Major Depressive Disorder, RecurrentNCT01931995
Investigation of Brain Network Dynamics in Depression
A study testing TMS positively correlated DLPFC and TMS to negatively correlated DLPFC in people with Major Depressive Disorder, Recurrent, run by Massachusetts General Hospital at 1 site in United States.
Trial summary
This research study is being done to gain a better understanding about brain networks that may be involved in depression. The investigators plan to examine how these networks change after the brain is stimulated with "Transcranial Magnetic Stimulation" (TMS). Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Major Depressive Disorder, Recurrent
- What is being tested?
- TMS positively correlated DLPFC and TMS to negatively correlated DLPFC
- Type of treatment
- Medical device, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2013to Jul 2018
- 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 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Ages 18-50
- Patients with Major Depressive Disorder, as confirmed by a referring provider, DSM-IVR criteria, and/or a Structured Clinical Interview (SCID)
- Score of ≥18 on the 24 item version of the Hamilton Depression Rating Scale (HDRS)
- Meeting criteria to safely receive fMRI scanning, PET scanning and rTMS.
Who cannot join
- Any subject who is pregnant or lactating
- Patients with bipolar disorder, schizoaffective disorder, suicidal ideation, or any history of psychosis. Concurrent anxiety disorders will be allowed.
- Any serious concurrent medical or neurological illness
- Any contraindication to receiving TMS, fMRI or PET scans including, but not limited to having: a pacemaker, metallic implants, implanted pumps, surgical aneurysm clips, history of severe head trauma, history of seizures or a first degree relative with epilepsy, been involved in a nuclear medicine study in the past 12 months, diabetes
Trial locations and contacts
1 site in 1 country.
United States1 site
Martinos Center for Biomedical Imaging/Massachusetts General Hospital
Charlestown, Massachusetts, 02129
About this study
Official title: Investigation of Cortico-limbic Networks and Their Dynamics in Major Depressive Disorder
This research study is being done to gain a better understanding about brain networks that may be involved in depression. The investigators plan to examine how these networks change after the brain is stimulated with "Transcranial Magnetic Stimulation" (TMS). TMS is a way of stimulating the brain in order to mildly activate or mildly suppress different brain areas, and is used to treat some forms of depression. It is hoped that this study will facilitate learning more about the structure and function of different brain areas and the ways that they are interconnected to form networks, both in depressed people and in people without depression. In this research study, the effects of TMS will be measured by obtaining "pictures" of the brain with "Magnetic Resonance Imaging" (MRI) and with "Positron Emission Tomography" (PET). More specifically, this will be accomplished with a combined MRI and PET scanner, which is capable of simultaneously obtaining both MRI and PET images of the brain. This scanning paradigm will allow the assessment of local metabolic changes resulting from TMS (with PET images) and brain network changes resulting from TMS (with fMRI). Changes resulting from TMS between 20 subjects with depression and 20 healthy volunteers will be calculated and will form the main outcome measure.
Read the detailed description
Repetitive transcranial magnetic stimulation (rTMS), when delivered to the dorsolateral prefrontal cortex (DLPFC) is a clinically effective treatment for major depressive disorder (MDD). Network models of MDD are increasingly gaining acceptance, and functional connectivity MRI (fcMRI) has revealed topographically specific aberrations in functional network architecture in MDD. And yet, despite hints that the therapeutic effects of rTMS are actuated through distributed impacts upon cortical and subcortical limbic centers, the network effects of rTMS remain mysterious. This study seeks to investigate the way rTMS to DLPFC modulates network functional connectivity between the site of stimulation and a critical limbic region, the subgenual cingulate (sgACC), and between the sgACC and other limbic regions. In this study, high frequency rTMS will be used to stimulate the left DLPFC (recapitulating the therapeutic methodology), specifically, regions of the DLPFC that are functionally correlated and anti-correlated with the sgACC. This will be accomplished in a group of patients with MDD, and in a group of carefully matched controls. These subjects will be scanned before and after rTMS is delivered, as a way of gauging its effects. The feasibility of this design was recently demonstrated by our group (Eldaief et al. PNAS 2011). Changes induced by the stimulation will be charted with a novel combined MRI-PET (Positron Emission Tomography) scanner at the MGH Martinos Center, which is capable of simultaneously recording fcMRI BOLD (Blood oxygenation level-dependent) and 18Flurodeoxyglucose (FDG) PET data. This will permit cortico-limbic networks to be characterized dynamically through (1) examination of the differential effects of stimulating two networks in the DLPFC, and (2) by tracking the dynamic interplay between rTMS induced changes in local glucose metabolism at DLPFC and sgACC on the one hand, and changes in distributed connectivity between these regions on the other. In an exploratory aim, MDD patients will return three months later (after they have undergone a non-specific treatment intervention with their psychiatric provider) for the identical rTMS/fcMRI/FDG-PET procedures. This aim will establish, as proof of principle, that treatment of MDD is associated with changes in cortico-limbic functional network architecture, and in cortico-limbic dynamics. Eventually, it is hoped that this work will lead to the emergence of aberrant cortical dynamics as a biomarker for MDD. In addition, this work might pollinate future studies which use aberrant cortical dynamics as a novel therapeutic target upon which neuromodulatory interventions might intervene.
