Ignite Creation Date:
2024-05-06 @ 10:48 AM
Last Modification Date:
2024-10-26 @ 12:35 PM
Study NCT ID:
NCT03351764
Status:
RECRUITING
Last Update Posted:
2024-07-12
First Post:
2017-11-22
Brief Title:
Development of Non-Invasive Brain Stimulation Techniques
Sponsor:
National Institute of Mental Health NIMH
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Development of Non-Invasive Brain Stimulation Techniques
Status:
RECRUITING
Status Verified Date:
2024-08-27
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background
Noninvasive brain stimulation NIBS may help diagnose and treat psychiatric and neurological illness But there is not enough research on how to apply NIBS This includes how strong to make it where on the brain to apply it and for how long Researchers also want to see what the brain is doing when it receives NIBS
Objective
To increase the effectiveness of NIBS
Eligibility
Healthy native English speakers ages 18-65
Design
Participants will be screened under another protocol with
Medical and psychiatric history
Psychiatric evaluation
Physical exam
Urine tests
All participants will start with a 2-hour visit for screening see below They may learn how to do tasks that will be used later After the screening session they will be scheduled for an MRI session
The next part of the study is 4 substudies Each substudy includes up to 4 sessions A session is usually 2-3 hours but can last up to 8 hours Participants can join multiple substudies but only 1 at a time They can do only 1 session on a given day
Each substudy includes the following
Behavioral tests Interviews questionnaires simple tasks and tests of memory attention and thinking
Electromyography Small sticky electrodes on the skin measure muscle activity
Transcranial magnetic stimulation A wire coil is held to the scalp A brief electrical current passes through the coil and affects brain activity
Magnetic resonance imaging MRI Participants lie on a table that slides into a machine that takes pictures of the brain A coil is placed over the head They will perform simple tasks while in the scanner They may also get TMS
Electroencephalography Small electrodes on the scalp record brain waves
Sponsoring Institution National Institute of M
Noninvasive brain stimulation NIBS may help diagnose and treat psychiatric and neurological illness But there is not enough research on how to apply NIBS This includes how strong to make it where on the brain to apply it and for how long Researchers also want to see what the brain is doing when it receives NIBS
Objective
To increase the effectiveness of NIBS
Eligibility
Healthy native English speakers ages 18-65
Design
Participants will be screened under another protocol with
Medical and psychiatric history
Psychiatric evaluation
Physical exam
Urine tests
All participants will start with a 2-hour visit for screening see below They may learn how to do tasks that will be used later After the screening session they will be scheduled for an MRI session
The next part of the study is 4 substudies Each substudy includes up to 4 sessions A session is usually 2-3 hours but can last up to 8 hours Participants can join multiple substudies but only 1 at a time They can do only 1 session on a given day
Each substudy includes the following
Behavioral tests Interviews questionnaires simple tasks and tests of memory attention and thinking
Electromyography Small sticky electrodes on the skin measure muscle activity
Transcranial magnetic stimulation A wire coil is held to the scalp A brief electrical current passes through the coil and affects brain activity
Magnetic resonance imaging MRI Participants lie on a table that slides into a machine that takes pictures of the brain A coil is placed over the head They will perform simple tasks while in the scanner They may also get TMS
Electroencephalography Small electrodes on the scalp record brain waves
Sponsoring Institution National Institute of M
Detailed Description:
Objectives
Noninvasive brain stimulation NIBS using magnetic and electrical means through the use of transcranial magnetic stimulation TMS and transcranial direct and alternating current stimulation tDCS and tACS respectively has proven to be a versatile tool in the investigation of cortical organization and function and has shown great potential as a means to diagnose and treat psychiatric and neurological illness Unfortunately this research has been slowed due to two fundamental problems that directly impact the usefulness of NIBS First the space of parameters used to produce NIBS is immensely large and has barely been explored Such parameters include intensity of stimulation pulse wave form and duration number and timing of pulses which in turn can involve trains of pulses their frequency duration number and intertrain intervals the shape of the magnetic or electric field produced for TMS meaning type of coil used its position and its orientation with three degrees of freedom for a figure eight coil and for tDCS and tACS the numbers sizes and placements of electrodes and for creating long-lasting effects the number and timing of NIBS sessions Differences- often even very small differences- in the particular values of any of these parameters have been shown to have significant