Probing the Dorsolateral Prefrontal Cortex and Central Executive Network for Improving Neuromodulation in Depression

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Device: Sham rTMS; Device: Neuronavigated 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 Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Device: Neuronavigated rTMS; Delivers patterned magnetic stimulation based on MRI images
Sham Comparator: 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.	Device: Sham rTMS; Delivers placebo magnetic stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Pre-intervention and up to 20 minutes post-intervention

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Institute of Mental Health (NIMH)

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Actual): March 27, 2025
• Study Completion (Actual): March 27, 2025

Study Registration Dates

• First Submitted: January 12, 2022
• First Submitted That Met QC Criteria: January 31, 2022
• First Posted (Actual): February 4, 2022

Study Record Updates

• Last Update Posted (Actual): July 15, 2026
• Last Update Submitted That Met QC Criteria: June 17, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 60980-2; R01MH129018 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No