- Conditions
- Major Depressive Disorder, Recurrent
- Being tested
- TMS positively correlated DLPFC, TMS to negatively correlated DLPFC
- Medical subject headings
- Depressive Disorder, Major, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TMS positively correlated DLPFCDevice
Also called This study will employ a TMS system that includes a stimulator, TMS coil and neuronavigation system
TMS, or transcranial magnetic stimulation, is a technique that is employed to non-invasively activate or suppress targeted regions of the cerebral cortex. One TMS system has been FDA approved to treat certain medically refractory forms of depression.
TMS to negatively correlated DLPFCProcedure or surgery
Also called This study will employ a TMS system that includes a stimulator, TMS coil and neuronavigation system
TMS, or transcranial magnetic stimulation, is a way of non-invasively activating or suppressing targeted regions of the cerebral cortex. One TMS system has been FDA approved to treat certain medically refractory forms of depression.
| Study group | Role | What they receive |
|---|---|---|
| TMS to positively correlated DLPFC | Active comparator | High frequency TMS to a target region of dorsolateral prefrontal cortex which is positively correlated with the subgenual cingulate cortex Receives: Device: TMS positively correlated DLPFC |
| TMS to negatively correlated DLPFC | Active comparator | High frequency TMS to a target region of dorsolateral prefrontal cortex which is positively correlated with the subgenual cingulate cortex Receives: Procedure: TMS to negatively correlated DLPFC |
What is being measured
The primary outcome is the main question the study is designed to answer.
Relative Changes in Corticolimbic Functional Connectivity as a Result of TMS
The primary outcome measure is the relative change in functional connectivity in prefrontal corticolimbic brain networks resulting from TMS stimulation of two nodes in the dorsolateral prefrontal cortex: one which is positively correlated to the subgenual cingulate and one which is negatively correlated to this area. Functional connectivity is a measure of correlation strength which biologically reflects correlations between low-frequency oscillations in the fMRI blood oxygenation level dependent signal. As a correlation, this ranges from -1 to 1. This is then Fisher transformed from an r value to a z value (range -2 to -2).
Measured: Assessed immediately following each intervention
Secondary outcomes (1)
Changes in Local Glucose Metabolism at Corticolimbic Network Nodes
This outcome measure will employ FDG PET scanning to assess changes in local glucose metabolism resulting from TMS to two dorsolateral prefrontal stimulation targets. More specially, changes in glucose metabolism will be assessed at the stimulation targets, in the subgenual cingulate and in the amygdala. This is measured in whole brain normalized standardized uptake values (wbnSUV).