impact on the size and duration of NIBS effects and yet little is known Parametric exploration has only been addressed in a limited way in the field and primarily only in motor cortex Second the interaction of any set of NIBS parameters with any individual brain is poorly understood and this has led to unpredictable efficacy and a large amount of inter-individual variability in NIBS studies The human brain is always in a complex dynamic state of change and it has become increasingly clear that the state of a cortical region and its associated network connections when NIBS is applied strongly influences its effects There are now a great many demonstrations of how the state of the cortical region being stimulated plays a large role in determining what specific NIBS effect occurs Not knowing the particular state of a brain when stimulating it has led to wide variability and unpredictability in NIBS effects Thus while the variable state of the target region in each subject is likely an important source of the large amount of inter-individual variability found in TMS and tDCS studies little research has been performed as yet This poses a huge challenge to the effectiveness of NIBS therapeutic interventions on an individual and precision medicine basis to the design and implementation of brain stimulation studies and to the test-retest reliability of the neurophysiological and behavioral measures used and their optimization
The purpose of this technical development protocol is to address these two fundamental deficiencies in NIBS research To do so we would like to 1 explore within safe ranges as established by international consensus the effects of different sets of NIBS stimulation parameters on behavioral and cortical function as measured by behavioral performance electroencephalography EEG electromyography EMG eye movements and MRI and 2 to develop the methodologies and analytic techniques behind those behavioral and physiological measures in order to increase their usefulness in interpreting NIBS effects In addition this protocol will be used to train new fellows coming to the Non-invasive Neuromodulation Unit NNU in the use of TMS techniques The NNU is exceptionally well-situated both in terms of expertise and resources to perform this protocol We expect that information emerging from these studies will allow us to 1 optimize NIBS effects across ranges of stimulation parameters and brain states within individual subjects and in terms test-retest reliability 2 to collect pilot data in healthy volunteers to establish feasibility and for power analysis for future patient-oriented hypothesis- driven protocols and 3 to train new fellows in the use of these different methods
We specifically propose to begin this development protocol with five substudies that span the NIBS areas in need of further research examining stimulus intensity stimulus timing and frequency stimulus targeting and methods for controlling brain state These explorations will provide a useful initial foray into NIBS parameter space and will in addition help develop means to more effectively dose TMS outside of motor cortex and reduce variability in TMS effects to test new methods of targeting TMS to develop the usefulness of EEG in TMS and to understand the relationship of TMS timing and endogenous oscillations
The protocol consists of the below substudies
Substudy 1 Using TMS-evoked potential TEP to dose TMS outside of the motor cortex
This study aims to begin an exploration of the feasibility of using EEG to evaluate the response to single pulses of TMS over differing cortical brain areas as a novel method of individualizing the dose of TMS in a site-specific fashion The local cortical response represents an evoked wave of neuronal activity in the immediate vicinity of the stimulating coil and could provide a useful dosing measure outside the motor cortex In this first step at two cortical locations motor cortex and occipital visual cortex we explore the relationship of TMS evoked potentials with functional evoked responses MEPs from motor cortex visual discrimination in visual cortex and with fMRI BOLD response to TMS at different intensities applied to both cortical locations
Substudy 2 The value of electric field modeling in TMS localization
The study question for this substudy is as follows Does inclusion of electric field modeling to TMS targeting increase the efficacy of TMS
The overall goal is to compare an electric field guided coil placement method with fMRI-guided and scalp-guided NIBS targeting approaches Including the latter condition additionally allows for the substudy to address the only study that compared scalp-based and fMRI-based targeting Sack et al 2009 The Sack et al study was designed as between groups using very small Ns of 5 the NIBS field would greatly benefit from a replication with a larger group and a within-subjects design In this first substudy we will test the efficacy of three E-field modeling approaches to TMS targeting with the intention of using the best method in a subsequent substudy to compare TMS targeting methods
Substudy 3 Controlling ongoing cortical state during NIBS with neurofeedback
