Traumatic Brain InjuryPhase 1/2NCT03050801
Functional Connectivity as a Biomarker of rTMS
A Phase 1/2 study testing rTMS in people with Traumatic Brain Injury, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Traumatic Brain Injury
- What is being tested?
- rTMS
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 68 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Mar 2017to 7 Aug 2020
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Experiments 1 and 2:
- Healthy individuals
- Age 18-50 (inclusive)
- English speaking and writing
- Experiment 3:
- Age 18-50 (inclusive)
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- 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.
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
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.
Read more
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:
- MRI for about 1 hour. Participants will lie in a machine that takes pictures in a magnetic field. Participants will do some memory tasks.
- Memory and attention tasks with pictures and with a computer
- Questions about their mental state and well-being
- TMS: A wire coil is held on the scalp and a short electrical current passes through it. Participants will hear a click and feel a pulling or twitch. They may be asked to make simple movements. rTMS is repeated magnetic pulses in short bursts. They will have this for about 20 minutes.
A week after the last visit, some participants will return for a memory test.
Read the detailed description
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.
- Conditions
- Traumatic Brain Injury
- Being tested
- rTMS
- Keywords
- Explicit Memory, Implicit Memory, Memory Disorder
- Medical subject headings
- Brain Injuries, Traumatic, Memory Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
rTMSDevice
Altering the connectivity of trans-synaptic pathways
| Study group | Role | What they receive |
|---|---|---|
| Parietal Cortex rTMS stimulation - 1 day | Experimental | Experiment 1 Receives: Device: rTMS |
| Parietal Cortex rTMS stimulation - 3 days | Experimental | Experiment 1 Receives: Device: rTMS |
| Parietal Cortex rTMS stimulation - 4 days | Experimental | Experiment 1 Receives: Device: rTMS |
| Experiment 2 - Parietal Cortex rTMS stimulation - 3 days | Experimental | Experiment 2 Receives: Device: rTMS |
| Experiment 2 - Vertex rTMS stimulation - 3 days | Experimental | Experiment 2 Receives: Device: rTMS |
| Experiment 2 - Prefrontal Cortex rTMS stimulation - 3 days | Experimental | Experiment 2 Receives: Device: rTMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Changes are calculated before and the day after rTMS and before and 7-14 days after rTMS
Secondary outcomes (1)
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.
Measured: Changes are calculated before and the day after rTMS, and before and 7-14 days after rTMS
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2017
- Study start24 Mar 2017
- Primary completion10 Mar 2020
- Study completion7 Aug 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Traumatic Brain InjuryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 68 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Eric M Wassermann, M.D., Principal investigator, National Institute of Neurological Disorders and Stroke (NINDS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03050801
- Sponsor's protocol ID
- 170055
- Other IDs
- 17-N-0055
- Status last verified
- Jun 2020
- First submitted
- 10 Feb 2017
- Last updated
- 12 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Wang JX, Rogers LM, Gross EZ, Ryals AJ, Dokucu ME, Brandstatt KL, Hermiller MS, Voss JL. Targeted enhancement of cortical-hippocampal brain networks and associative memory. Science. 2014 Aug 29;345(6200):1054-7. doi: 10.1126/science.1252900.
PubMed 25170153
Study at a glance
From the registry record, last updated by the sponsor on 12 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Functional Connectivity as a Biomarker of rTMS
- ClinicalTrials.gov ID
- NCT03050801
- Acronym / sponsor ID
- 170055
- Conditions
- Traumatic Brain Injury
- Keywords
- Explicit Memory, Implicit Memory, Memory Disorder
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 68 participants (actual)
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)US National Institutes of Health
- Study start
- 24 Mar 2017 (actual)
- Primary completion
- 10 Mar 2020 (actual)
- Study completion
- 7 Aug 2020 (actual)
- First posted
- 13 Feb 2017 (actual)
- Results
- Posted 12 Apr 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- MRI for about 1 hour. Participants will lie in a machine that takes pictures in a magnetic field. Participants will do some memory tasks.
- Memory and attention tasks with pictures and with a computer
- Questions about their mental state and well-being
- TMS: A wire coil is held on the scalp and a short electrical current passes through it. Participants will hear a click and feel a pulling or twitch. They may be asked to make simple movements. rTMS is repeated magnetic pulses in short bursts. They will have this for about 20 minutes.
A week after the last visit, some participants will return for a memory test.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Parietal Cortex rTMS stimulation - 1 day | Experimental | Device: rTMSExperiment 1 |
| Parietal Cortex rTMS stimulation - 3 days | Experimental | Device: rTMSExperiment 1 |
| Parietal Cortex rTMS stimulation - 4 days | Experimental | Device: rTMSExperiment 1 |
| Experiment 2 - Parietal Cortex rTMS stimulation - 3 days | Experimental | Device: rTMSExperiment 2 |
| Experiment 2 - Vertex rTMS stimulation - 3 days | Experimental | Device: rTMSExperiment 2 |
| Experiment 2 - Prefrontal Cortex rTMS stimulation - 3 days | Experimental | Device: rTMSExperiment 2 |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- Healthy individuals
- Age 18-50 (inclusive)
- English speaking and writing
- Age 18-50 (inclusive)
- English speaking and writing
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| rTMSAltering the connectivity of trans-synaptic pathways | Device | Experiment 2 - Parietal Cortex rTMS stimulation - 3 days, Experiment 2 - Prefrontal Cortex rTMS stimulation - 3 days, Experiment 2 - Vertex rTMS stimulation - 3 days, Parietal Cortex rTMS stimulation - 1 day, Parietal Cortex rTMS stimulation - 3 days, Parietal Cortex rTMS stimulation - 4 days |
Primary outcome
Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex
Time frame: Changes are calculated before and the day after rTMS
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.
Associative Memory Test Score Changes
Time frame: Changes are calculated before and the day after rTMS and before and 7-14 days after rTMS
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.
1 secondary outcome
Implicit Weather Prediction Task (WPT)
Time frame: Changes are calculated before and the day after rTMS, and before and 7-14 days after rTMS
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Apr 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 25170153Wang JX, Rogers LM, Gross EZ, Ryals AJ, Dokucu ME, Brandstatt KL, Hermiller MS, Voss JL. Targeted enhancement of cortical-hippocampal brain networks and associative memory. Science. 2014 Aug 29;345(6200):1054-7. doi: 10.1126/science.1252900.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Eric M Wassermann, M.D. principal investigator
National Institute of Neurological Disorders and Stroke (NINDS)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing rTMS in people with Traumatic Brain Injury, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Apr 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex (time frame: Changes are calculated before and the day after rTMS). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03050801, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Apr 2021.