Neuromodulation of the Fear Extinction Circuit Using Temporally and Anatomically Specific TMS in Humans

Study Overview
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Brief Summary
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This study aims to explore the mechanisms of how transcranial magnetic stimulation (TMS) impacts fear circuits. The overarching objectives are to understand how varying TMS parameters affect targeted brain regions in order to optimize its impact on enhancing fear extinction memory consolidation in a population with known fear extinction deficiencies: post-traumatic stress disorder (PTSD). 250 subjects will take part in this research study across NYU Langone Health. The study will include preliminary screenings, baseline visits, and experimental visits across four days

Detailed Description
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The experiments proposed are aimed to understand how timing and location of transcranial magnetic stimulation (TMS) in humans will impact their ability to reduce conditioned fear responses and impact the activation of their brain regions involved in fear regulation. The researchers will use a novel TMS approach to vary timing and location of its delivery so that the researchers can characterize and establish best time and location to obtain optimal impact on fear inhibition, and then test these parameters in PTSD patients and see if such can rescue extinction deficits in PTSD. The anticipated impact is to enhance our understanding of the neural mechanisms of associated with TMS use and explore potential novel approaches for advancing PTSD treatment.

Official Title
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Neuromodulation of the Fear Extinction Circuit Using Temporally and Anatomically Specific TMS in Humans