The study question for this substudy is as follows Does controlling brain states using neurofeedback result in greater intra- and inter-individual variability in responses to TMS
This study aims to explore the use of real-time fMRI neurofeedback to control the activated state of the amygdala while it is targeted transynaptically with short trains of 5 Hz rTMS
Substudy 4 Using cTMS EEG to understand mechanism and to optimize theta-burst stimulation TBS
The study question for this substudy is as follows What are the effects of TBS on EMG across different waveforms of TMS pulses
In this substudy we aim to parametrically examine the effects of intertrial interval on TBS response and to harness the flexible control of pulse parameters using the cTMS device Rogue Research Inc Canada to investigate the effects of TBS
Substudy 5 using TMS as a probe of the fronto-striatal network a key circuit implicated in reward processing
We seek to establish whether TMS can reach in a dose-dependent way a targeted subcortical region transynaptically which is too distant for effective stimulation directly Specifically we will test whether TMS delivered to the dorsolateral prefrontal cortex DLPFC or the pre-supplementary motor area pre-SMA results in changes in activation of the striatum in a dose- dependent fashion This hypothesis will be tested with the perturbation-imaging procedure of TMSfMRI interleaving ie while participants receive TMS during both resting state and task based fMRI
Study Population
Up to 180 healthy volunteers age 18 and older The number is the sum of requested participants N25 in the 5 substudies with an additional 25 given an anticipated 20 drop-out rate
Design
Healthy adult volunteers will participate typically using repeated measures design given the goals of exploring parametric NIBS effects and to establish reliability in those effects although between groups designs might be required in some cases eg when learning is involved Experiments will be carried out in two phases with Phase I involving screening and baseline procedures and Phase II being the experimental NIBS sessions Phase I will include consenting and screening It will generally include an MRI session due to the need for at least a structural MRI to be used for neuronavigation in NIBS targeting Phase I may also include introduction and training in some behavioral task or tasks as well as baseline measures of EEG and EMG as needed In Phase II the experimental NIBS sessions will be performed with each participant The number of sessions will be variable in general between 1 and 4 lasting about 1-3 hours each depending on the exploratory question NIBS may be given in conjunction with EEG EMG andor fMRI either simultaneously or in a pre-post manner The NIBS stimulation parameters will never exceed safe ranges as established in international consensus safety reports Experimental control comparisons may be between sham and active NIBS andor in the latter case being NIBS to different scalp locations or at different times or in the case of parametric studies differing values of the parameter in question
The experience in the NIBS field over the past three decades provides no evidence that there is an upper limit on the number of NIBS sessions an individual can safely participate in This conclusion is primarily based on the many thousands of individuals who have received TMS treatment for depression according to the FDA-cleared labeling in which six weeks of daily weekday treatment 30 sessions involving 3000 pulses of rTMS per session are provided with no new unexpected adverse events reported Thus the amount of participation will only be limited in two ways first subjects participate in one experimental session per day A single session which generally lasts between 1-3 hours may last no longer than 8 hours to allow for the initial testing paradigm followed by retests or performing other components of the same substudy later in the day with appropriate rest breaks and meal breaks during long sessions Second subjects can participate in only one substudy at a time
Outcome measures
Substudy 1 MEP and TEP amplitudes and latencies fMRI BOLD changes visual discrimination threshold
Substudy 2 Pre-post change in behavioral performance RT and accuracy and in parietal fMRI BOLD response across conditions
Substudy 3 Individual and group BOLD fMRI signal in the amygdala and task-related functional connectivity changes between the amygdala and cortical networks associated with emotion processing
Substudy 4 Amplitude and latency of MEP
Substudy 5 change in fMRI BOLD response in the striatum as the result of surface cortical TMS
