Traumatic Brain Injury
Conditions
Keywords
Explicit Memory, Implicit Memory, Memory Disorder
Brief 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. 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.
Interventions
DEVICErTMS
Altering the connectivity of trans-synaptic pathways
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Implicit Weather Prediction Task (WPT) | Changes are calculated before and the day after rTMS, and before and 7-14 days after rTMS | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
Participants were pre-screened by telephone and scheduled for consent and formal screening. Participants meeting eligibility were enrolled in the experiment. Study participants were either enrolled in Experiment 1 or 2. Experiment 1 was designed to determine the optimal number of rTMS sessions to produce a meaningful change in brain connectivity. Experiment 2 used the optimal number of rTMS sessions identified in Experiment 1, to stimulate different brain regions to study the effect on memory.
Participants by arm
| Arm | Count |
|---|---|
| Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day Experiment 1
rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 1 day | 3 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days Experiment 1
rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days | 6 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days Experiment 1
rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 4 days | 6 |
| Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days Experiment 2
rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Parietal Cortex over 3 days | 15 |
| Experiment 2: Vertex rTMS Stimulation - 3 Days Experiment 2
rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Vertex, over 3 days | 15 |
| Experiment 2: Prefrontal rTMS Stimulation - 3 Days Experiment 2
rTMS: Altering the connectivity of trans-synaptic pathways with rTMS applied to the Prefrontal Cortex over 3 days | 2 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Experiment 1 | Change of experimental design | 0 | 3 | 0 | 0 | 0 | 0 |
| Experiment 1 | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Experiment 1 | Physician Decision | 0 | 3 | 0 | 0 | 0 | 0 |
| Experiment 1 | Unable to obtain critical rTMS measure | 0 | 0 | 2 | 0 | 0 | 0 |
| Experiment 2 | Discomfort during stimulation | 0 | 0 | 0 | 0 | 0 | 2 |
| Experiment 2 | Lost to Follow-up | 0 | 0 | 0 | 1 | 1 | 0 |
| Experiment 2 | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 |
| Experiment 2 | Poor data quality | 0 | 0 | 0 | 4 | 1 | 0 |
| Experiment 2 | Pregnancy | 0 | 0 | 0 | 0 | 1 | 0 |
| Experiment 2 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Vertex rTMS Stimulation - 3 Days | Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Experiment 2: Prefrontal rTMS Stimulation - 3 Days |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 47 Participants | 3 Participants | 6 Participants | 15 Participants | 15 Participants | 6 Participants | 2 Participants |
| Age, Continuous | 25.27 Years STANDARD_DEVIATION 4.88 | 28.33 Years STANDARD_DEVIATION 9.24 | 26.67 Years STANDARD_DEVIATION 3.14 | 25.60 Years STANDARD_DEVIATION 5.46 | 24.93 Years STANDARD_DEVIATION 4.4 | 23.83 Years STANDARD_DEVIATION 2.64 | 21.00 Years STANDARD_DEVIATION 2.82 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 0 Participants | 0 Participants | 6 Participants | 2 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 3 Participants | 6 Participants | 9 Participants | 13 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 1 Participants | 1 Participants | 5 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 2 Participants | 3 Participants | 5 Participants | 10 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Female | 19 Participants | 0 Participants | 3 Participants | 6 Participants | 6 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 28 Participants | 3 Participants | 3 Participants | 9 Participants | 9 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 13 | 0 / 8 | 0 / 21 | 0 / 19 | 0 / 4 |
| other Total, other adverse events | 0 / 3 | 0 / 13 | 0 / 8 | 1 / 21 | 0 / 19 | 2 / 4 |
| serious Total, serious adverse events | 0 / 3 | 0 / 13 | 0 / 8 | 0 / 21 | 0 / 19 | 0 / 4 |
Outcome results
Primary
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
Population: Experiment 1 identified the optimal number of rTMS sessions to be applied in Experiment 2. The optimal number of rTMS sessions, i.e., 3 days, was applied to different regions of the brain in Experiment 2. Therefore, only the Experiment 2 data is reported for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Associative Memory Test Score Changes | Changes one day after rTMS | 0.08 Change in proportion of remembered pairs | Standard Deviation 0.133 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Associative Memory Test Score Changes | Changes 7-14 days after rTMS | 0.08 Change in proportion of remembered pairs | Standard Deviation 0.173 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Associative Memory Test Score Changes | Changes one day after rTMS | 0.01 Change in proportion of remembered pairs | Standard Deviation 0.166 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Associative Memory Test Score Changes | Changes 7-14 days after rTMS | 0.02 Change in proportion of remembered pairs | Standard Deviation 0.149 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Associative Memory Test Score Changes | Changes one day after rTMS | 0.03 Change in proportion of remembered pairs | Standard Deviation 0.035 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Associative Memory Test Score Changes | Changes 7-14 days after rTMS | 0.13 Change in proportion of remembered pairs | Standard Deviation 0.071 |
Primary
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
Population: Healthy volunteers participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex | -0.03 Change in z-transformed R-value | Standard Deviation 0.089 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex | 0.13 Change in z-transformed R-value | Standard Deviation 0.202 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex | 0.02 Change in z-transformed R-value | Standard Deviation 0.123 |
| Experiment 2: Parietal Cortex rTMS Stimulation - 3 Days | Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex | -0.01 Change in z-transformed R-value | Standard Deviation 0.109 |
| Experiment 2: Vertex rTMS Stimulation - 3 Days | Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex | -0.05 Change in z-transformed R-value | Standard Deviation 0.141 |
| Experiment 2: Prefrontal Cortex rTMS Stimulation - 3 Days | Functional Connectivity (FC) Changes Between the Left Hippocampus and Left Parietal Cortex | 0.03 Change in z-transformed R-value | Standard Deviation 0.088 |
Secondary
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
Population: Experiment 1 identified the optimal number of rTMS sessions to be applied in Experiment 2. The optimal number of rTMS sessions, i.e., 3 days, was applied to different regions of the brain in Experiment 2. Therefore, only the Experiment 2 data is reported for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Implicit Weather Prediction Task (WPT) | Changes one day after rTMS | -0.03 Change in proportion of optimal response | Standard Deviation 0.158 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 1 Day | Implicit Weather Prediction Task (WPT) | Changes 7-14 days after rTMS | -0.02 Change in proportion of optimal response | Standard Deviation 0.143 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Implicit Weather Prediction Task (WPT) | Changes one day after rTMS | 0.06 Change in proportion of optimal response | Standard Deviation 0.196 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 3 Days | Implicit Weather Prediction Task (WPT) | Changes 7-14 days after rTMS | 0.02 Change in proportion of optimal response | Standard Deviation 0.156 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Implicit Weather Prediction Task (WPT) | Changes one day after rTMS | 0.06 Change in proportion of optimal response | Standard Deviation 0.02 |
| Experiment 1: Parietal Cortex rTMS Stimulation - 4 Days | Implicit Weather Prediction Task (WPT) | Changes 7-14 days after rTMS | 0.01 Change in proportion of optimal response | Standard Deviation 0.03 |