Measured: Assessed immediately following each intervention.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Aug 2013 (estimated)
- Study startFeb 2013
- Primary completionJun 2018
- Study completionJul 2018
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.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Major Depressive Disorder, RecurrentStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe 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
- Other
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mark C. Eldaief, MD, Brigham and Women's Hospital
- Investigators
- Mark C Eldaief, M.D., Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01931995
- Sponsor's protocol ID
- 2012p001784
- Status last verified
- Jun 2021
- First submitted
- 19 Aug 2013
- Last updated
- 7 Jul 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Sun W, Billot A, McMains S, Rodrigues K, Braga RM, Izquierdo-Garcia D, Eldaief MC. Relationships between local metabolic activity and distributed functional connectivity in major depressive disorder. Transl Psychiatry. 2025 Dec 1;16(1):65. doi: 10.1038/s41398-025-03766-w.
PubMed 41326377
Study at a glance
From the registry record, last updated by the sponsor on 7 Jul 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigation of Cortico-limbic Networks and Their Dynamics in Major Depressive Disorder
- ClinicalTrials.gov ID
- NCT01931995
- Acronym / sponsor ID
- 2012p001784
- Conditions
- Major Depressive Disorder, Recurrent
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Study start
- Feb 2013
- Primary completion
- Jun 2018 (actual)
- Study completion
- Jul 2018 (actual)
- First posted
- 30 Aug 2013 (estimated)
- Results
- Posted 7 Jul 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This research study is being done to gain a better understanding about brain networks that may be involved in depression. The investigators plan to examine how these networks change after the brain is stimulated with "Transcranial Magnetic Stimulation" (TMS). TMS is a way of stimulating the brain in order to mildly activate or mildly suppress different brain areas, and is used to treat some forms of depression. It is hoped that this study will facilitate learning more about the structure and function of different brain areas and the ways that they are interconnected to form networks, both in depressed people and in people without depression. In this research study, the effects of TMS will be measured by obtaining "pictures" of the brain with "Magnetic Resonance Imaging" (MRI) and with "Positron Emission Tomography" (PET). More specifically, this will be accomplished with a combined MRI and PET scanner, which is capable of simultaneously obtaining both MRI and PET images of the brain. This scanning paradigm will allow the assessment of local metabolic changes resulting from TMS (with PET images) and brain network changes resulting from TMS (with fMRI). Changes resulting from TMS between 20 subjects with depression and 20 healthy volunteers will be calculated and will form the main outcome measure.
Detailed description
Repetitive transcranial magnetic stimulation (rTMS), when delivered to the dorsolateral prefrontal cortex (DLPFC) is a clinically effective treatment for major depressive disorder (MDD). Network models of MDD are increasingly gaining acceptance, and functional connectivity MRI (fcMRI) has revealed topographically specific aberrations in functional network architecture in MDD. And yet, despite hints that the therapeutic effects of rTMS are actuated through distributed impacts upon cortical and subcortical limbic centers, the network effects of rTMS remain mysterious. This study seeks to investigate the way rTMS to DLPFC modulates network functional connectivity between the site of stimulation and a critical limbic region, the subgenual cingulate (sgACC), and between the sgACC and other limbic regions. In this study, high frequency rTMS will be used to stimulate the left DLPFC (recapitulating the therapeutic methodology), specifically, regions of the DLPFC that are functionally correlated and anti-correlated with the sgACC. This will be accomplished in a group of patients with MDD, and in a group of carefully matched controls. These subjects will be scanned before and after rTMS is delivered, as a way of gauging its effects. The feasibility of this design was recently demonstrated by our group (Eldaief et al. PNAS 2011). Changes induced by the stimulation will be charted with a novel combined MRI-PET (Positron Emission Tomography) scanner at the MGH Martinos Center, which is capable of simultaneously recording fcMRI BOLD (Blood oxygenation level-dependent) and 18Flurodeoxyglucose (FDG) PET data. This will permit cortico-limbic networks to be characterized dynamically through (1) examination of the differential effects of stimulating two networks in the DLPFC, and (2) by tracking the dynamic interplay between rTMS induced changes in local glucose metabolism at DLPFC and sgACC on the one hand, and changes in distributed connectivity between these regions on the other. In an exploratory aim, MDD patients will return three months later (after they have undergone a non-specific treatment intervention with their psychiatric provider) for the identical rTMS/fcMRI/FDG-PET procedures. This aim will establish, as proof of principle, that treatment of MDD is associated with changes in cortico-limbic functional network architecture, and in cortico-limbic dynamics. Eventually, it is hoped that this work will lead to the emergence of aberrant cortical dynamics as a biomarker for MDD. In addition, this work might pollinate future studies which use aberrant cortical dynamics as a novel therapeutic target upon which neuromodulatory interventions might intervene.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| TMS to positively correlated DLPFC | Active comparator | Device: TMS positively correlated DLPFCHigh frequency TMS to a target region of dorsolateral prefrontal cortex which is positively correlated with the subgenual cingulate cortex |
| TMS to negatively correlated DLPFC | Active comparator | Procedure: TMS to negatively correlated DLPFCHigh frequency TMS to a target region of dorsolateral prefrontal cortex which is positively correlated with the subgenual cingulate cortex |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Ages 18-50
- Patients with Major Depressive Disorder, as confirmed by a referring provider, DSM-IVR criteria, and/or a Structured Clinical Interview (SCID)
- Score of ≥18 on the 24 item version of the Hamilton Depression Rating Scale (HDRS)
- Meeting criteria to safely receive fMRI scanning, PET scanning and rTMS.