Conditions
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PTSD

Intervention / Treatment
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* Device: Transcranial magnetic stimulation (TMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 - 70 years of age Right-handed (Edinburgh Inventory - Oldfield 1971) To be balanced for age, gender, and years of education, as well as self-identified race/ethnicity. Inclusion Criteria: PTSD Subjects Diagnosis of primary PTSD (as determined by SCID) Inclusion Criteria: Healthy Controls (HC) SCID diagnosis consistent with no current or past history of Axis I psychiatric disorders. Willing and able to provide informed consent Exclusion Criteria: Current alcohol or substance use disorder (within the past 6 months) Lifetime history of seizure or significant head trauma (i.e., extended loss of consciousness, neurological sequelae, or known structural brain lesion) or other significant neurologic disease Lifetime history of psychosis, bipolar disorder, tic disorder, or eating disorder is excluded. Past and current unipolar mood disorders without psychosis and anxiety disorders will be allowed so long as they are not primary and not associated with psychosis. Use of psychotropic medication within 4 weeks prior to study (within 6 weeks for fluoxetine, or other long-lived compounds; within one year for neuroleptics). Pregnancy (to be ruled out by urine ß-HCG). Metallic implants or devices contraindicating magnetic resonance imaging. Currently taking medications that lower the seizure threshold. These include antipsychotics, high dose theophylline or stimulants such as methylphenidate. Patients taking bupropion must be on a stable dose *last 3 months) and take less than or equal to 300 mg/day. Implanted devices in subject's head (shunts, cochlear implants); metal in subject's head (other than dental implants).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTSD group<br>Participants will undergo a 3-day experimental paradigm. Before the experiment, participants will undergo a resting-state fMRI scan to determine the specific anatomical location of the TMS target for that particular individual (day 1). The resting-state scan will be about 10 minutes. Functional MRI scans will occur on days 1, 2, 3, and TMS on day 2. A blood draw will occur on experimental day 1 or, if needed due to scheduling, on any of the other experimental visits. | Device: Transcranial magnetic stimulation (TMS)<br>* Research subjects will undergo non-invasive TMS, with a frequency of 20Hz and intensity of 120% of their resting motor threshold (rMT) at varying time points and locations.<br>|
| Active Comparator: Healthy Control group<br>Participants will undergo a 3-day experimental paradigm. Before the experiment, participants will undergo a resting-state fMRI scan to determine the specific anatomical location of the TMS target for that particular individual (day 1). The resting-state scan will be about 10 minutes. Functional MRI scans will occur on days 1, 2, 3, and TMS on day 2. A blood draw will occur on experimental day 1 or, if needed due to scheduling, on any of the other experimental visits | Device: Transcranial magnetic stimulation (TMS)<br>* Research subjects will undergo non-invasive TMS, with a frequency of 20Hz and intensity of 120% of their resting motor threshold (rMT) at varying time points and locations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin Conductance Response (SCR) | Conductance is measured by placing two electrodes next to the skin and passing a tiny electric charge between the two points. SCR is proportionally related to the number of sweat glands that are activated, meaning in essence that the more emotionally aroused an individual is, the more the SCR amount is increased. | Baseline | 
| Skin Conductance Response (SCR) | Conductance is measured by placing two electrodes next to the skin and passing a tiny electric charge between the two points. SCR is proportionally related to the number of sweat glands that are activated, meaning in essence that the more emotionally aroused an individual is, the more the SCR amount is increased. | Experimental Day 1 | 
| Skin Conductance Response (SCR) | Conductance is measured by placing two electrodes next to the skin and passing a tiny electric charge between the two points. SCR is proportionally related to the number of sweat glands that are activated, meaning in essence that the more emotionally aroused an individual is, the more the SCR amount is increased. | Experimental Day 2 | 
| Skin Conductance Response (SCR) | Conductance is measured by placing two electrodes next to the skin and passing a tiny electric charge between the two points. SCR is proportionally related to the number of sweat glands that are activated, meaning in essence that the more emotionally aroused an individual is, the more the SCR amount is increased. | Experimental Day 3 | 
| Blood Oxygen Levels | fMRI data, including blood-oxygen-level-dependent (BOLD) responses, is used in neuroimaging studies assess neural correlate activations and observe the increase/decrease in activation of a particular brain area in response to a specific cue. When these cells are active, there is an increase in blood oxygen in the surrounding area. | Experimental Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Score on Patient Health Questionnaire (PHQ-9) | PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and measuring the severity of depression. The participant will self-report how often he/she has been bothered by 9 problems over the last 2 weeks. The total score range is 0-27. A PHQ-9 score total of 0-4 points equals normal or minimal depression. Scoring between 5-9 points indicates mild depression, 10-14 points indicates moderate depression, 15-19 points indicates moderately severe depression, and 20 or more points indicates severe depression. | Baseline | 
| Score on Patient Health Questionnaire (PHQ-9) | PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and measuring the severity of depression. The participant will self-report how often he/she has been bothered by 9 problems over the last 2 weeks. The total score range is 0-27. A PHQ-9 score total of 0-4 points equals normal or minimal depression. Scoring between 5-9 points indicates mild depression, 10-14 points indicates moderate depression, 15-19 points indicates moderately severe depression, and 20 or more points indicates severe depression. | Experimental Day 1 | 
