CRCNS US-France Research Proposal: Probing the Dorsolateral Prefrontal Cortex and Central Executive Network for Improving Neuromodulation in Depression
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Transcranial Magnetic Stimulation (TMS) / Electroencephalography (EEG) change
研究概览
简要总结
Depression is a highly prevalent condition characterized by persistent low mood, energy, and activity that can affect one's thoughts, mood, behavior, and sense of well-being. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulatory technique, is an effective treatment for depression when targeting the dorsolateral prefrontal cortex (dlPFC) of the central executive network (CEN). However, remission rates are suboptimal and individual methods to target the dlPFC are lacking. In this study, we will enroll 50 patients with major depression and in a single rTMS 'dose,' prospective, randomized, double-blind, cross-over design will assess whether rTMS targeted to an individual's central executive network (CEN) assessed by single pulse TMS can enhance network modulation. If successful, this work will lead to a clinical rTMS trial comparing this personalized targeting approach against standard rTMS.
详细描述
There is a critical need for more effective treatments for depression, which currently affect 20% of Americans during our lifetimes. Brain stimulation treatments, including repetitive transcranial magnetic stimulation (rTMS), represent the front line of innovative approaches by directly targeting and correcting specific dysfunctional brain networks. A core dysfunctional network in major depressive disorder is the fronto-parietal central executive network (CEN), a network critical for decision making and cognitive control. The CEN includes the dorsolateral prefrontal cortex (dlPFC), the target of FDA-cleared rTMS treatment for depression. rTMS to the dlPFC is thought to improve depression by modulating local dlPFC excitability and enhancing downstream CEN connectivity. However, our ability to probe the CEN and study this potential mechanism on an individual basis is critically lacking, likely contributing to suboptimal rTMS remission rates (20-40%). We hypothesize that the CEN connectivity is weakened in depression and can be maximally modulated by individualizing localization.
To test this hypothesis, a single rTMS 'dose,' prospective, randomized, double-blind, cross-over design with 50 depressed patients was conducted to characterize the effects of intermittent theta burst stimulation (iTBS) on frontoparietal network excitability. Participants were 18-65 years old and screened to exclude psychiatric or neurological disorders, including moderate or greater depressive symptoms.
Participants first underwent MRI scanning to obtain structural brain data for neuronavigation. During the experimental session, intermittent theta burst stimulation (iTBS) was applied to the dlPFC to modulate the CEN. Two stimulation conditions were administered in randomized order: real iTBS and sham iTBS. To probe network-level changes, single-pulse TMS (spTMS) was applied to both the dlPFC and posterior parietal cortex (PPC) before and after iTBS. These probes were interleaved with iTBS in alternating blocks, allowing for repeated assessments of cortical excitability and connectivity across time. TMS-evoked potentials (TEPs) were recorded using EEG to quantify changes in both local (dlPFC) and downstream (parietal cortex) responses. The primary outcome was the change in TMS-evoked EEG responses (e.g., early TEP components) following iTBS.
This study design enables characterization of the temporal dynamics and dose-dependent effects of iTBS on human brain networks. Findings from this work provide insight into mechanisms of noninvasive brain stimulation and may inform future efforts to optimize personalized neuromodulation strategies for neuropsychiatric disorders.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women, ages 18 to 65
- •Depression assessed through in-depth Structured Clinical Interview for DMS-5 (SCID-I)
- •PHQ9 > 10 for disease severity
- •Must comprehend English well to ensure adequate comprehension of the EEG and TMS instructions, and of clinical scales
- •Right-handed
- •No current or history of neurological disorders
- •No seizure disorder or risk of seizures
- •No use of PRN medication within 24 hours of the scheduled study appointment
排除标准
- •Those with a contraindication for MRIs (e.g. implanted metal)
- •Any unstable medical condition
- •History of head trauma with loss of consciousness
- •History of seizures
- •Neurological or uncontrolled medical disease
- •Active substance abuse
- •Diagnosis of psychotic or bipolar disorder
- •A prior history of ECT or rTMS failure
- •Currently taking medications that substantially reduce seizure threshold (e.g., olanzapine, chlorpromazine, lithium)
- •Currently pregnant or breastfeeding
研究组 & 干预措施
Individualized CEN-targeted rTMS
Individualized CEN-targeted rTMS will combine neuronavigated rTMS and single pulse TMS-EEG to identify the region of the dlPFC making the strongest connection with the parietal node of the CEN. First, regions of the dlPFC strongly connected to the parietal CEN will be identified by applying single TMS pulses in grid-like fashion to ROIs within the dlPFC. For each anatomical dlPFC subunit probed with TMS, the TMS-EEG response will be quantified in the parietal region of the CEN. The dlPFC subunit that demonstrates the strongest TMS-EEG response in parietal cortex will be chosen for rTMS. rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS session for adverse events and/or side effects.
