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Funding issues
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This device-study includes a pilot, physiological investigation of normal human subjects. The aim is to determine how existing non-invasive neuromodulation devices affect brain circuitry as measured by EEG recording. Currently, the application of non-invasive neuromodulation is rarely guided by detailed knowledge of how neural activity is altered in the brain circuits that are targeted for intervention. This gap in knowledge is problematic for interpreting response variability, which is common. To address this gap, the current proposal aims to combine two forms of neuromodulation sequentially, transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), to regulate homeostatic plasticity prior to rTMS delivery at different frequencies of rTMS. Homeostatic plasticity, the initial activation state of a targeted circuit, is a key determinant of whether rTMS induces long term potentiation (LTP) or long term depression (LTD) Yet, homeostatic plasticity is rarely measured or controlled in rTMS studies. We aim to control homeostatic plasticity by preconditioning the targeted circuits with tDCS prior to rTMS delivery. The protocol included an exploratory aim to examine physiological changes in patients with tinnitus but this aim was not part of the pilot physiological investigation and it could not be completed due to funding limitations.
Background and Rationale: The current proposal aims to combine two forms of neuromodulation, transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), to regulate homeostatic plasticity prior to rTMS delivery at two different frequencies (1Hz and 10Hz). Homeostatic plasticity, the initial activation state of a targeted circuit, is a theoretical determinant of whether rTMS induces long term potentiation (LTP) or long term depression (LTD).Yet, homeostatic plasticity is rarely measured or controlled in rTMS studies. In a physiological investigation of health subjects, we aim to control homeostatic plasticity by preconditioning the targeted circuits with tDCS prior to rTMS delivery. The justification for this study is that controlling homeostatic plasticity can reduce subject variability and the knowledge gained can be used to optimize rTMS delivery. What is needed to move the field forward is a method for combining tDCS and rTMS and for measuring neuronal responses directly which we aim to establish in this study. The pilot study project will examine the targeted effects of neuromodulation in normal subjects. The brain regions targeted for intervention include auditory areas in the temporal cortex (TC) that process sounds and functionally connected regions of the dorsolateral frontal cortex (DLFC) that mediate sensory habituation. Due to funding limitations, only the 1 Hz rTMS condition could be initiated.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| tDCS and 1 Hz rTMS delivered over TC | Experimental | Participants receive sham and active 2mA tDCS over the temporal cortex (TC) prior to receiving sham and active 1 Hz rTMS (900 rTMS pulses at 110% motor threshold) delivered to the TC. . |
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| tDCS and 10Hz rTMS delivered over TC | Experimental | Participants receive sham and active 2mA tDCS over the temporal cortex (TC) prior to receiving sham and active 10 Hz rTMS (900 rTMS pulses at 110% motor threshold) delivered to the TC. |
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| tDCS over DLFC and 1 Hz rTMS over TC | Experimental | Participants receive sham and active 2mA tDCS over the dorsolateral frontal cortex (DLFC) prior to receiving sham and active 1 Hz rTMS (900 rTMS pulses at 110% motor threshold) delivered to the TC. |
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| tDCS over DLFC and 10 Hz rTMS over TC | Experimental | Participants receive sham and active 2mA tDCS over the dorsolateral frontal cortex (DLFC) prior to receiving sham and active 10 Hz rTMS (900 rTMS pulses at 110% motor threshold) delivered to the TC. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| sham tDCS and sham rTMS | Device | Both combinations of tDCS and rTMS in this intervention are sham. |
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| Measure | Description | Time Frame |
|---|---|---|
| Log Transformed P100 Amplitude of TEPs From the Global Mean Field Analysis. | TEPs refer to TMS-evoked EEG potentials. The P100 amplitude of TEPs is one means of assessing cortical excitability. The P100 amplitude has been shown to be a reliable metric in studies of healthy subjects. The P100 amplitude is used in this study to assess the excitation state of two regions of interest (ROIs), one in the TC and one in the DLPFC, at each period of TEP recording (i.e., Baseline, Post tDCS, Post rTMS, and 20 minute delay). | Up to 8 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mark Mennemeier, PhD | University of Arkansas | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Arkansas for Medical Sciences | Little Rock | Arkansas | 72205 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | tDCS and 1 Hz rTMS Delivered Over TC | Participants receive sham and active 2mA tDCS over the temporal cortex (TC) prior to receiving sham and active 1 Hz rTMS (900 rTMS pulses at 110% motor threshold) delivered to the TC. . sham tDCS and sham rTMS: Both combinations of tDCS and rTMS in this intervention are sham. sham tDCS and active rTMS: tDCS in this intervention is sham and rTMS is active active tDCS and active rTMS: Both combinations of tDCS and rTMS in this intervention are active |
| FG001 | tDCS Over DLFC and 1 Hz rTMS Over TC | Participants receive sham and active 2mA tDCS over the dorsolateral frontal cortex (DLFC) prior to receiving sham and active 1 Hz rTMS (900 rTMS pulses at 110% motor threshold) delivered to the TC. sham tDCS and sham rTMS: Both combinations of tDCS and rTMS in this intervention are sham. sham tDCS and active rTMS: tDCS in this intervention is sham and rTMS is active active tDCS and active rTMS: Both combinations of tDCS and rTMS in this intervention are active |
| FG002 | tDCS and 10Hz rTMS Delivered Over TC | Participants receive sham and active 2mA tDCS over the temporal cortex (TC) prior to receiving sham and active 10 Hz rTMS (900 rTMS pulses at 110% motor threshold) delivered to the TC. sham tDCS and sham rTMS: Both combinations of tDCS and rTMS in this intervention are sham. sham tDCS and active rTMS: tDCS in this intervention is sham and rTMS is active active tDCS and active rTMS: Both combinations of tDCS and rTMS in this intervention are active |
| FG003 | tDCS Over DLFC and 10 Hz rTMS Over TC | Participants receive sham and active 2mA tDCS over the dorsolateral frontal cortex (DLFC) prior to receiving sham and active 10 Hz rTMS (900 rTMS pulses at 110% motor threshold) delivered to the TC. sham tDCS and sham rTMS: Both combinations of tDCS and rTMS in this intervention are sham. sham tDCS and active rTMS: tDCS in this intervention is sham and rTMS is active active tDCS and active rTMS: Both combinations of tDCS and rTMS in this intervention are active |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Baseline characteristics are reported for the two arms to which subjects were assigned.