| Score on Patient Health Questionnaire (PHQ-9) | PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and measuring the severity of depression. The participant will self-report how often he/she has been bothered by 9 problems over the last 2 weeks. The total score range is 0-27. A PHQ-9 score total of 0-4 points equals normal or minimal depression. Scoring between 5-9 points indicates mild depression, 10-14 points indicates moderate depression, 15-19 points indicates moderately severe depression, and 20 or more points indicates severe depression. | Experimental Day 2 | 
| Score on Patient Health Questionnaire (PHQ-9) | PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and measuring the severity of depression. The participant will self-report how often he/she has been bothered by 9 problems over the last 2 weeks. The total score range is 0-27. A PHQ-9 score total of 0-4 points equals normal or minimal depression. Scoring between 5-9 points indicates mild depression, 10-14 points indicates moderate depression, 15-19 points indicates moderately severe depression, and 20 or more points indicates severe depression. | Experimental Day 3 | 
| Score on State-Trait Anxiety Inventory (STAI) - Form Y1 | STAI - Form Y1 is a commonly used measure of trait and state anxiety that consists of 20 statement which people have used to describe themselves. Each statement is scored from 1 (Not at all) to 4 (very much so). The total score range is 20-80; STAI scores are commonly classified as no or low anxiety (20-37), moderate anxiety (38-44), and high anxiety (45-80). | Baseline | 
| Score on State-Trait Anxiety Inventory (STAI) - Form Y1 | STAI - Form Y1 is a commonly used measure of trait and state anxiety that consists of 20 statement which people have used to describe themselves. Each statement is scored from 1 (Not at all) to 4 (very much so). The total score range is 20-80; STAI scores are commonly classified as no or low anxiety (20-37), moderate anxiety (38-44), and high anxiety (45-80). | Experimental Day 1 | 
| Score on State-Trait Anxiety Inventory (STAI) - Form Y1 | STAI - Form Y1 is a commonly used measure of trait and state anxiety that consists of 20 statement which people have used to describe themselves. Each statement is scored from 1 (Not at all) to 4 (very much so). The total score range is 20-80; STAI scores are commonly classified as no or low anxiety (20-37), moderate anxiety (38-44), and high anxiety (45-80). | Experimental Day 2 | 
| Score on State-Trait Anxiety Inventory (STAI) - Form Y1 | STAI - Form Y1 is a commonly used measure of trait and state anxiety that consists of 20 statement which people have used to describe themselves. Each statement is scored from 1 (Not at all) to 4 (very much so). The total score range is 20-80; STAI scores are commonly classified as no or low anxiety (20-37), moderate anxiety (38-44), and high anxiety (45-80). | Experimental Day 3 | 
| Score on Intolerance of Uncertainty Scale (IUS-12) - Short Form | IUS-12 is a 12-item self-report questionnaire where items are rated on 5-point Likert scales. IUS-12 is based on a definition of general uncertainty-related reactions that may be present in different anxiety disorders. Each item is scored from 1 (not at all characteristic of me) to 5 (entirely characteristic of me). The total score range is 12-60; the higher the score, the greater the intolerance of uncertainty. | Baseline | 
| Score on Intolerance of Uncertainty Scale (IUS-12) - Short Form | IUS-12 is a 12-item self-report questionnaire where items are rated on 5-point Likert scales. IUS-12 is based on a definition of general uncertainty-related reactions that may be present in different anxiety disorders. Each item is scored from 1 (not at all characteristic of me) to 5 (entirely characteristic of me). The total score range is 12-60; the higher the score, the greater the intolerance of uncertainty. | Experimental Day 1 | 
| Score on Intolerance of Uncertainty Scale (IUS-12) - Short Form | IUS-12 is a 12-item self-report questionnaire where items are rated on 5-point Likert scales. IUS-12 is based on a definition of general uncertainty-related reactions that may be present in different anxiety disorders. Each item is scored from 1 (not at all characteristic of me) to 5 (entirely characteristic of me). The total score range is 12-60; the higher the score, the greater the intolerance of uncertainty. | Experimental Day 2 | 
| Score on Intolerance of Uncertainty Scale (IUS-12) - Short Form | IUS-12 is a 12-item self-report questionnaire where items are rated on 5-point Likert scales. IUS-12 is based on a definition of general uncertainty-related reactions that may be present in different anxiety disorders. Each item is scored from 1 (not at all characteristic of me) to 5 (entirely characteristic of me). The total score range is 12-60; the higher the score, the greater the intolerance of uncertainty. | Experimental Day 3 | 
| Score on Childhood Trauma Questionnaire (CTQ) | CTQ consists of 28 items scored from 1 (never true) to 5 (very often true). The questions ask the participant about some of his/her experiences growing up as a child and a teenager. The total score range is 28-140; the higher the score, the greater the childhood trauma. | Baseline | 
| Score on Childhood Trauma Questionnaire (CTQ) | CTQ consists of 28 items scored from 1 (never true) to 5 (very often true). The questions ask the participant about some of his/her experiences growing up as a child and a teenager. The total score range is 28-140; the higher the score, the greater the childhood trauma. | Experimental Day 1 | 
| Score on Childhood Trauma Questionnaire (CTQ) | CTQ consists of 28 items scored from 1 (never true) to 5 (very often true). The questions ask the participant about some of his/her experiences growing up as a child and a teenager. The total score range is 28-140; the higher the score, the greater the childhood trauma. | Experimental Day 2 | 
| Score on Childhood Trauma Questionnaire (CTQ) | CTQ consists of 28 items scored from 1 (never true) to 5 (very often true). The questions ask the participant about some of his/her experiences growing up as a child and a teenager. The total score range is 28-140; the higher the score, the greater the childhood trauma. | Experimental Day 3 |