Depression
Conditions
Brief summary
For the proposed 2-year study, the investigators will conduct a within-subject, counterbalanced investigation using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to examine the acute effects of theta-burst stimulation (TBS) on function in dorsomedial prefrontal cortex (dmPFC) in 35 young adults with depression (18-25 years, 50% female).
Detailed description
Each participant will undergo 3 sessions of TMS, one each of continuous and intermittent TBS--with the goal of decreasing or increasing dmPFC responding, respectively--and one of sham TBS. Session order will be counterbalanced, with a double-blind approach to condition. Brain function, behavior, and mood will be assessed before and after each TBS session. Broadly, the investigators predict that inhibitory TBS to the dmPFC will enhance neural, behavioral, and subjective aspects of reward function by reducing dmPFC function and dmPFC connectivity with the ventral striatum (VS).
Interventions
Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered without interruption for a total duration of 40 seconds.
Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered during 2 second periods (10 bursts/period) interleaved with 8-second stimulation-free intervals, for a total duration of 190 seconds.
For the sham of theta burst stimulation, the device providing Theta Burst Stimulation can be placed in the same position and turned on, creating a similar experience for the participant, without providing any neural stimulation. Sham TBS will be delivered with a Cool-B65 Active/Placebo Coil, which includes a sham setting, and MagLink research software.
Sponsors
Study design
Masking description
The content of each TBS condition will be unknown to participants and to the research staff member conducting assessment of change neural, behavioral, and subjective response with TBS.
Intervention model description
All participants will receive intermittent Theta Burst Stimulation (TBS), continuous TBS, and sham TBS mimicking stimulation, in randomized, double-blind order across three sessions.
Eligibility
Inclusion criteria
• DSM-5 Diagnosis of Major Depressive Disorder, Persistent Depressive Disorder (Dysthymia), Other Specified Depressive Disorder, or Other Unspecified Depressive Disorder
Exclusion criteria
* Bipolar disorder, substance dependence, or lifetime history of psychosis * Neurological disorder (e.g., seizure disorder) * Pregnant * MRI contradictions: claustrophobia, permanent orthodontic devices, metal implants or other forms of metal in the body that cannot be removed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dorsomedial Prefrontal Cortex Activation | Task fMRI is conducted after each of 3 TBS sessions (intermittent, continuous, sham; in randomized, counterbalanced order) at approx 3, 5, and 7 weeks after study entry. | This measure captures brain function in the dorsomedial prefrontal cortex (dmPFC) based on blood oxygen level dependent (BOLD) response measured using functional magnetic resonance imaging (fMRI) during a reward task. Data are analyzed using Statistical Parametric Mapping. Magnitude of dmPFC response is in arbitrary units, with higher values reflecting higher activation. Theoretical minimum and maximum scores do not exist. Study hypotheses predict that dmPFC will decrease (based on statistical significance) with continuous TBS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive Affect | pre and post each of 3 TBS administrations, with TBS lasting up to 190 seconds. cTBS, iTBS, and sham TBS each occurred in a single day. | Self-reported pleasant mood was measured with the Positive Affect (PA) scale of the Positive and Negative Affect Schedule (PANAS). This scale consists of a number of words that describe different feelings and emotions, participants are instructed to read each item and then mark to which extent they have felt like this in the past few hours. The PA scale contains 10 items, with each item rated on a 5-point scale of 1 (very slightly or not at all), 2 (a little), 3 (moderately), 4 (quite a bit), or 5 (extremely). Higher scores indicate greater PA. The total PA score is calculated by finding the sum of the 10 positive items. Scores range from 10-50. A higher score indicates higher intensity of positive affect. The PANAS PA data analyzed were from administrations pre- and post-TBS at visits #3-5 (approximately 30 minutes before and 1 hour after TBS administration). |
| VS-dmPFC Functional Connectivity | Task fMRI is conducted after each of 3 TBS sessions (intermittent, continuous, sham; in randomized, counterbalanced order). Sessions occur at approx 3, 5, and 7 weeks after study entry. | Outcome measure is assessed with functional magnetic resonance imaging (fMRI), in which brain function is recorded during a reward task. Functional connectivity between 2 regions of neural reward circuitry, the ventral striatum (VS) and the dorsomedial prefrontal cortex (dmPFC), is computed using general psychophysiologic interaction for this pair of regions in Statistical Parametric Mapping software. FC data are in arbitrary units, with higher values reflecting higher degree of coordination between the regions. Theoretical minimum and maximum scores do not exist. Higher scores do not represent better or worse outcomes or change in health. Based on study hypotheses, FC is predicted to decrease with continuous TBS, based on significance of statistical tests. |
Countries
United States
Participant flow
Pre-assignment details
29 participants completed enrollment in the study. Prior to randomization, all 29 participants completed study visit #1 and study visit #2. Out of those 29, 4 participants were withdrawn after study visit #2 and before randomization. 25 participants were randomized and completed the study intervention.
