Amygdala Activation
Conditions
Brief summary
Posttraumatic stress disorder (PTSD) is a highly debilitating disease with response rates to pharmacological treatment rarely exceeding 60%. Preliminary attempts have been made to use repetitive transcranial magnetic stimulation (rTMS) as a non-pharmacological treatment alternative, but thus far rTMS approaches have demonstrated only modest efficacy. A major factor contributing to these limited effects stems from the depth penetration of TMS, which is not sufficient to directly modulate deep subcortical structures, such as the amygdala, that are affected in PTSD. Moreover, while rTMS effects have been shown to be state-dependent, (i.e. vary substantially according to the neural state during stimulation), this important factor is rarely considered during the clinical application of rTMS. The current study addresses both of these limitations to improve the therapeutic efficacy of rTMS for PTSD. Here we will develop a protocol to test if connectivity-based rTMS is able to modulate amygdala activity through the functional connections with medial prefrontal cortex, taking advantage of state-dependency to enhance rTMS effects by actively engaging the amygdala through a fear perception task. BOLD activation in the amygdala and its connectivity with the frontal cortex will constitute the primary outcomes to test rTMS efficacy. Heart rate variability and skin galvanic responses, acquired during the presentation of fearful faces, will be used as continuous moderators of task engagement during rTMS. If successful, this study will pave the way for a large-scale study to investigate whether state-dependent, connectivity-based rTMS of the amygdala can improve rTMS efficacy as a clinical treatment for PTSD.
Interventions
DEVICErepetitive transcranial magnetic stimulation
excitatory 5Hz rTMS will be used
DEVICESham repetitive transcranial magnetic stimulation
an electrical sham coil reproducing the same clicking sound and tactile sensation than the active rTMS will be used
Sponsors
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* Age Restrictions: Young Group (from 18 to 35 years old) * Use of effective method of birth control for women of childbearing capacity. * Willing to provide informed consent.
Exclusion criteria
* Current or recent (within the past 6 months) history of substance abuse or dependence. * Current serious medical illness. * History of seizure, epilepsy, stroke, brain surgery, head injury, cranial metal implants, known structural brain lesion, devices that may be affected by rTMS or MRI (pacemaker, medication pump, cochlear implant, implanted brain stimulator) * Inability or unwilling to give informed consent. * Diagnosed any Axis I DSM-IV disorder (MINI, DSM-IV). * Clinically defined neurological disorder. * Increased risk of seizure for any reason, including prior diagnosis of increased intracranial pressure, or currently taking medication that lowers the seizure threshold. * Claustrophobia (MRI scanner). * Pregnancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Effect of a rTMS Session on Brain Activation as Measured by the Cerebral Blood Flow (Blood Oxygenation Level Dependent Signal) | right after the rTMS session, up to one hour | Blood oxygenation level dependent (BOLD) will be assessed to evaluate the acute effect of rTMS applied over the medial prefrontal cortex on the amygdala activation. This outcome (expressed a z-score) represents the amygdala activation, either after active rTMS or after sham rTMS. Higher z-scores for active than for sham rTMS indicates that amygdala activity increases after active rTMS compared to sham rTMS, on the other hand lower z-score after active rTMS vs. after Sham rTMS indicated that the amygdala activity would have been reduced with active rTMS. |
Countries
United States
Participant flow
Pre-assignment details
Across the 25 enrolled participants, 7 were excluded after the first visit for different reasons such as: contraindications, too high resting motor threshold or technical difficulties
Participants by arm
| Arm | Count |
|---|---|
| Repetitive TMS (rTMS) excitatory rTMS applied over the medial prefrontal cortex (fMRI-guided)
repetitive transcranial magnetic stimulation: excitatory 5Hz rTMS will be used | 10 |
| Sham Repetitive TMS (rTMS) electrical sham coil applied over the medial prefrontal cortex (fMRI-guided)
Sham repetitive transcranial magnetic stimulation: an electrical sham coil reproducing the same clicking sound and tactile sensation than the active rTMS will be used | 8 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | technical difficulties | 0 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Repetitive TMS (rTMS) | Sham Repetitive TMS (rTMS) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 8 Participants | 18 Participants |
| Race/Ethnicity, Customized Ethnicity African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Asian | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Ethnicity White | 4 Participants | 5 Participants | 9 Participants |
| Region of Enrollment United States | 10 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 |
| other Total, other adverse events | 0 / 7 | 0 / 6 |
| serious Total, serious adverse events | 0 / 7 | 0 / 6 |
Outcome results
Primary
Acute Effect of a rTMS Session on Brain Activation as Measured by the Cerebral Blood Flow (Blood Oxygenation Level Dependent Signal)
Blood oxygenation level dependent (BOLD) will be assessed to evaluate the acute effect of rTMS applied over the medial prefrontal cortex on the amygdala activation. This outcome (expressed a z-score) represents the amygdala activation, either after active rTMS or after sham rTMS. Higher z-scores for active than for sham rTMS indicates that amygdala activity increases after active rTMS compared to sham rTMS, on the other hand lower z-score after active rTMS vs. after Sham rTMS indicated that the amygdala activity would have been reduced with active rTMS.
Time frame: right after the rTMS session, up to one hour
Population: Participants who completed the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Repetitive TMS (rTMS) | Acute Effect of a rTMS Session on Brain Activation as Measured by the Cerebral Blood Flow (Blood Oxygenation Level Dependent Signal) | 0.67 z score in the amygdala | Standard Deviation 0.48 |
| Sham Repetitive TMS (rTMS) | Acute Effect of a rTMS Session on Brain Activation as Measured by the Cerebral Blood Flow (Blood Oxygenation Level Dependent Signal) | -0.48 z score in the amygdala | Standard Deviation 0.87 |
Comparison: Hypothesis: Active rTMS applied over the node in the medial prefrontal cortex the most strongly negatively connected to the right amygdala will decrease amygdala BOLD activation compared to sham rTMSp-value: =0.03t-test, 2 sided