Anxiety, Generalized Anxiety Disorder, Panic Disorder, Social Anxiety Disorder
Conditions
Keywords
functional magnetic resonance imaging
Brief summary
This study seeks to understand emotion regulation in those with anxiety using real-time functional magnetic resonance imaging neurofeedback, a tool that allows individuals to control brain activity. The goal of this project is to understand how receiving feedback about one's own brain activity relates to emotion regulation ability. This work will help the study team understand the brain areas involved in emotion regulation and could lay the groundwork to test if psychotherapy outcomes can be enhanced using neurofeedback. The study hypotheses include: * Participants receiving veritable-Neurofeedback (NF) will show a greater activation increase in the prefrontal cortex (PFC) compared to sham-NF * Participants receiving veritable-NF will show greater cognitive reappraisal (CR) ability compared to those receiving sham-NF * Prefrontal cortex activation will positively correlate with CR ability
Detailed description
Due to an unforeseen error in our online neurofeedback script, in which the location of the brain region being targeted was not properly read by the script, participants in the veritable-NF group received feedback to the medial parietal cortex (MPC) instead of the PFC. A third, unrandomized arm has been added to this registration to enroll an additional subset of participants who are indeed receiving feedback to the PFC. The pre-existing veritable-NF arm has been relabeled to reflect which region of the brain was actually targeted. Additionally, the masking description has been reset to None.
Interventions
Participants will have 4 visits (some can be done virtually). The baseline visit will include an interview and questionnaires. Eligible participants will have a practice session at visit 2, and may do a mock scanner if the visit is in person. Visit 3 will take place within 5 days of the practice session and participants will be asked to complete questionnaires and have an fMRI with the real neurofeedback. Visit 4 will take place one month after visit 3 and will include a follow-up interview with a trainer assessor as well as questionnaires. Additionally, 2 weeks after visit 3 participants will also complete some questionnaires online.
OTHERfMRI with Sham-NF
Participants will have 4 visits (some can be done virtually). The baseline visit will include an interview and questionnaires. Eligible participants will have a practice session at visit 2, and may do a mock scanner if the visit is in person. Visit 3 will take place within 5 days of the practice session and participants will be asked to complete questionnaires and have an fMRI with feedback that looks similar to real neurofeedback, but is computer generated. Visit 4 will take place 2 weeks after visit 3 and participants will complete more questionnaires.
Sponsors
Brain & Behavior Research Foundation
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
(Veritable-NF (MPC) and Sham-NF only): All staff present during the MRI session, as well as the participant, will be blinded to group assignment. A designated member of the study team will remain unblinded during the duration of the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Primary diagnosis (primary source of distress and/or interference) of generalized anxiety disorder, social anxiety disorder, panic disorder or illness anxiety disorder based on structured interview. Comorbid phobic disorders allowed, but these cannot be the primary source of interference or distress due to the lowered chances of encountering anxiety-provoking stimuli during the study period * Score of 2 or more on at least 1 question from the GAD/CROSS-AD composite * Medically and physically able to consent * Not regularly taking any medication, prescription or non-prescription, with psychotropic effects other than: 1. Buspirone, or antidepressant (e.g., selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI)) with stable dosage for past 4 weeks 2. Hormonal contraceptives of any type for any duration * For females, not currently pregnant or actively trying to become pregnant * Ability to tolerate small, enclosed spaces without anxiety * No metals, implants or metallic substances within or on the body that might cause adverse effects to the subject in a strong magnetic field, or interfere with image acquisition (per protocol) * Size compatible with scanner gantry (per protocol)
Exclusion criteria
* Current diagnosis of Obsessive Compulsive Disorder, Posttraumatic Stress Disorder, or Bipolar Disorder * Current substance abuse or dependence (past 6 months) * Active suicidality with plan or intent * Current psychosis * History of serious neurological illness or current medical condition that could compromise brain function, such as liver failure * History of closed head injury, e.g., loss of consciousness greater (\>) approximately (\ ) 5 minutes, hospitalization, neurological sequela
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Prefrontal Cortex (PFC) Activity (Baseline to Transfer Run) From the Reappraise > Look Contrast on the Emotion Regulation Task (ERT) | Approximately 60 minutes | The PFC was defined in MNI space using significant group level activation in the posterior medical frontal cortex from the reappraise\>look contrast from earlier pilot subjects. Percent signal change in this region was extracted for all participants. Change in PFC activity was calculated as the linear slope of change across all 5 runs of the task. To this end, a linear regression was conducted for each participant separately with run as the independent variable and PFC percent signal change as the dependent variable to calculate change in percent signal change over time. These slopes were then averaged for each group . |