Participants by arm
| Arm | Count |
|---|---|
| Intermittent, Continuous, Sham Order 3 sessions of theta burst stimulation administered in the following order: 1) Intermittent theta burst stimulation, 2) Continuous theta burst stimulation, 3) Sham theta burst stimulation.
Intermittent Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered without interruption for a total duration of 40 seconds.
Continuous Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered during 2 second periods (10 bursts/period) interleaved with 8-second stimulation-free intervals, for a total duration of 190 seconds.
Sham Theta Burst Stimulation: For the sham of theta burst stimulation, the device providing Theta Burst Stimulation can be placed in the same position and turned on, creating a similar experience for the participant, without providing any neural stimulation. | 5 |
| Intermittent, Sham, Continuous Order 3 sessions of theta burst stimulation administered in the following order: 1) Intermittent theta burst stimulation, 2) Sham theta burst stimulation, 3) Continuous theta burst stimulation.
Intermittent Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered without interruption for a total duration of 40 seconds.
Continuous Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered during 2 second periods (10 bursts/period) interleaved with 8-second stimulation-free intervals, for a total duration of 190 seconds.
Sham Theta Burst Stimulation: For the sham of theta burst stimulation, the device providing Theta Burst Stimulation can be placed in the same position and turned on, creating a similar experience for the participant, without providing any neural stimulation. | 4 |
| Continuous, Intermittent, Sham Order 3 sessions of theta burst stimulation administered in the following order: 1) Continuous theta burst stimulation, 2) Intermittent theta burst stimulation, 3) Sham theta burst stimulation.
Intermittent Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered without interruption for a total duration of 40 seconds.
Continuous Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered during 2 second periods (10 bursts/period) interleaved with 8-second stimulation-free intervals, for a total duration of 190 seconds.
Sham Theta Burst Stimulation: For the sham of theta burst stimulation, the device providing Theta Burst Stimulation can be placed in the same position and turned on, creating a similar experience for the participant, without providing any neural stimulation. | 4 |
| Continuous, Sham, Intermittent Order 3 sessions of theta burst stimulation administered in the following order: 1) Continuous theta burst stimulation, 2) Sham theta burst stimulation, 3) Intermittent theta burst stimulation.
Intermittent Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered without interruption for a total duration of 40 seconds.
Continuous Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered during 2 second periods (10 bursts/period) interleaved with 8-second stimulation-free intervals, for a total duration of 190 seconds.
Sham Theta Burst Stimulation: For the sham of theta burst stimulation, the device providing Theta Burst Stimulation can be placed in the same position and turned on, creating a similar experience for the participant, without providing any neural stimulation. | 5 |
| Sham, Intermittent, Continuous Order 3 sessions of theta burst stimulation administered in the following order: 1) Sham theta burst stimulation, 2) Intermittent theta burst stimulation, 3) Continuous theta burst stimulation.
Intermittent Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered without interruption for a total duration of 40 seconds.
Continuous Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered during 2 second periods (10 bursts/period) interleaved with 8-second stimulation-free intervals, for a total duration of 190 seconds.
Sham Theta Burst Stimulation: For the sham of theta burst stimulation, the device providing Theta Burst Stimulation can be placed in the same position and turned on, creating a similar experience for the participant, without providing any neural stimulation. | 4 |
| Sham, Continuous, Intermittent Order 3 sessions of theta burst stimulation administered in the following order: 1) Sham theta burst stimulation, 2) Continuous theta burst stimulation, 3) Intermittent theta burst stimulation.
Intermittent Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered without interruption for a total duration of 40 seconds.
Continuous Theta Burst Stimulation: Theta Burst Stimulation, a form of Transcranial Magnetic Stimulation, will be applied to the dorsomedial prefrontal cortex. will include 600 pulses delivered in brief bursts of three pulses with a frequency of 50 Hz, at an intensity of 110% of resting motor threshold, and administered every 200 ms (5 Hz). Bursts will be delivered during 2 second periods (10 bursts/period) interleaved with 8-second stimulation-free intervals, for a total duration of 190 seconds.
