Ignite Creation Date:
2024-10-26 @ 3:38 PM
Last Modification Date:
2024-10-26 @ 3:38 PM
Study NCT ID:
NCT06572683
Status:
ENROLLING_BY_INVITATION
Last Update Posted:
None
First Post:
2024-08-12
Brief Title:
Resonant Frequency rTMS A Novel Approach to Target Circuit Modulation in Major Depressive Disorder
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Resonant Frequency rTMS A Novel Approach to Target Circuit Modulation in Major Depressive Disorder
Status:
ENROLLING_BY_INVITATION
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
R01RF
Brief Summary:
The purpose of the study is to develop a more personalized brain stimulation using repetitive transcranial magnetic stimulation or rTMS approach to treat major depressive disorder MDD The investigators had previously developed a personalized rTMS treatment by examining the effectiveness of different rTMS frequency from 5 to 18 Hertz Hz The optimal treatment frequency is termed resonance frequency and varies across individuals There has not been a systematic method to identify the best stimulation frequency in an individual-specific way In this project the investigators will identify and compare 3 rTMS frequencies all targeting the brain region called left dorsolateral prefrontal cortex DLPFC 1 that engages brain circuit connectivity the most- the investigators call this resonant frequency RF-max RF-max 1 that is the lowest ranked resonance frequency called RF-min and 1 that is standard of care treatment - rTMS of 10 Hz as a point of comparison
This study is a multi-sites project that will be conducted at UCLA and Butler hospital This study will enroll 84 participants with MDD over the course of 45 years
Participants will undergo a brain imaging scan or magnetic resonance imaging MRI 3 electroencephalograms or EEG a measurement of electrical activity of the brain to identify rTMS resonance frequencies RFs 3 sessions of different resonant frequencies of rTMS in combination with EEG totaling up to 7 in person visits Participation will take up to 4 weeks
This study is a multi-sites project that will be conducted at UCLA and Butler hospital This study will enroll 84 participants with MDD over the course of 45 years
Participants will undergo a brain imaging scan or magnetic resonance imaging MRI 3 electroencephalograms or EEG a measurement of electrical activity of the brain to identify rTMS resonance frequencies RFs 3 sessions of different resonant frequencies of rTMS in combination with EEG totaling up to 7 in person visits Participation will take up to 4 weeks
Detailed Description:
Repetitive Transcranial Magnetic Stimulation rTMS is an effective treatment for Major Depressive Disorder MDD but response rates are highly variable across individuals Clinical improvement with rTMS is believed to reflect engagement of a target mood-regulating circuit This innovative study aims to enhance target circuit engagement through stimulation at an individuals optimal resonant frequency RF Circuit connectivity is maintained by oscillations at one or more RFs specific to that circuit for that individual Personalizing stimulation frequency is an opportunity to optimize repetitive transcranial magnetic stimulation rTMS effectiveness but there has been no method to identify optimal RF for rTMS treatment in a patient-specific way The investigators developed a novel rTMS-electroencephalography TMS-EEG interrogation method that identifies RFs by examining the degree of resonance induced by stimulation frequencies from 5-18 Hz for a target circuit originating in left dorsolateral prefrontal cortex DLPFC Frequencies are then ranked based on resonance properties degree to which they increase connectivity in the target circuit and the highest-ranked frequency is identified The pilot data suggest that MDD treatment at maximum RF rTMSRF-MAX rapidly modifies connectivity and leads to early symptom improvement providing preliminary support for a RF-based personalized approach to rTMS
This project will provide a mechanistic understanding and validation of the RF approach through three aims and hypotheses
1 Establish reliability of a method for RF determination in a DLPFC-based target circuit H1 An individuals RF median values and rankings will be stable across repeated measurements
2 Demonstrate superior neurophysiologic engagement of the target circuit with rTMSRF-MAX stimulation H2 rTMSRF-MAX will be associated with greater increases in connectivity in a left DLPFC-based target circuit than rTMS at the lowest ranked resonant frequency rTMSRF-MIN
3 Contrast the neuroanatomic distribution and degree of target circuit engagement by rTMS RF-MAX and rTMS RF-MIN stimulation H3 Whole-brain EEG source localization will display a distinct distribution and degree of regional brain activation following rTMSRF-MAX and rTMSRF-MIN with rTMSRF-MAX better engaging circuits previously reported to be related to antidepressant response
rTMS typically is administered to the left dorsolateral prefrontal cortex DLPFC at a frequency of 10 Hz and in the naturalistic setting response rates range from 41-56 There is an urgent unmet need to improve outcomes of rTMS treatment for MDD as the patients who receive it are the most chronically and severely ill with the highest risk for completed suicide
