiatric disorder such as (but not limited to) stroke, Parkinson disease, Alzheimer disease, schizophrenia or major depression
History of seizure
Medications acting on the central nervous system
Ferromagnetic metal in the cranial cavity or eye, implanted neural stimulator, cochlear implant, or ocular foreign body
Implanted cardiac pacemaker or auto-defibrillator or pump
Non-removable body piercing
Claustrophobia
Inability to lie supine for 1 hour
Pregnancy, nursing, or plans to become pregnant during the study.
Members of the NINDS Behavioral Neurology Unit (BNU)
For Experiment 2: Participation in Experiment 1
Experiment 1
Device: rTMS
Experiment 1
Device: rTMS
Experiment 1
Device: rTMS
Experiment 2
Device: rTMS
Experiment 2
Device: rTMS
Experiment 2
Device: rTMS
Altering the connectivity of trans-synaptic pathways
Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex
Transcranial Magnetic Stimulation (TMS) is a non-invasive technique which applies magnetic pulses to the brain via a coil inducing an electrical current in the brain. Stimulation is typically applied at sufficient intensity to trigger action potentials in nearby neurons.The motor threshold is defined as the minimum percentage of the stimulator output to elicit a motor evoked potential. Repetitive TMS (rTMS) was delivered at 100% of the motor evoked potential threshold with repeated magnetic pulses at a frequency of 20 Hz. Functional MRI (fMRI) measures the change in oxygenated blood in the brain; at rest these levels fluctuate over time. These fluctuations can be similar between different parts of the brain. FC is the similarity in fluctuations of these fMRI signals and suggest how strongly two regions communicate with each other. We measured how TMS can change FC between specific areas of the brain. A positive score suggests a stronger communication between regions of the brain.
Time frame: Changes are calculated before and the day after rTMS
Associative Memory Test Score Changes
Participants studied 20 face-word pairs, and after a short delay, were required to recall the word associated with each pair. The number of correctly remembered pairs was recorded. rTMS was administered over different regions of the brain over 3 days. The Associative Memory test was administered at baseline (within a week before the first rTMS session), 1 day after the last rTMS session, and again 7-14 days after the last rTMS session. We calculated improvements on this task by subtracting the number of successfully remembered pairs 1 day after stimulation from the number remembered at baseline ("Changes one day after rTMS"). We also calculated whether these improvements lasted longer by subtracting the number of successfully remembered pairs 7-14 days after stimulation from the number remembered at baseline ("Changes 7-14 days after rTMS"). Positive scores represent increases in associative memory.
Time frame: Changes are calculated before and the day after rTMS and before and 7-14 days after rTMS
Implicit Weather Prediction Task (WPT)
Participants learn implicit, probabilistic relationships between stimuli and responses through feedback. 1, 2 and 3 card combinations of 4 possible cards are presented on a computer; the subject is asked to predict whether it will be rainy or fine. After each prediction, the subject receives corrective feedback. Each card is independently associated with one outcome with a fixed probability.The WPT was administered at baseline and 1 day after and 7-14 days after the last rTMS session. Scores at each time point represent the proportion of responses associated with a reward (optimal responses). We calculated improvement by subtracting the number of optimal responses 1 day after stimulation from the number at baseline (Changes one day after rTMS). We also calculated if these improvements lasted longer by subtracting the number of optimal responses 7-14 days after stimulation from the number at baseline (Changes 7-14 days after rTMS).Positive scores represent increases in implicit memory.
Time frame: Changes are calculated before and the day after rTMS, and before and 7-14 days after rTMS
Healthy Volunteers with an age range of 18-50 years were recruited for participation in Experiment 1 and 2. HV participants self-referred either directly or via the NIH Clinical Research Volunteer Program. Interested participants were pre-screened over the telephone. Participants with Traumatic Brain Injury were not recruited for this study, as Experiment 3 was not performed.
| Milestone | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal Cortex Stimulation |
|---|---|---|---|---|---|---|
| Started | 3 | 13 | 8 | 0 | 0 | 0 |
| Completed | 3 | 6 | 6 | 0 | 0 | 0 |
| Not completed | 0 | 7 | 2 | 0 | 0 | 0 |
| Withdrew: Lost to follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Physician decision | 0 | 3 | 0 | 0 | 0 | 0 |
| Withdrew: Change of experimental design | 0 | 3 | 0 | 0 | 0 | 0 |
| Withdrew: Unable to obtain critical rtms measure | 0 | 0 | 2 | 0 | 0 | 0 |
| Milestone | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal Cortex Stimulation |
|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 21 | 19 | 4 |
| Completed | 0 | 0 | 0 | 15 | 15 | 2 |
| Not completed | 0 | 0 | 0 | 6 | 4 | 2 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 1 | 1 | 0 |
| Withdrew: Physician decision | 0 | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Pregnancy | 0 | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 1 | 0 | 0 |
| Withdrew: Poor data quality | 0 | 0 | 0 | 4 | 1 | 0 |
| Withdrew: Discomfort during stimulation | 0 | 0 | 0 | 0 | 0 | 2 |
Transcranial Magnetic Stimulation (TMS) is a non-invasive technique which applies magnetic pulses to the brain via a coil inducing an electrical current in the brain. Stimulation is typically applied at sufficient intensity to trigger action potentials in nearby neurons.The motor threshold is defined as the minimum percentage of the stimulator output to elicit a motor evoked potential. Repetitive TMS (rTMS) was delivered at 100% of the motor evoked potential threshold with repeated magnetic pulses at a frequency of 20 Hz. Functional MRI (fMRI) measures the change in oxygenated blood in the brain; at rest these levels fluctuate over time. These fluctuations can be similar between different parts of the brain. FC is the similarity in fluctuations of these fMRI signals and suggest how strongly two regions communicate with each other. We measured how TMS can change FC between specific areas of the brain. A positive score suggests a stronger communication between regions of the brain.