Sham Theta Burst Stimulation: For the sham of theta burst stimulation, the device providing Theta Burst Stimulation can be placed in the same position and turned on, creating a similar experience for the participant, without providing any neural stimulation. | 3 |
| Total | 25 |
Baseline characteristics
| Characteristic | Intermittent, Continuous, Sham Order | Total | Sham, Continuous, Intermittent Order | Sham, Intermittent, Continuous Order | Continuous, Sham, Intermittent Order | Continuous, Intermittent, Sham Order | Intermittent, Sham, Continuous Order |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 21 years STANDARD_DEVIATION 1.22 | 21.175 years STANDARD_DEVIATION 2.15 | 21 years STANDARD_DEVIATION 1.73 | 20.25 years STANDARD_DEVIATION 2.63 | 21.8 years STANDARD_DEVIATION 2.39 | 22 years STANDARD_DEVIATION 2.45 | 21 years STANDARD_DEVIATION 2.45 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 22 Participants | 3 Participants | 4 Participants | 5 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 6 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 16 Participants | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 2 Participants |
| Region of Enrollment United States | 5 participants | 25 participants | 3 participants | 4 participants | 5 participants | 4 participants | 4 participants |
| Sex: Female, Male Female | 5 Participants | 23 Participants | 3 Participants | 4 Participants | 5 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 0 / 25 | 0 / 25 | 1 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 | 0 / 25 |
Outcome results
Dorsomedial Prefrontal Cortex Activation
This measure captures brain function in the dorsomedial prefrontal cortex (dmPFC) based on blood oxygen level dependent (BOLD) response measured using functional magnetic resonance imaging (fMRI) during a reward task. Data are analyzed using Statistical Parametric Mapping. Magnitude of dmPFC response is in arbitrary units, with higher values reflecting higher activation. Theoretical minimum and maximum scores do not exist. Study hypotheses predict that dmPFC will decrease (based on statistical significance) with continuous TBS.
Time frame: Task fMRI is conducted after each of 3 TBS sessions (intermittent, continuous, sham; in randomized, counterbalanced order) at approx 3, 5, and 7 weeks after study entry.
Population: Cases included in analysis are those from participants who completed all study procedures (i.e., all TMS sessions, all MRI scans), had available data, and passed data quality criteria
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intermittent TBS | Dorsomedial Prefrontal Cortex Activation | 0.16 score in arbitrary units | Standard Deviation 3.79 |
| Continuous TBS | Dorsomedial Prefrontal Cortex Activation | 1.35 score in arbitrary units | Standard Deviation 4.3 |
| Sham TBS | Dorsomedial Prefrontal Cortex Activation | 0.36 score in arbitrary units | Standard Deviation 3.6 |
Positive Affect
Self-reported pleasant mood was measured with the Positive Affect (PA) scale of the Positive and Negative Affect Schedule (PANAS). This scale consists of a number of words that describe different feelings and emotions, participants are instructed to read each item and then mark to which extent they have felt like this in the past few hours. The PA scale contains 10 items, with each item rated on a 5-point scale of 1 (very slightly or not at all), 2 (a little), 3 (moderately), 4 (quite a bit), or 5 (extremely). Higher scores indicate greater PA. The total PA score is calculated by finding the sum of the 10 positive items. Scores range from 10-50. A higher score indicates higher intensity of positive affect. The PANAS PA data analyzed were from administrations pre- and post-TBS at visits #3-5 (approximately 30 minutes before and 1 hour after TBS administration).
Time frame: pre and post each of 3 TBS administrations, with TBS lasting up to 190 seconds. cTBS, iTBS, and sham TBS each occurred in a single day.
Population: Only participants who completed the PA measure at all time points (pre/post each condition, all 3 conditions) were included in analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intermittent TBS | Positive Affect | Pre | 20.70 score on a scale | Standard Deviation 6.74 |
| Intermittent TBS | Positive Affect | Post | 20.45 score on a scale | Standard Deviation 7.35 |
| Continuous TBS | Positive Affect | Pre | 20.05 score on a scale | Standard Deviation 6.24 |
| Continuous TBS | Positive Affect | Post | 19.80 score on a scale | Standard Deviation 7.8 |
| Sham TBS | Positive Affect | Post | 22.10 score on a scale | Standard Deviation 9.71 |
| Sham TBS | Positive Affect | Pre | 20.45 score on a scale | Standard Deviation 6.06 |
VS-dmPFC Functional Connectivity
Outcome measure is assessed with functional magnetic resonance imaging (fMRI), in which brain function is recorded during a reward task. Functional connectivity between 2 regions of neural reward circuitry, the ventral striatum (VS) and the dorsomedial prefrontal cortex (dmPFC), is computed using general psychophysiologic interaction for this pair of regions in Statistical Parametric Mapping software. FC data are in arbitrary units, with higher values reflecting higher degree of coordination between the regions. Theoretical minimum and maximum scores do not exist. Higher scores do not represent better or worse outcomes or change in health. Based on study hypotheses, FC is predicted to decrease with continuous TBS, based on significance of statistical tests.
Time frame: Task fMRI is conducted after each of 3 TBS sessions (intermittent, continuous, sham; in randomized, counterbalanced order). Sessions occur at approx 3, 5, and 7 weeks after study entry.
Population: Cases included in analysis are those from participants who completed all MRI scans, had available fMRI data, and had data that passed quality criteria
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intermittent TBS | VS-dmPFC Functional Connectivity | 2.28 arbitrary units | Standard Deviation 7.64 |
| Continuous TBS | VS-dmPFC Functional Connectivity | 4.10 arbitrary units | Standard Deviation 13.7 |
| Sham TBS | VS-dmPFC Functional Connectivity | 1.16 arbitrary units | Standard Deviation 5.61 |