Regulating Homeostatic Plasticity and the Physiological Response to rTMS

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Regulating Homeostatic Plasticity and the Physiological Response to rTMS

Conditions
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Tinnitus

Intervention / Treatment
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* Device: sham tDCS and sham rTMS
* Device: sham tDCS and active rTMS
* Device: active tDCS and active rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: complete the informed consent process men and women, age: 21-65 years negative pregnancy test (female subjects of childbearing age must take a pregnancy test). Exclusion Criteria: a personal or family history of epilepsy, severe head injury, aneurysm, stroke, previous cranial neurosurgery, sever or recurrent migraine headaches, metal implants in the head or neck, a pacemaker, pregnancy, medications that lower seizure threshold,

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tDCS and 1 Hz rTMS delivered over TC<br>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. . | Device: sham tDCS and sham rTMS<br>* Both combinations of tDCS and rTMS in this intervention are sham.<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);Device: sham tDCS and active rTMS<br>* tDCS in this intervention is sham and rTMS is active<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);Device: active tDCS and active rTMS<br>* Both combinations of tDCS and rTMS in this intervention are active<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);|
| Experimental: tDCS and 10Hz rTMS delivered over TC<br>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. | Device: sham tDCS and sham rTMS<br>* Both combinations of tDCS and rTMS in this intervention are sham.<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);Device: sham tDCS and active rTMS<br>* tDCS in this intervention is sham and rTMS is active<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);Device: active tDCS and active rTMS<br>* Both combinations of tDCS and rTMS in this intervention are active<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);|
| Experimental: tDCS over DLFC and 1 Hz rTMS over TC<br>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. | Device: sham tDCS and sham rTMS<br>* Both combinations of tDCS and rTMS in this intervention are sham.<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);Device: sham tDCS and active rTMS<br>* tDCS in this intervention is sham and rTMS is active<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);Device: active tDCS and active rTMS<br>* Both combinations of tDCS and rTMS in this intervention are active<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);|
| Experimental: tDCS over DLFC and 10 Hz rTMS over TC<br>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. | Device: sham tDCS and sham rTMS<br>* Both combinations of tDCS and rTMS in this intervention are sham.<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);Device: sham tDCS and active rTMS<br>* tDCS in this intervention is sham and rTMS is active<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);Device: active tDCS and active rTMS<br>* Both combinations of tDCS and rTMS in this intervention are active<br>* Other names: transcranial direct current stimulation (tDCS), repetative transcranial magnetic stimulation (rTMS);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 |