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| ID | Title | Description |
|---|---|---|
| BG000 | tDCS and 1 Hz rTMS Delivered Over TC | Baseline characteristics for participants assigned to the arm that received tDCS and 1Hz rTMS over the temporal cortex. |
| BG001 | tDCS and 1 Hz rTMS Delivered Over DLPF |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Log Transformed P100 Amplitude of TEPs From the Global Mean Field Analysis. | TEPs refer to TMS-evoked EEG potentials. The P100 amplitude of TEPs is one means of assessing cortical excitability. The P100 amplitude has been shown to be a reliable metric in studies of healthy subjects. The P100 amplitude is used in this study to assess the excitation state of two regions of interest (ROIs), one in the TC and one in the DLPFC, at each period of TEP recording (i.e., Baseline, Post tDCS, Post rTMS, and 20 minute delay). | The analyses population is 5 subjects who were assigned to the arm "tDCS and 1 Hz rTMS over the temporal cortex". The group titles reflect sequences of sham and active tDCS and rTMS conditions used to create contrasts for data analysis. Outcome measures are not reported for the DLPF arm because, due to insufficient resources and the required personnel needed to perform the extensive data cleaning and pipeline analysis, no P100 amplitude data can be reported. | Posted | Mean | Standard Deviation | log µV | Up to 8 weeks |
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Three lab visits over 6 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cumulative Report of Adverse Events | Adverse events data were collected irrespective of Arm/Group assignment. Adverse events were coded as either serious/nonserious, expected/unexpected, and related or unrelated to the intervention. There was only 1 adverse event (a mild headache, which was nonserious, expected and related to active rTMS). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Skin and subcutaneous tissue disorders | Systematic Assessment | Mild headache reported after TMS stimulation. |
Our pilot study funding ended. Subjects could not be recruited for the 10 Hz rTMS arm. A proposed study of tinnitus patients could not be initiated. Data analysis could only be completed for one arm.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Mark Mennemeier | University of Arkansas for Medical Sciences | 205 410 2413 | msmennemeier@uams.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 26, 2018 | Sep 29, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D014012 | Tinnitus |
| ID | Term |
|---|---|
| D006311 | Hearing Disorders |
| D004427 | Ear Diseases |
| D010038 | Otorhinolaryngologic Diseases |
| D012678 | Sensation Disorders |
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| ID | Term |
|---|---|
| D065908 | Transcranial Direct Current Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D003295 | Convulsive Therapy |
| D013000 | Psychiatric Somatic Therapies |
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This prospective, experimental design includes a block randomized, blinded, sham controlled, mixed effects model with sequential assignment to treatment arms (1 or 10 Hz rTMS) and random assignment to the tDCS conditions within each arm. The order of the three experimental conditions within each arm is randomized.
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| sham tDCS and active rTMS | Device | tDCS in this intervention is sham and rTMS is active |
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| active tDCS and active rTMS | Device | Both combinations of tDCS and rTMS in this intervention are active |
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Baseline characteristics for participants assigned to the arm that received tDCS and 1Hz rTMS over the dorsolateral frontal cortex.
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Mean baseline P100 amplitude of the GMFA | The mean of the P100 amplitude during a baseline recording, before any of the tDCS or rTMS interventions have been introduced. | Outcome measures are not reported for the DLPF arm because, due to insufficient resources and the required personnel needed to perform the data cleaning and pipeline analysis, no P100 amplitude data can be reported. | Mean | Standard Deviation | µV |
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| Sham tDCS Preconditioning |
TEPs recorded post sham tDCS but before rTMS. |
| OG001 | Active tDCS Preconditioning | TEPs recorded after active tDCS preconditioning but before rTMS. |
| OG002 | Sham tDCS Preconditioning of Sham rTMS | TEPs recorded after sham tDCS preconditioning and sham rTMS. |
| OG003 | Sham tDCS Preconditioning of Active rTMS | TEPs recorded after sham tDCS preconditioning and active rTMS. |
| OG004 | Active tDCS Preconditioning of Active rTMS | TEPs recorded after active tDCS preconditioning and active rTMS. |
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| 0 |
| 10 |
| 0 |
| 10 |
| 1 |
| 10 |
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| D009461 |
| Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |
| Unknown or Not Reported |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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