| Change in z-transformed R-value | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal Cortex rTMS Stimulation - 3 Days |
|---|---|---|---|---|---|---|
| Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex | -0.03 ± 0.089 | 0.13 ± 0.202 | 0.02 ± 0.123 | -0.01 ± 0.109 | -0.05 ± 0.141 | 0.03 ± 0.088 |
Participants studied 20 face-word pairs, and after a short delay, were required to recall the word associated with each pair. The number of correctly remembered pairs was recorded. rTMS was administered over different regions of the brain over 3 days. The Associative Memory test was administered at baseline (within a week before the first rTMS session), 1 day after the last rTMS session, and again 7-14 days after the last rTMS session. We calculated improvements on this task by subtracting the number of successfully remembered pairs 1 day after stimulation from the number remembered at baseline ("Changes one day after rTMS"). We also calculated whether these improvements lasted longer by subtracting the number of successfully remembered pairs 7-14 days after stimulation from the number remembered at baseline ("Changes 7-14 days after rTMS"). Positive scores represent increases in associative memory.
| Change in proportion of remembered pairs | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal Cortex rTMS Stimulation - 3 Days |
|---|---|---|---|
| Changes one day after rTMS | 0.08 ± 0.133 | 0.01 ± 0.166 | 0.03 ± 0.035 |
| Changes 7-14 days after rTMS | 0.08 ± 0.173 | 0.02 ± 0.149 | 0.13 ± 0.071 |
Participants learn implicit, probabilistic relationships between stimuli and responses through feedback. 1, 2 and 3 card combinations of 4 possible cards are presented on a computer; the subject is asked to predict whether it will be rainy or fine. After each prediction, the subject receives corrective feedback. Each card is independently associated with one outcome with a fixed probability.The WPT was administered at baseline and 1 day after and 7-14 days after the last rTMS session. Scores at each time point represent the proportion of responses associated with a reward (optimal responses). We calculated improvement by subtracting the number of optimal responses 1 day after stimulation from the number at baseline (Changes one day after rTMS). We also calculated if these improvements lasted longer by subtracting the number of optimal responses 7-14 days after stimulation from the number at baseline (Changes 7-14 days after rTMS).Positive scores represent increases in implicit memory.
| Change in proportion of optimal response | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal Cortex rTMS Stimulation - 3 Days |
|---|---|---|---|
| Changes one day after rTMS | -0.03 ± 0.158 | 0.06 ± 0.196 | 0.06 ± 0.02 |
| Changes 7-14 days after rTMS | -0.02 ± 0.143 | 0.02 ± 0.156 | 0.01 ± 0.03 |
Collected over Adverse events were collected during and immediately after study procedures. Participants experiencing adverse events at completion of study procedures, were followed until AE resolution.. Non-serious events are listed at a 4.4% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) |
| Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | 0/13 (0%) | 0/13 (0%) | 0/13 (0%) |
| Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | 0/8 (0%) | 0/8 (0%) | 0/8 (0%) |
| Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | 0/21 (0%) | 0/21 (0%) | 1/21 (4.8%) |
| Experiment 2: Vertex rTMS Stimulation - 3 Days | 0/19 (0%) | 0/19 (0%) | 0/19 (0%) |
| Experiment 2: Prefrontal Cortex rTMS Stimulation - 3 Days | 0/4 (0%) | 0/4 (0%) | 2/4 (50%) |
| Event | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal Cortex rTMS Stimulation - 3 Days |
|---|---|---|---|---|---|---|
| Intolerance to stimulationNervous system disorders | 0/3 | 0/13 | 0/8 | 0/21 | 0/19 | 2/4 |
| MigraineNervous system disorders | 0/3 | 0/13 | 0/8 | 1/21 | 0/19 | 0/4 |
| Age, Categorical(Participants) | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal rTMS Stimulation - 3 Days | Total |
|---|---|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 3 | 6 | 6 | 15 | 15 | 2 | 47 |
| >=65 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Age, Continuous(Years) | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal rTMS Stimulation - 3 Days | Total |
|---|---|---|---|---|---|---|---|
| Mean | 28.33 ± 9.24 | 23.83 ± 2.64 | 26.67 ± 3.14 | 25.60 ± 5.46 | 24.93 ± 4.40 | 21.00 ± 2.82 | 25.27 ± 4.88 |
| Sex: Female, Male(Participants) | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal rTMS Stimulation - 3 Days | Total |
|---|---|---|---|---|---|---|---|
| Female | 0 | 3 | 3 | 6 | 6 | 1 | 19 |
| Male | 3 | 3 | 3 | 9 | 9 | 1 | 28 |
| Ethnicity (NIH/OMB)(Participants) | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal rTMS Stimulation - 3 Days | Total |
|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 0 | 1 | 0 | 6 | 2 | 0 | 9 |
| Not Hispanic or Latino | 3 | 5 | 6 | 9 | 13 | 2 | 38 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal rTMS Stimulation - 3 Days | Total |
|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 1 | 0 | 1 | 5 | 2 | 1 | 10 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 2 | 1 | 1 | 1 | 0 | 5 |
| White | 2 | 3 | 3 | 5 | 10 | 1 | 24 |
| More than one race | 0 | 0 | 1 | 1 | 2 | 0 | 4 |
| Unknown or Not Reported | 0 | 1 | 0 | 3 | 0 | 0 | 4 |
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National Institute of Neurological Disorders and Stroke (NINDS)