MDD is increasingly conceptualized as a disorder of brain circuitry instead of individual brain regions Lack of clinical response to rTMS treatment is conceptualized as a failure to engage brain circuitry through the site of stimulation It has become clear that the effects of rTMS propagate beyond the stimulation target and affect a network of regions with strong functional connections to the stimulation site The therapeutic benefit of rTMS appears to be in part based upon the modulation of widespread network function The investigators have previously demonstrated that clinical outcome of standard 10 Hz rTMS treatment was most robustly predicted by rTMS-induced changes in electroencephalographic EEG network connectivity rather than by changes in oscillatory power Specifically The investigators showed that the similarity of the frequency spectra in the alpha band alpha spectral correlation a connectivity metric between the frontal and parietal regions following a single 3000-pulse session of 10 Hz rTMS was a robust predictor of outcome following a full course of rTMS treatments
Research to improve rTMS outcomes has focused on a personalized medicine approach in which rTMS stimulation parameters are adjusted to improve engagement of brain circuitry on an individual basis One approach to enhancing circuit engagement has been to adjust the neuroanatomic region to which stimulation is administered This approach is based upon findings that emphasize the importance of DLPFC connectivity to deeper structures eg subgenual anterior cingulate and meta-analyses of imaging data suggesting that distinct symptom biotypes of MDD may respond preferentially to different stimulation regions of interest ROIs The innovation of this proposal is to explore frequency of stimulation as the basis for personalized rTMS MDD treatment has been reported to be effective using stimulation frequencies from 1-50 Hz but some individuals may respond to treatment at one frequency but not another While personalized ROI targeting is being systematically explored individualized frequency targeting has remained largely unexplored This is surprising because one immediate effect of rTMS is entrainment of oscillations in underlying cortex to match the frequency of stimulation Changes in oscillations rapidly spread through brain networks to related brain regions and may be related to the therapeutic mechanism of rTMS Frequency of stimulation therefore constitutes an important parameter to consider when investigating ways to enhance rTMS efficacy for MDD
The investigators have hypothesized that rTMS stimulation at an individuals RF may yield greater therapeutic benefit than stimulation at a single common frequency ie 10 Hz for all patients The investigators developed a novel method that enables identification of RFs within a specific network for each individual This method is based upon a TMS-EEG frequency interrogation paradigm that examines the resonance characteristics of frequencies up to 18 Hz in circuits connected to L DLPFC The investigators used this TMS-EEG interrogation paradigm to determine the maximal RF RFMAX in 56 MDD patients prior to starting their first rTMS treatment While 10 Hz was an RFMAX for some patients 73 had RFMAX outside of the alpha band and thus distant from the 10 Hz stimulation protocol that comprises a common practice standard for rTMS treatment This suggests that many patients could potentially benefit from an RF approach to treatment
The pilot work suggests that RF stimulation induces significant changes in both MDD symptoms and circuit connectivity involving left DLPFC In order to test the clinical significance of the RF rTMS rTMS RF treatment approach The investigators examined the effects of RFMAX stimulation on early symptom improvement ESI in patients with MDD ESI is commonly seen after 10 daily rTMS treatment sessions for MDD our group and others have shown that it is associated with a high probability of full clinical response at the end of a full treatment course In a prospective pilot study 56 subjects received 10 once-daily sessions of rTMS at either maximum RF rTMSRF-MAX N23 or a frequency that was not the highest-ranked RF non-RF N33 Connectivity in a left DLPFC-based circuit as measured with EEG Spectral Correlation Coefficient SCC showed significantly greater increases with rTMSRF-MAX than non-RF stimulation depressive symptoms as measured by the Patient Health Questionnaire-9 PHQ-9 improved on average by 32 significantly more than the group of patients who received standard rTMS treatment 13 T-test p 003 These preliminary findings suggest that the TMS-EEG interrogation method can be used to identify individual RFs that provide stronger engagement of a target circuit and that doing so may lead to greater symptom improvement than conventional rTMS stimulation