| Difference in Negative Affect Ratings of Images From International Affective Picture System (IAPS) | Within 10 minutes of exiting the scanner | The Self-Assessment Manikin (SAM) is a pictorial assessment technique in which a changing manikin figure depicts values along the primary dimension of affective valence (positive/negative). Users may indicate emotional reactions along a scale from 1-9, with higher numbers indicating greater negative affect. After the scan, participants will rate each image they saw along this scale. Differences in SAM ratings from look to reappraise trials (e.g., average reappraise score minus average look score) will be evaluated and compared between sham-NF and veritable-NF groups. Higher difference score indicates that images viewed during reappraisal are seen as more positive than those viewed during the look condition. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Amygdala-PFC Functional Connectivity (Baseline to Transfer) From Reappraise > Look Contrast | Each run is approximately 9 minutes long. Run 5 starts approximately 30 minutes after the completion of run 1. | To examine amygdala connectivity, the study team will use a psychophysiological interaction analysis. Deconvolved time series from anatomical left and right amygdala seeds for each participant will be multiplied by a vector for the reappraise \> look contrast at each run (baseline, neurofeedback (NF1, NF2, NF3), transfer). Regressors for the seed time series, the original condition and the interaction term will be convolved with the canonical hemodynamic response function. Change in connectivity from pre-to-post training will be calculated by subtracting the baseline-run contrast map from the transfer-run contrast map. Resulting contrast maps will be entered into second-level random effects analyses in the software SPM, where voxels in the PFC will be examined at p\<0.05 FWE-corrected threshold. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Veritable-NF (MPC) Functional magnetic resonance imaging (fMRI) with Veritable-NF: Participants will have 4 visits (some can be done virtually). The baseline visit will include an interview and questionnaires. Eligible participants will have a practice session at visit 2, and may do a mock scanner if the visit is in person. Visit 3 will take place within 5 days of the practice session and participants will be asked to complete questionnaires and have an fMRI with the real neurofeedback. Visit 4 will take place one month after visit 3 and will include a follow-up interview with a trainer assessor as well as questionnaires. Additionally, 2 weeks after visit 3 participants will also complete some questionnaires online. | 7 |
| Sham-NF fMRI with Sham-NF: Participants will have 4 visits (some can be done virtually). The baseline visit will include an interview and questionnaires. Eligible participants will have a practice session at visit 2, and may do a mock scanner if the visit is in person. Visit 3 will take place within 5 days of the practice session and participants will be asked to complete questionnaires and have an fMRI with feedback that looks similar to real neurofeedback, but is computer generated. Visit 4 will take place 2 weeks after visit 3 and participants will complete more questionnaires. | 6 |
| Veritable-NF (PFC) Functional magnetic resonance imaging (fMRI) with Veritable-NF: Participants will have 4 visits (some can be done virtually). The baseline visit will include an interview and questionnaires. Eligible participants will have a practice session at visit 2, and may do a mock scanner if the visit is in person. Visit 3 will take place within 5 days of the practice session and participants will be asked to complete questionnaires and have an fMRI with the real neurofeedback. Visit 4 will take place one month after visit 3 and will include a follow-up interview with a trainer assessor as well as questionnaires. Additionally, 2 weeks after visit 3 participants will also complete some questionnaires online. | 8 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Veritable-NF (MPC) | Sham-NF | Veritable-NF (PFC) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 6 Participants | 8 Participants | 21 Participants |
| Age, Continuous | 28.4 years STANDARD_DEVIATION 11.6 | 30.3 years STANDARD_DEVIATION 11.9 | 28.3 years STANDARD_DEVIATION 8.9 | 28.9 years STANDARD_DEVIATION 10.2 |
| Hamilton Anxiety Rating Scale | 13.29 score on a scale STANDARD_DEVIATION 8.83 | 14.50 score on a scale STANDARD_DEVIATION 9.33 | 16.88 score on a scale STANDARD_DEVIATION 9.06 | 15.00 score on a scale STANDARD_DEVIATION 8.74 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 6 Participants | 7 Participants | 19 Participants |
| Region of Enrollment United States | 7 participants | 6 participants | 8 participants | 21 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 | 0 / 8 |
| other Total, other adverse events | 0 / 7 | 1 / 6 | 0 / 8 |
| serious Total, serious adverse events | 0 / 7 | 0 / 6 | 0 / 8 |
Outcome results
Primary
Change in Prefrontal Cortex (PFC) Activity (Baseline to Transfer Run) From the Reappraise > Look Contrast on the Emotion Regulation Task (ERT)
The PFC was defined in MNI space using significant group level activation in the posterior medical frontal cortex from the reappraise\>look contrast from earlier pilot subjects. Percent signal change in this region was extracted for all participants. Change in PFC activity was calculated as the linear slope of change across all 5 runs of the task. To this end, a linear regression was conducted for each participant separately with run as the independent variable and PFC percent signal change as the dependent variable to calculate change in percent signal change over time. These slopes were then averaged for each group .
