Major Depressive DisorderNCT05224063
Probing the Dorsolateral Prefrontal Cortex and Central Executive Network for Improving Neuromodulation in Depression
A study testing Neuronavigated rTMS in people with Major Depressive Disorder, run by Stanford University at 1 site in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Neuronavigated rTMS
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jan 2023to 27 Mar 2025
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 10Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: CRCNS US-France Research Proposal: Probing the Dorsolateral Prefrontal Cortex and Central Executive Network for Improving Neuromodulation in Depression
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.
Read the detailed description
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.
- Conditions
- Major Depressive Disorder
- Being tested
- Neuronavigated rTMS, Sham rTMS
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Neuronavigated rTMSDevice
Delivers patterned magnetic stimulation based on MRI images
Sham rTMSDevice
Delivers placebo magnetic stimulation
| Study group | Role | What they receive |
|---|---|---|
| Neuronavigated rTMS | Active comparator | 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. Receives: Device: Neuronavigated rTMS |
| Sham rTMS | Sham comparator | 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. Receives: Device: Sham rTMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in TMS-evoked EEG Responses Following Intermittent Theta Burst Stimulation (iTBS)
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.
Measured: Pre-intervention and up to 20 minutes post-intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Feb 2022
- Study start1 Jan 2023
- Primary completion27 Mar 2025
- Study completion27 Mar 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Corey Keller, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05224063
- Sponsor's protocol ID
- 60980-2
- Other IDs
- R01MH129018
- Status last verified
- Jun 2026
- First submitted
- 12 Jan 2022
- Last updated
- 15 Jul 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 15 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CRCNS US-France Research Proposal: Probing the Dorsolateral Prefrontal Cortex and Central Executive Network for Improving Neuromodulation in Depression
- ClinicalTrials.gov ID
- NCT05224063
- Acronym / sponsor ID
- 60980-2
- Conditions
- Major Depressive Disorder
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 1 Jan 2023 (actual)
- Primary completion
- 27 Mar 2025 (actual)
- Study completion
- 27 Mar 2025 (actual)
- First posted
- 4 Feb 2022 (actual)
- Results
- Posted 15 Jul 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Neuronavigated rTMS | Active comparator | Device: Neuronavigated rTMSNeuronavigated 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. |
| Sham rTMS | Sham comparator | Device: Sham rTMSSham 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Neuronavigated rTMSDelivers patterned magnetic stimulation based on MRI images | Device | Neuronavigated rTMS |
| Sham rTMSDelivers placebo magnetic stimulation | Device | Sham rTMS |
Primary outcome
Change in TMS-evoked EEG Responses Following Intermittent Theta Burst Stimulation (iTBS)
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jul 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Neuronavigated rTMS in people with Major Depressive Disorder, run by Stanford University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Jul 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in TMS-evoked EEG Responses Following Intermittent Theta Burst Stimulation (iTBS) (time frame: Pre-intervention and up to 20 minutes post-intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jul 2026.