Major Depressive Disorder
Conditions
Keywords
depression, TMS, fMRI
Brief summary
This is not a treatment study. In this study, the researchers are primarily interested in examining whether functional MRI (fMRI)-guided transcranial magnetic stimulation (TMS) may be more effective than traditional TMS methods at temporarily influencing neural circuit communication. The investigators test this by combining TMS and fMRI technologies to probe and modulate brain activity. If the novel fMRI-guided TMS stimulation used in this study is more effective than traditional methods, future studies may utilize similar personalized TMS targeting methods to yield even better clinical outcomes.
Detailed description
This study will involve a baseline Magnetic Resonance Imaging (MRI) scan, Transcranial Magnetic Stimulation (TMS), and TMS interleaved with functional MRI (fMRI) scans. After screening, eligible participants will undergo a 1-hour MRI scan, encompassing structural and functional scans to establish TMS stimulation targets for subsequent visits. During the baseline TMS/fMRI session or pre-intervention TMS/fMRI, single pulses of TMS and a short round of repetitive TMS (rTMS) will be administered to the participant's individualized target while functional MRI scans (fMRI) are collected. Following this, participants will commence a short TMS intervention regimen involving daily rTMS over 3 consecutive days. The day after the intervention, participants will undergo another TMS/fMRI session, or the post-intervention TMS/fMRI, to capture potential changes from the 3-day intervention. Clinical assessments will be conducted at baseline before the first TMS/fMRI session and again after the final TMS/fMRI session to assess symptom changes.
Interventions
DEVICETranscranial Magnetic Stimulation
Transcranial Magnetic Stimulation (TMS) is a non-invasive form of brain stimulation. TMS can influence activity in various brain regions, and it allows researchers to test or modify brain circuit communication. Repetitive TMS (rTMS) is FDA-approved for depression treatment. TMS is administered over 5 study visits: an initial TMS/fMRI session, a 3-day TMS intervention regimen, and a post-intervention TMS/fMRI session. During TMS/fMRI sessions, participants receive single pulses of TMS pre/post a short round of Intermittent Theta Burst Stimulation (iTBS), a modified rTMS protocol. Throughout the 3-day intervention regimen, participants receive two full rounds of iTBS daily. All study participants receive active TMS.
Sponsors
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
All subjects receive active TMS to their individualized fMRI-guided target. Participants will first receive TMS in the MRI scanner, then over the course of 3-Day TMS Intervention Regimen, and lastly in a final MRI scan.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* 18 to 60 years old, inclusive * Right-handed * Currently experiencing a major depressive episode (MDD) * Capacity to give informed consent and follow study procedures * Command of English language to understand/ respond to written and verbal instructions
Exclusion criteria
* MRI contraindications (i.e., metal in body, claustrophobia, etc.) * TMS contraindications (i.e., seizure disorder) * Diagnosis of exclusionary psychiatric disorder (i.e., schizophrenia, bipolar) * Current use of psychiatric medication and unable/ willing to safely withdraw * Refusal to abstain from alcohol or drugs for duration of study * Medication use that reduces seizure threshold * Medication that interferes with blood flow (i.e., opioids, antihypertensive) * Known neurological disorder or significant disability that interferes with study procedures * Woman who is pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Evoked Functional Brain Activity Pre/Post Short iTBS Stimulation Before and After the 3-Day TMS Intervention Regimen | 5 days | Change in subgenual anterior cingulate evoked response (fMRI BOLD) at all four timepoints across the two TMS/fMRI scan sessions: pre-intervention and preceding a single round of iTBS in the scanner (pre-tx, pre-iTBS); pre-intervention, following single iTBS in the scanner (pre-tx, post-iTBS); post intervention, preceding iTBS in the scanner (post-tx, pre-iTBS); and post-intervention, post-iTBS in the scanner (post-tx, post-iTBS). Greater negative change is associated with more clinical improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Depression, Anxiety and Stress Scale (DASS-21) Score Pre/Post the 3-Day TMS Intervention Regimen | Up to one week | The Depression, Anxiety, and Stress Scale (DASS-21) is a self-report tool with 21 items, assessing depression, anxiety, and stress levels. The scale scores range from 0 to 63, with higher scores indicating more severe or frequent emotional symptoms. The change in DASS-21 score will be evaluated pre and post the 3-day TMS Intervention Regimen. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Evoked Functional Brain Activity Before and After the 3-Day TMS Intervention Regimen | Up to one week | Change in subgenual anterior cingulate evoked response (fMRI BOLD) Before and After the 3-Day TMS Intervention Regimen Greater negative change is associated with more clinical improvement. |
Countries
United States
Participant flow
Pre-assignment details
Of the 86 subjects screened for the study, 41 were enrolled and 45 did not start study procedures (32 screen failed, 9 withdrew from participation, and 4 lost to follow-up).
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants follow the same procedures.
TMS/ fMRI Stimulation: The study uses a modified repetitive TMS stimulation protocol. Participants receive active TMS on five separate days: a baseline TMS/ fMRI scan, three mini TMS sessions, and a final TMS/ fMRI scan.