干预措施: Individualized CEN-targeted rTMS (Device)
Individualized CEN-targeted rTMS
Individualized CEN-targeted rTMS will combine neuronavigated rTMS and single pulse TMS-EEG to identify the region of the dlPFC making the strongest connection with the parietal node of the CEN. First, regions of the dlPFC strongly connected to the parietal CEN will be identified by applying single TMS pulses in grid-like fashion to ROIs within the dlPFC. For each anatomical dlPFC subunit probed with TMS, the TMS-EEG response will be quantified in the parietal region of the CEN. The dlPFC subunit that demonstrates the strongest TMS-EEG response in parietal cortex will be chosen for rTMS. rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS session for adverse events and/or side effects.
干预措施: Sham rTMS (Device)
Neuronavigated rTMS
Neuronavigated rTMS will be delivered using neuro-navigation based on participants' own MRI images to target the dlPFC. rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS session for adverse events and/or side effects.
干预措施: Neuronavigated rTMS (Device)
Neuronavigated rTMS
Neuronavigated rTMS will be delivered using neuro-navigation based on participants' own MRI images to target the dlPFC. rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS session for adverse events and/or side effects.
干预措施: Sham rTMS (Device)
Scalp-targeted rTMS
Scalp-targeted rTMS will be delivered using standard BEAM F3 targeting methodology to target the dlPFC. rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS session for adverse events and/or side effects.
干预措施: Scalp-targeted rTMS (Device)
Scalp-targeted rTMS
Scalp-targeted rTMS will be delivered using standard BEAM F3 targeting methodology to target the dlPFC. rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS session for adverse events and/or side effects.
干预措施: Sham rTMS (Device)
Sham rTMS
Sham rTMS will be delivered for one session to mimic active rTMS conditions. To maximize sham validity, both 1) a direction- sensor TMS coil will alert the operators to flip the coil if the wrong side is being used, and 2) low-intensity electrical stimulation to match the active rTMS frequency will be applied to scalp electrodes under the coil for sham and placed but not activated in the active arm. The rTMS coil will be positioned using neuro-navigation based on participants' own MRI images, mimicking active rTMS. Sham rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the sham rTMS session for adverse events and/or side effects.
干预措施: Sham rTMS (Device)
结局指标
主要结局
Transcranial Magnetic Stimulation (TMS) / Electroencephalography (EEG) change
时间窗: Up to 2 hours
Change in TMS-EEG measures will be assessed before, during, and after each rTMS session. Specifically, the amplitude of the change 30ms after a single TMS pulse in the frontoparietal region will be quantified. Brain changes will be compared between CEN EEG-targeted, neuronavigated, scalp-targeted, and sham rTMS to identify the location, strength, and dose response of change for each condition.
Change in TMS-evoked EEG Responses Following Intermittent Theta Burst Stimulation (iTBS)
时间窗: Pre-intervention and up to 20 minutes post-intervention
TMS-evoked EEG responses were measured before and after intermittent theta burst stimulation (iTBS) using single-pulse TMS probes applied to prefrontal and parietal regions. The primary measure was the change in early TMS-evoked potentials (TEPs), defined as the peak-to-peak amplitude within approximately 20-50 ms following the TMS pulse. Changes in electrophysiological responses were assessed across timepoints (pre-intervention, early post-intervention, and late post-intervention) and compared between active and sham stimulation conditions to characterize modulation of frontoparietal network excitability.
次要结局
未报告次要终点
研究者
Corey Keller
Associate Professor, Department of Psychiatry and Behavioral Sciences
Stanford University