Time frame: Approximately 60 minutes
Population: 1 participant in the sham group had too much motion during the neurofeedback runs of the scans to be included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veritable-NF (MPC) | Change in Prefrontal Cortex (PFC) Activity (Baseline to Transfer Run) From the Reappraise > Look Contrast on the Emotion Regulation Task (ERT) | 0.042 Percent signal change per run | Standard Deviation 0.077 |
| Sham-NF | Change in Prefrontal Cortex (PFC) Activity (Baseline to Transfer Run) From the Reappraise > Look Contrast on the Emotion Regulation Task (ERT) | 0.019 Percent signal change per run | Standard Deviation 0.056 |
| Veritable-NF (PFC) | Change in Prefrontal Cortex (PFC) Activity (Baseline to Transfer Run) From the Reappraise > Look Contrast on the Emotion Regulation Task (ERT) | 0.007 Percent signal change per run | Standard Deviation 0.075 |
Primary
Difference in Negative Affect Ratings of Images From International Affective Picture System (IAPS)
The Self-Assessment Manikin (SAM) is a pictorial assessment technique in which a changing manikin figure depicts values along the primary dimension of affective valence (positive/negative). Users may indicate emotional reactions along a scale from 1-9, with higher numbers indicating greater negative affect. After the scan, participants will rate each image they saw along this scale. Differences in SAM ratings from look to reappraise trials (e.g., average reappraise score minus average look score) will be evaluated and compared between sham-NF and veritable-NF groups. Higher difference score indicates that images viewed during reappraisal are seen as more positive than those viewed during the look condition.
Time frame: Within 10 minutes of exiting the scanner
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veritable-NF (MPC) | Difference in Negative Affect Ratings of Images From International Affective Picture System (IAPS) | 0.57 score on a scale | Standard Deviation 0.73 |
| Sham-NF | Difference in Negative Affect Ratings of Images From International Affective Picture System (IAPS) | 0.29 score on a scale | Standard Deviation 0.26 |
| Veritable-NF (PFC) | Difference in Negative Affect Ratings of Images From International Affective Picture System (IAPS) | 0.03 score on a scale | Standard Deviation 0.35 |
Secondary
Change in Amygdala-PFC Functional Connectivity (Baseline to Transfer) From Reappraise > Look Contrast
To examine amygdala connectivity, the study team will use a psychophysiological interaction analysis. Deconvolved time series from anatomical left and right amygdala seeds for each participant will be multiplied by a vector for the reappraise \> look contrast at each run (baseline, neurofeedback (NF1, NF2, NF3), transfer). Regressors for the seed time series, the original condition and the interaction term will be convolved with the canonical hemodynamic response function. Change in connectivity from pre-to-post training will be calculated by subtracting the baseline-run contrast map from the transfer-run contrast map. Resulting contrast maps will be entered into second-level random effects analyses in the software SPM, where voxels in the PFC will be examined at p\<0.05 FWE-corrected threshold.
Time frame: Each run is approximately 9 minutes long. Run 5 starts approximately 30 minutes after the completion of run 1.
Population: 1 participant in the sham group had too much motion during the neurofeedback runs of the scans to be included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Veritable-NF (MPC) | Change in Amygdala-PFC Functional Connectivity (Baseline to Transfer) From Reappraise > Look Contrast | 0 Number of significant voxels in the PFC |
| Sham-NF | Change in Amygdala-PFC Functional Connectivity (Baseline to Transfer) From Reappraise > Look Contrast | 0 Number of significant voxels in the PFC |
| Veritable-NF (PFC) | Change in Amygdala-PFC Functional Connectivity (Baseline to Transfer) From Reappraise > Look Contrast | 0 Number of significant voxels in the PFC |