Again, this level of stimulation is considered to be sub-threshold for that of a TMS treatment protocol. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Baseline MRI and Assessments | Physician Decision | 2 |
| Mini TMS Sessions (3 Visits) | Withdrawal by Subject | 1 |
| Targeting TMS Scan | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 28.9 years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Sex/Gender, Customized Gender Now Female | 23 Participants |
| Sex/Gender, Customized Gender Now Male | 18 Participants |
| Snaith-Hamilton Pleasure Scale | 5.84 units on a scale STANDARD_DEVIATION 3.48 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 41 |
| other Total, other adverse events | 5 / 41 |
| serious Total, serious adverse events | 0 / 41 |
Outcome results
Primary
Changes in Evoked Functional Brain Activity Pre/Post Short iTBS Stimulation Before and After the 3-Day TMS Intervention Regimen
Change in subgenual anterior cingulate evoked response (fMRI BOLD) at all four timepoints across the two TMS/fMRI scan sessions: pre-intervention and preceding a single round of iTBS in the scanner (pre-tx, pre-iTBS); pre-intervention, following single iTBS in the scanner (pre-tx, post-iTBS); post intervention, preceding iTBS in the scanner (post-tx, pre-iTBS); and post-intervention, post-iTBS in the scanner (post-tx, post-iTBS). Greater negative change is associated with more clinical improvement.
Time frame: 5 days
Population: Of the 37 participants who completed all study procedures, the data from 36 participants was analyzed. Data one subject was not usable.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| All Enrolled Participants | Changes in Evoked Functional Brain Activity Pre/Post Short iTBS Stimulation Before and After the 3-Day TMS Intervention Regimen | Pre-tx/Pre-iTBS | -0.2684097 % BOLD signal change |
| All Enrolled Participants | Changes in Evoked Functional Brain Activity Pre/Post Short iTBS Stimulation Before and After the 3-Day TMS Intervention Regimen | Pre-tx/Post-iTBS | -0.1897918 % BOLD signal change |
| All Enrolled Participants | Changes in Evoked Functional Brain Activity Pre/Post Short iTBS Stimulation Before and After the 3-Day TMS Intervention Regimen | Post-tx/Pre-iTBS | -0.2640429 % BOLD signal change |
| All Enrolled Participants | Changes in Evoked Functional Brain Activity Pre/Post Short iTBS Stimulation Before and After the 3-Day TMS Intervention Regimen | Post-tx/Post-iTBS | -0.4190647 % BOLD signal change |
Comparison: Statistical analysis of fMRI-guided TMS evoked subgenual anterior cingulate responses (fMRI BOLD) change at Pre-tx/Pre-iTBS. Statistics are from one-sample T-tests vs. 0, 2-tailed. Negative t-values represent negative mean fMRI BOLD percent signal change. Alternative hypothesis: true mean is not equal to 0.p-value: <0.001t-test, 2 sided
Comparison: Statistical analysis of fMRI-guided TMS evoked subgenual anterior cingulate responses (fMRI BOLD) change at Pre-tx/Post-iTBS. Statistics are from one-sample T-tests vs. 0, 2-tailed. Negative t-values represent negative mean fMRI BOLD percent signal change. Alternative hypothesis: true mean is not equal to 0.p-value: 0.005t-test, 2 sided
Comparison: Statistical analysis of fMRI-guided TMS evoked subgenual anterior cingulate responses (fMRI BOLD) change at Post-tx/Pre-iTBS. Statistics are from one-sample T-tests vs. 0, 2-tailed. Negative t-values represent negative mean fMRI BOLD percent signal change. Alternative hypothesis: true mean is not equal to 0.p-value: 0.005t-test, 2 sided
Comparison: Statistical analysis of fMRI-guided TMS evoked subgenual anterior cingulate responses (fMRI BOLD) change at Post-tx/Post-iTBS. Statistics are from one-sample T-tests vs. 0, 2-tailed. Negative t-values represent negative mean fMRI BOLD percent signal change. Alternative hypothesis: true mean is not equal to 0.p-value: <0.001t-test, 2 sided
Secondary
Change in Depression, Anxiety and Stress Scale (DASS-21) Score Pre/Post the 3-Day TMS Intervention Regimen
The Depression, Anxiety, and Stress Scale (DASS-21) is a self-report tool with 21 items, assessing depression, anxiety, and stress levels. The scale scores range from 0 to 63, with higher scores indicating more severe or frequent emotional symptoms. The change in DASS-21 score will be evaluated pre and post the 3-day TMS Intervention Regimen.
Time frame: Up to one week
Population: Of the 37 participants who completed all study procedures, the data of one subject was unusable. Therefore, the data of 36 participants was used for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Enrolled Participants | Change in Depression, Anxiety and Stress Scale (DASS-21) Score Pre/Post the 3-Day TMS Intervention Regimen | Pre 3-day TMS intervention | 26.78 score on a scale | Standard Error 1.566064 |
| All Enrolled Participants | Change in Depression, Anxiety and Stress Scale (DASS-21) Score Pre/Post the 3-Day TMS Intervention Regimen | Post 3-day TMS intervention | 17.61 score on a scale | Standard Error 2.012374 |
Other Pre-specified
Change in Evoked Functional Brain Activity Before and After the 3-Day TMS Intervention Regimen
Change in subgenual anterior cingulate evoked response (fMRI BOLD) Before and After the 3-Day TMS Intervention Regimen Greater negative change is associated with more clinical improvement.
Time frame: Up to one week
Population: Of the 37 participants who completed all study procedures, the data of one subject was unusable. Therefore, the data of 36 participants was used for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Enrolled Participants | Change in Evoked Functional Brain Activity Before and After the 3-Day TMS Intervention Regimen | Pre 3-day TMS intervention | -0.19 % BOLD signal change | Standard Error 0.063308 |
| All Enrolled Participants | Change in Evoked Functional Brain Activity Before and After the 3-Day TMS Intervention Regimen | Post 3-day TMS intervention | -0.42 % BOLD signal change | Standard Error 0.083043 |
Comparison: Analysis to investigate the correlation between changes in DASS-21 Scores (Secondary Outcome) and Evoked Functional Brain Activity (Other Pre-specified Outcome) pre and post the 3-Day TMS Intervention Regimen.p-value: 0.007Regression, Linear