Resonant Frequency rTMS: A Novel Approach to Target Circuit Modulation in Major Depressive Disorder
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 入组人数
- 84
- 试验地点
- 2
- 主要终点
- Repeatability of the Resonant Frequency measure
研究概览
简要总结
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 4.5 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.
详细描述
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 individual's 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:
- Establish reliability of a method for RF determination in a DLPFC-based target circuit. H1: An individual's RF median values and rankings will be stable across repeated measurements.
- 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).
- 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 3,000-pulse session of 10 Hz rTMS was a robust predictor of outcome following a full course of rTMS treatments.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All subjects must be between 18-75 years of age.
- •Must have confirmed diagnosis of severe *Major Depressive Disorder (single or recurrent episode) as confirmed by the Mini-International Neuropsychiatric Interview (MINI) or/and a score of 17 or above on the Hamilton Depression Rating Scale (HAMD).
- •Failure to respond to a minimum of 2 trials of antidepressant medication.
- •Failure to respond from at least two different agent classes.
- •Accompanied by at least two evidence-based augmentation therapies (Benzodiazepines do not count).
- •Must have a trial of psychotherapy known to be effective in the treatment of MDD of an adequate frequency and duration.
- •Subjects are willing and able to adhere to the treatment schedule and required study visits.
- •TMS treatment is clinically-approved only for those suffering from Major Depressive Disorder as their primary diagnosis.
排除标准
- •Are mentally or legally incapacitated, unable to give informed consent
- •Have an infection or poor skin condition over the scalp where the device will be positioned.
- •Have increased risk of seizure because of family history, stroke, or currently use medications that lead to increased risk for seizure.
- •Diagnosis of acute or chronic psychotic symptoms or disorders (such as schizophrenia, schizophreniform or schizoaffective disorder) in the current depressive episode.
- •Neurological conditions that include epilepsy, cerebrovascular disease, dementia, increased intracranial pressure, having a history of repetitive or severe head trauma, or with primary or secondary tumors in the central nervous system.
- •Presence of an implanted magnetic-sensitive medical device present in the body scan, located less than or equal to 30 centimeters from the transcranial magnetic stimulation magnetic coil or other implanted metal items, including but not limited to a cochlear implant, implanted cardioverter defibrillator, pacemaker, vagus nerve stimulator, or metal aneurysm clips or coils, staples, or stents. (Note: Dental amalgam fillings are not affected by the magnetic field and are acceptable for use with transcranial magnetic stimulation and MRI.)
- •Current diagnosis of substance use disorder.
结局指标
主要结局
Repeatability of the Resonant Frequency measure
时间窗: 1 week per subject (Three RF measurements will happen within 1 week)
Resonant Frequency (RF) of brain oscillations will be measured three times for each participant. Each time, all unique frequencies will be assigned a ranking corresponding to the degree of elicited network activity. We will then compute pairwise Spearman's correlation coefficients (R) between individual rankings obtained at time 1 (T1) vs time 2 (T2), T1 vs Time 3 (T3), and T2 vs T3. We expect that all R-values will be above R = 0.4. This will be single-subject level analysis.
Changes in Electroencephalograms (EEG) functional connectivity
时间窗: Ten days for each subject (2 sessions (RFmax/RFmin) separated by one week).
Electroencephalograms functional connectivity (EEG-FC) will be measured after rTMS stimulation 1) at the maximal and 2) at the minimal RF (RFmax, RFmin, respectively), as derived from the ranking using Outcome Measure 1. We will compare changes in EEG-FC after RFmax to changes in EEG-FC after RFmin. This will be a group-level analysis.
Spatial maps of source-localized EEG connectivity
时间窗: Ten days for each subject (2 sessions (RFmax/RFmin) separated by one week)
We will quantitatively compare the spatial extend of source-localized connectivity elicited by RFmax vs. RFmix stimulation. Binary statistical connectivity maps will be compared for size and percentage of overlap between the two conditions.
Percent overlap between spatial maps of source-localized EEG connectivity and fMRI-based MDD-rTMS responsive network
时间窗: 1 week per subject.
Similar to Outcome measure 3, but instead of comparing the spatial extend of EEG connectivity between RFmax vs. RFmin, this analysis will quantify the similarity to an MDD-rTMS responsive network derived from functional MRI data (Siddiqi et al. 2020).
次要结局
未报告次要终点
研究者
Andrew F. Leuchter
Principal Investigator
University of California, Los Angeles