Additional preliminary data suggest that RF stimulation reliably activates a specific brain circuit In the 23 subjects who underwent RF treatment increased connectivity measured by EEG spectral correlation coefficients was seen between the stimulation site in left DLPFC indicated by the F3 electrode and electrodes in the bilateral prefrontal and left parietal regions These regions constitute the empirically-derived target circuit that The investigators will examine in the second aim of our proposal
Results of these pilot studies provide compelling evidence that interrogating the effects of different frequencies of stimulation at a single neuroanatomic region left DLPFC reveals physiological data about a target circuit that may be leveraged to personalize rTMS treatment through selection of a stimulation frequency that leads to early changes in connectivity and symptom improvement Greater mechanistic understanding and validation of the RF approach is required however before it can be relied upon as a clinical method Findings from this project could significantly advance the goal of a personalized medicine approach to rTMS treatment Study Design The investigators will identify the participants individual resonant frequencies RF by a series of pulse trains between 5-18 Hz at 05 Hz intervals at a total of 27 unique frequencies delivered in a random order The total procedure takes 35 minutes The investigators will conduct this procedure 3 times over the course of 3 days 1 procedure per day The sessions will be separated by 48 hours The investigators will then determine the optimal resonant frequency by ranking all interrogated frequencies based on their degree of elicited connectivity changes within the defined target circuit The optimal RF RFMAX will be the stimulation frequency that ranks highest with regard to connectivity increase RFMAX RFMIN is the lowest ranked frequency Participants will then undergo six rTMS treatment sessions two at RFMAX two at RFMIN two at 10 Hz in random order The two sessions at the same frequency will be administered on the same day separated by 1h break The sessions will be separated by 48 hours
This project will provide a mechanistic understanding and validation of the RF approach through three aims and hypotheses
1 Establish reliability of a method for RF determination in a DLPFC-based target circuit H1 An individuals RF median values and rankings will be stable across repeated measurements
2 Demonstrate superior neurophysiologic engagement of the target circuit with rTMSRF-MAX stimulation H2 rTMSRF-MAX will be associated with greater increases in connectivity in a left DLPFC-based target circuit than rTMS at the lowest ranked resonant frequency rTMSRF-MIN
3 Contrast the neuroanatomic distribution and degree of target circuit engagement by rTMS RF-MAX and rTMS RF-MIN stimulation H3 Whole-brain EEG source localization will display a distinct distribution and degree of regional brain activation following rTMSRF-MAX and rTMSRF-MIN with rTMSRF-MAX better engaging circuits previously reported to be related to antidepressant response
rTMS typically is administered to the left dorsolateral prefrontal cortex DLPFC at a frequency of 10 Hz and in the naturalistic setting response rates range from 41-56 There is an urgent unmet need to improve outcomes of rTMS treatment for MDD as the patients who receive it are the most chronically and severely ill with the highest risk for completed suicide
MDD is increasingly conceptualized as a disorder of brain circuitry instead of individual brain regions Lack of clinical response to rTMS treatment is conceptualized as a failure to engage brain circuitry through the site of stimulation It has become clear that the effects of rTMS propagate beyond the stimulation target and affect a network of regions with strong functional connections to the stimulation site The therapeutic benefit of rTMS appears to be in part based upon the modulation of widespread network function The investigators have previously demonstrated that clinical outcome of standard 10 Hz rTMS treatment was most robustly predicted by rTMS-induced changes in electroencephalographic EEG network connectivity rather than by changes in oscillatory power Specifically The investigators showed that the similarity of the frequency spectra in the alpha band alpha spectral correlation a connectivity metric between the frontal and parietal regions following a single 3000-pulse session of 10 Hz rTMS was a robust predictor of outcome following a full course of rTMS treatments
Research to improve rTMS outcomes has focused on a personalized medicine approach in which rTMS stimulation parameters are adjusted to improve engagement of brain circuitry on an individual basis One approach to enhancing circuit engagement has been to adjust the neuroanatomic region to which stimulation is administered This approach is based upon findings that emphasize the importance of DLPFC connectivity to deeper structures eg subgenual anterior cingulate and meta-analyses of imaging data suggesting that distinct symptom biotypes of MDD may respond preferentially to different stimulation regions of interest ROIs The innovation of this proposal is to explore frequency of stimulation as the basis for personalized rTMS MDD treatment has been reported to be effective using stimulation frequencies from 1-50 Hz but some individuals may respond to treatment at one frequency but not another While personalized ROI targeting is being systematically explored individualized frequency targeting has remained largely unexplored This is surprising because one immediate effect of rTMS is entrainment of oscillations in underlying cortex to match the frequency of stimulation Changes in oscillations rapidly spread through brain networks to related brain regions and may be related to the therapeutic mechanism of rTMS Frequency of stimulation therefore constitutes an important parameter to consider when investigating ways to enhance rTMS efficacy for MDD