Noninvasive brain stimulation NIBS using magnetic and electrical means through the use of transcranial magnetic stimulation TMS and transcranial direct and alternating current stimulation tDCS and tACS respectively has proven to be a versatile tool in the investigation of cortical organization and function and has shown great potential as a means to diagnose and treat psychiatric and neurological illness Unfortunately this research has been slowed due to two fundamental problems that directly impact the usefulness of NIBS First the space of parameters used to produce NIBS is immensely large and has barely been explored Such parameters include intensity of stimulation pulse wave form and duration number and timing of pulses which in turn can involve trains of pulses their frequency duration number and intertrain intervals the shape of the magnetic or electric field produced for TMS meaning type of coil used its position and its orientation with three degrees of freedom for a figure eight coil and for tDCS and tACS the numbers sizes and placements of electrodes and for creating long-lasting effects the number and timing of NIBS sessions Differences- often even very small differences- in the particular values of any of these parameters have been shown to have significant impact on the size and duration of NIBS effects and yet little is known Parametric exploration has only been addressed in a limited way in the field and primarily only in motor cortex Second the interaction of any set of NIBS parameters with any individual brain is poorly understood and this has led to unpredictable efficacy and a large amount of inter-individual variability in NIBS studies The human brain is always in a complex dynamic state of change and it has become increasingly clear that the state of a cortical region and its associated network connections when NIBS is applied strongly influences its effects There are now a great many demonstrations of how the state of the cortical region being stimulated plays a large role in determining what specific NIBS effect occurs Not knowing the particular state of a brain when stimulating it has led to wide variability and unpredictability in NIBS effects Thus while the variable state of the target region in each subject is likely an important source of the large amount of inter-individual variability found in TMS and tDCS studies little research has been performed as yet This poses a huge challenge to the effectiveness of NIBS therapeutic interventions on an individual and precision medicine basis to the design and implementation of brain stimulation studies and to the test-retest reliability of the neurophysiological and behavioral measures used and their optimization
The purpose of this technical development protocol is to address these two fundamental deficiencies in NIBS research To do so we would like to 1 explore within safe ranges as established by international consensus the effects of different sets of NIBS stimulation parameters on behavioral and cortical function as measured by behavioral performance electroencephalography EEG electromyography EMG eye movements and MRI and 2 to develop the methodologies and analytic techniques behind those behavioral and physiological measures in order to increase their usefulness in interpreting NIBS effects In addition this protocol will be used to train new fellows coming to the Non-invasive Neuromodulation Unit NNU in the use of TMS techniques The NNU is exceptionally well-situated both in terms of expertise and resources to perform this protocol We expect that information emerging from these studies will allow us to 1 optimize NIBS effects across ranges of stimulation parameters and brain states within individual subjects and in terms test-retest reliability 2 to collect pilot data in healthy volunteers to establish feasibility and for power analysis for future patient-oriented hypothesis- driven protocols and 3 to train new fellows in the use of these different methods
We specifically propose to begin this development protocol with five substudies that span the NIBS areas in need of further research examining stimulus intensity stimulus timing and frequency stimulus targeting and methods for controlling brain state These explorations will provide a useful initial foray into NIBS parameter space and will in addition help develop means to more effectively dose TMS outside of motor cortex and reduce variability in TMS effects to test new methods of targeting TMS to develop the usefulness of EEG in TMS and to understand the relationship of TMS timing and endogenous oscillations
The protocol consists of the below substudies
Substudy 1 Using TMS-evoked potential TEP to dose TMS outside of the motor cortex
This study aims to begin an exploration of the feasibility of using EEG to evaluate the response to single pulses of TMS over differing cortical brain areas as a novel method of individualizing the dose of TMS in a site-specific fashion The local cortical response represents an evoked wave of neuronal activity in the immediate vicinity of the stimulating coil and could provide a useful dosing measure outside the motor cortex In this first step at two cortical locations motor cortex and occipital visual cortex we explore the relationship of TMS evoked potentials with functional evoked responses MEPs from motor cortex visual discrimination in visual cortex and with fMRI BOLD response to TMS at different intensities applied to both cortical locations
Substudy 2 The value of electric field modeling in TMS localization
The study question for this substudy is as follows Does inclusion of electric field modeling to TMS targeting increase the efficacy of TMS