Key exclusion criteria (4 listed)
- Any subject who is pregnant or lactating
- Patients with bipolar disorder, schizoaffective disorder, suicidal ideation, or any history of psychosis. Concurrent anxiety disorders will be allowed.
- Any serious concurrent medical or neurological illness
- Any contraindication to receiving TMS, fMRI or PET scans including, but not limited to having: a pacemaker, metallic implants, implanted pumps, surgical aneurysm clips, history of severe head trauma, history of seizures or a first degree relative with epilepsy, been involved in a nuclear medicine study in the past 12 months, diabetes
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 |
|---|---|---|
| TMS positively correlated DLPFCAlso: This study will employ a TMS system that includes a stimulator, TMS coil and neuronavigation systemTMS, or transcranial magnetic stimulation, is a technique that is employed to non-invasively activate or suppress targeted regions of the cerebral cortex. One TMS system has been FDA approved to treat certain medically refractory forms of depression. | Device | TMS to positively correlated DLPFC |
| TMS to negatively correlated DLPFCAlso: This study will employ a TMS system that includes a stimulator, TMS coil and neuronavigation systemTMS, or transcranial magnetic stimulation, is a way of non-invasively activating or suppressing targeted regions of the cerebral cortex. One TMS system has been FDA approved to treat certain medically refractory forms of depression. | Procedure or surgery | TMS to negatively correlated DLPFC |
Primary outcome
Relative Changes in Corticolimbic Functional Connectivity as a Result of TMS
Time frame: Assessed immediately following each intervention
The primary outcome measure is the relative change in functional connectivity in prefrontal corticolimbic brain networks resulting from TMS stimulation of two nodes in the dorsolateral prefrontal cortex: one which is positively correlated to the subgenual cingulate and one which is negatively correlated to this area. Functional connectivity is a measure of correlation strength which biologically reflects correlations between low-frequency oscillations in the fMRI blood oxygenation level dependent signal. As a correlation, this ranges from -1 to 1. This is then Fisher transformed from an r value to a z value (range -2 to -2).
1 secondary outcome
Changes in Local Glucose Metabolism at Corticolimbic Network Nodes
Time frame: Assessed immediately following each intervention.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jul 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41326377Sun W, Billot A, McMains S, Rodrigues K, Braga RM, Izquierdo-Garcia D, Eldaief MC. Relationships between local metabolic activity and distributed functional connectivity in major depressive disorder. Transl Psychiatry. 2025 Dec 1;16(1):65. doi: 10.1038/s41398-025-03766-w.
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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.
Mark C Eldaief, M.D. principal investigator
Brigham and Women's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing TMS positively correlated DLPFC and TMS to negatively correlated DLPFC in people with Major Depressive Disorder, Recurrent, run by Massachusetts General Hospital 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 4 inclusion and 4 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 7 Jul 2021. 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. 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 7 Jul 2021). 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?
Relative Changes in Corticolimbic Functional Connectivity as a Result of TMS (time frame: Assessed immediately following each intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01931995, which also lists 1 linked publication.
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 7 Jul 2021.