The investigators have hypothesized that rTMS stimulation at an individuals RF may yield greater therapeutic benefit than stimulation at a single common frequency ie 10 Hz for all patients The investigators developed a novel method that enables identification of RFs within a specific network for each individual This method is based upon a TMS-EEG frequency interrogation paradigm that examines the resonance characteristics of frequencies up to 18 Hz in circuits connected to L DLPFC The investigators used this TMS-EEG interrogation paradigm to determine the maximal RF RFMAX in 56 MDD patients prior to starting their first rTMS treatment While 10 Hz was an RFMAX for some patients 73 had RFMAX outside of the alpha band and thus distant from the 10 Hz stimulation protocol that comprises a common practice standard for rTMS treatment This suggests that many patients could potentially benefit from an RF approach to treatment
The pilot work suggests that RF stimulation induces significant changes in both MDD symptoms and circuit connectivity involving left DLPFC In order to test the clinical significance of the RF rTMS rTMS RF treatment approach The investigators examined the effects of RFMAX stimulation on early symptom improvement ESI in patients with MDD ESI is commonly seen after 10 daily rTMS treatment sessions for MDD our group and others have shown that it is associated with a high probability of full clinical response at the end of a full treatment course In a prospective pilot study 56 subjects received 10 once-daily sessions of rTMS at either maximum RF rTMSRF-MAX N23 or a frequency that was not the highest-ranked RF non-RF N33 Connectivity in a left DLPFC-based circuit as measured with EEG Spectral Correlation Coefficient SCC showed significantly greater increases with rTMSRF-MAX than non-RF stimulation depressive symptoms as measured by the Patient Health Questionnaire-9 PHQ-9 improved on average by 32 significantly more than the group of patients who received standard rTMS treatment 13 T-test p 003 These preliminary findings suggest that the TMS-EEG interrogation method can be used to identify individual RFs that provide stronger engagement of a target circuit and that doing so may lead to greater symptom improvement than conventional rTMS stimulation
Additional preliminary data suggest that RF stimulation reliably activates a specific brain circuit In the 23 subjects who underwent RF treatment increased connectivity measured by EEG spectral correlation coefficients was seen between the stimulation site in left DLPFC indicated by the F3 electrode and electrodes in the bilateral prefrontal and left parietal regions These regions constitute the empirically-derived target circuit that The investigators will examine in the second aim of our proposal
Results of these pilot studies provide compelling evidence that interrogating the effects of different frequencies of stimulation at a single neuroanatomic region left DLPFC reveals physiological data about a target circuit that may be leveraged to personalize rTMS treatment through selection of a stimulation frequency that leads to early changes in connectivity and symptom improvement Greater mechanistic understanding and validation of the RF approach is required however before it can be relied upon as a clinical method Findings from this project could significantly advance the goal of a personalized medicine approach to rTMS treatment Study Design The investigators will identify the participants individual resonant frequencies RF by a series of pulse trains between 5-18 Hz at 05 Hz intervals at a total of 27 unique frequencies delivered in a random order The total procedure takes 35 minutes The investigators will conduct this procedure 3 times over the course of 3 days 1 procedure per day The sessions will be separated by 48 hours The investigators will then determine the optimal resonant frequency by ranking all interrogated frequencies based on their degree of elicited connectivity changes within the defined target circuit The optimal RF RFMAX will be the stimulation frequency that ranks highest with regard to connectivity increase RFMAX RFMIN is the lowest ranked frequency Participants will then undergo six rTMS treatment sessions two at RFMAX two at RFMIN two at 10 Hz in random order The two sessions at the same frequency will be administered on the same day separated by 1h break The sessions will be separated by 48 hours
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None