The overall goal is to compare an electric field guided coil placement method with fMRI-guided and scalp-guided NIBS targeting approaches Including the latter condition additionally allows for the substudy to address the only study that compared scalp-based and fMRI-based targeting Sack et al 2009 The Sack et al study was designed as between groups using very small Ns of 5 the NIBS field would greatly benefit from a replication with a larger group and a within-subjects design In this first substudy we will test the efficacy of three E-field modeling approaches to TMS targeting with the intention of using the best method in a subsequent substudy to compare TMS targeting methods
Substudy 3 Controlling ongoing cortical state during NIBS with neurofeedback
The study question for this substudy is as follows Does controlling brain states using neurofeedback result in greater intra- and inter-individual variability in responses to TMS
This study aims to explore the use of real-time fMRI neurofeedback to control the activated state of the amygdala while it is targeted transynaptically with short trains of 5 Hz rTMS
Substudy 4 Using cTMS EEG to understand mechanism and to optimize theta-burst stimulation TBS
The study question for this substudy is as follows What are the effects of TBS on EMG across different waveforms of TMS pulses
In this substudy we aim to parametrically examine the effects of intertrial interval on TBS response and to harness the flexible control of pulse parameters using the cTMS device Rogue Research Inc Canada to investigate the effects of TBS
Substudy 5 using TMS as a probe of the fronto-striatal network a key circuit implicated in reward processing
We seek to establish whether TMS can reach in a dose-dependent way a targeted subcortical region transynaptically which is too distant for effective stimulation directly Specifically we will test whether TMS delivered to the dorsolateral prefrontal cortex DLPFC or the pre-supplementary motor area pre-SMA results in changes in activation of the striatum in a dose- dependent fashion This hypothesis will be tested with the perturbation-imaging procedure of TMSfMRI interleaving ie while participants receive TMS during both resting state and task based fMRI
Study Population
Up to 180 healthy volunteers age 18 and older The number is the sum of requested participants N25 in the 5 substudies with an additional 25 given an anticipated 20 drop-out rate
Design
Healthy adult volunteers will participate typically using repeated measures design given the goals of exploring parametric NIBS effects and to establish reliability in those effects although between groups designs might be required in some cases eg when learning is involved Experiments will be carried out in two phases with Phase I involving screening and baseline procedures and Phase II being the experimental NIBS sessions Phase I will include consenting and screening It will generally include an MRI session due to the need for at least a structural MRI to be used for neuronavigation in NIBS targeting Phase I may also include introduction and training in some behavioral task or tasks as well as baseline measures of EEG and EMG as needed In Phase II the experimental NIBS sessions will be performed with each participant The number of sessions will be variable in general between 1 and 4 lasting about 1-3 hours each depending on the exploratory question NIBS may be given in conjunction with EEG EMG andor fMRI either simultaneously or in a pre-post manner The NIBS stimulation parameters will never exceed safe ranges as established in international consensus safety reports Experimental control comparisons may be between sham and active NIBS andor in the latter case being NIBS to different scalp locations or at different times or in the case of parametric studies differing values of the parameter in question
The experience in the NIBS field over the past three decades provides no evidence that there is an upper limit on the number of NIBS sessions an individual can safely participate in This conclusion is primarily based on the many thousands of individuals who have received TMS treatment for depression according to the FDA-cleared labeling in which six weeks of daily weekday treatment 30 sessions involving 3000 pulses of rTMS per session are provided with no new unexpected adverse events reported Thus the amount of participation will only be limited in two ways first subjects participate in one experimental session per day A single session which generally lasts between 1-3 hours may last no longer than 8 hours to allow for the initial testing paradigm followed by retests or performing other components of the same substudy later in the day with appropriate rest breaks and meal breaks during long sessions Second subjects can participate in only one substudy at a time
Outcome measures
Substudy 1 MEP and TEP amplitudes and latencies fMRI BOLD changes visual discrimination threshold
Substudy 2 Pre-post change in behavioral performance RT and accuracy and in parietal fMRI BOLD response across conditions
Substudy 3 Individual and group BOLD fMRI signal in the amygdala and task-related functional connectivity changes between the amygdala and cortical networks associated with emotion processing
Substudy 4 Amplitude and latency of MEP
Substudy 5 change in fMRI BOLD response in the striatum as the result of surface cortical TMS
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 18-M-0015 | None | None | None |