TMS and Exposure Therapy
TMS and Exposure Therapy
Spider phobia is an exceedingly common phobia throughout the world. The current standard
 treatment involves exposure therapy, which consists of a series of brief exposures of an
 individual to the thing they fear, in this case spiders. This study aims to examine the use
 of a neuromodulatory technology, transcranial magnetic stimulation (TMS), as a possible
 treatment option for spider phobia. TMS uses low-intensity electromagnetic energy to
 stimulate the brain, introducing energy into critical hubs of brain networks to "reset" their
 function and alleviate symptoms with very few side-effects.

 This study will consist of four separate visits. After screening subjects for spider phobia,
 baseline testing of subjective distress measures and physiologic stress data (heart rate
 variability and sweat response) during a prolonged spider exposure test will be collected.
 Subjects will then be placed into one of two groups: one receiving exposure therapy and
 intermittent Theta Burst Stimulation (iTBS) TMS (active study group), and another receiving
 exposure therapy with iTBS to a circuit not involved in a phobic reaction (control study
 group). Subjects will undergo their first treatment session during the first visit following
 the baseline data collection; the second and third treatments will occur the following two
 days. The fourth visit will occur one week after the third and consist of the same testing as
 the first visit; the same data will be collected. Changes from pre- to post-treatment in both
 subjective and physiologic data will be compared between the treatment and sham groups to
 examine effects of TMS on spider phobia.
OVERVIEW The experiment will consist of four days. Day 1 will include informed consent,
 questionnaires, a behavioral approach test with a spider, a series of short exposures with a
 spider, and the first TMS treatment (for a total of approximately 75-90 minutes). Day 2 will
 occur one to two days after Day 1 and will consist of a second series of short exposures with
 a spider and the second TMS treatment (30 minutes). Day 3 will occur one to two days after
 Day 2 and will also consist of a series of short exposures and a TMS treatment (30 minutes).
 Day 4 will occur five to seven days after Day 3 and will consist of post-study questionnaires
 and an identical behavioral approach test as is conducted on the first visit (30 minutes).
 Participants will be randomized to either an active TMS treatment group (using an iTBS
 stimulation protocol over the participant's ventro-medial prefrontal cortex, an area involved
 in phobic response) or a control TMS treatment group (using the same iTBS stimulation
 protocol over the central sulcus and between hemispheres, a site not associated with memory
 or fear response).

 Prospective participants will be recruited from two groups: 1) undergraduate students
 recruited through the UCLA Psychology Department Subject Pool (i.e., SONA) and 2) general
 population over the age of 18 recruited via flyers. All prospective participants will be
 screened with the 31-question Spider Phobia Questionnaire (SPQ) to ensure eligibility for
 participation, with a minimum total score equal to or greater than 17 required for
 participation.(Klorman, Weerts, Hastings, Melamed, & Lang, 1974) Participants will be
 enrolled for the study only if they are able to complete all four visits of the experiment.
 Exclusion criteria will include:

 1. Subject is mentally or legally incapacitated, unable to give informed consent.

 2. Subjects with psychosis (psychotic depression, schizophrenia, or schizoaffective
 diagnoses (lifetime)); bipolar disorder (lifetime); dementia (lifetime); delirium within
 the past 6 months; eating disorder within the past year; obsessive-compulsive disorder
 (lifetime); post-traumatic stress disorder within the past year; acute risk for suicide
 or self-injurious behavior. Patients with diagnostic uncertainty or ambiguity (e.g.
 rule-out pseudodementia of depression) will be excluded.

 3. Subjects with a HamD suicidality item score of '3' or '4,' corresponding to "suicidal
 ideas or gestures" or "attempts at suicide," will be excluded.

 4. Subjects with exposure to ECT within the past 6 months, previous TMS treatment for any
 condition, or VNS treatment (lifetime).

 5. Past history of skull fracture; cranial surgery entering the calvarium; space occupying
 intracranial lesion; stroke, CVA, or TIAs; cerebral aneurysm; Parkinson's or
 Huntington's disease; or Multiple Sclerosis.

 6. Any history of intracranial implant including cochlear implant, implanted
 electrodes/stimulators, aneurysm clips or coils, stents, bullet fragments; implanted
 cardiac pacemaker, defibrillator, vagus nerve stimulator, deep brain stimulator; or
 other implanted devices or objects contraindicated by product labeling.

 7. Neurological conditions including epilepsy, cerebrovascular disease, dementia, increased
 intracranial pressure, history of repetitive or severe head trauma, or with primary or
 secondary tumors in the CNS.

 8. current pregnancy or breast feeding.

 9. Infection or loss of integrity of skin over the forehead, where the device will be
 positioned.

 10. Increased risk of seizure as indicated by: a) history (or family history) of seizure or
 epilepsy; b) history of stroke, head injury, or unexplained seizures; c) concurrent
 medication use such as tricyclic antidepressants, neuroleptic medications, or other
 drugs that are known to lower the seizure threshold; d) secondary conditions that may
 significantly alter electrolyte balance or lower seizure threshold; e) no quantifiable
 motor threshold such that TMS dosage cannot be accurately determined.

 11. Known bee, insect, or arachnid allergy

 12. Other medical contraindications to any of the study procedures.

 Participants will be assigned course credit or receive financial compensation after
 participating in the study. Those who participate through SONA recruitment will receive
 course credit. Participants will sign up for the study only if they are able to make all four
 visits of the experiment. If a participant does not attend all three visits, course credit
 will still be given for the amount of time the participant spent doing the experiment (i.e.,
 1 credit for 1 hour).

 After screening, participants will be emailed blank copies of the forms, questionnaires, and
 screening tools that will be completed during the first visit, and they will be informed that
 they may complete the forms in advance and bring the completed forms with them to save time,
 should they desire. They will be asked to not return their forms via email, and to only bring
 them to the first visit.

 DAY 1 On Day 1, participants will first provide informed consent after the nature of the
 study has been fully explained and the participant has had time to ask questions. After
 obtaining informed consent, participants will complete a demographics and eligibility
 questionnaire (see Section 10.1, Item 1.0) or hand in their already-completed forms, which
 will be reviewed by the researcher upon completion. Ineligible participants (i.e.,
 participants with bee, insect, or spider allergies, with scores below 17 on the SPQ, who do
 not speak English, are taking medications that lower the seizure threshold, or other
 exclusion criteria as listed in section 11.1) will be informed that they do not meet criteria
 and the research session will be terminated at this time. Participants found to be ineligible
 will still receive 1 credit for their time. All to-be-administered questionnaires are listed
 below and uploaded in Section 10.1, Item 1.0 of this IRB submission.

 Spider Phobia Questionnaire (SPQ; Klorman et al, 1974) Demographics & Eligibility
 Questionnaire Fear of Spiders Questionnaire (FSQ; Szymanski & O'Donohue, 1995) PHQ2 PHQ9
 Hamilton Rating Scale for Depression (specifically the suicidality item) GAD7 Tracking and
 Reimbursement (this questionnaire is used exclusively to track the number of visits completed
 and information necessary to ensuring that participants receive the proper financial or
 course credit compensation for their time; it contains no research data used for the study)

 All participants will complete a BAT with a live tarantula. This phase of the experiment
 consists of 9 steps, lasting 30 seconds each with a 30 second pause between each step. During
 the BAT, self-reported and physiological data will be collected at each step. Skin
 conductance response (SCR) and heart-rate variability (HRV) will be utilized as physiologic
 measures of fearful arousal using BIOPAC MP150 hardware and AcqKnowledge version 4.2 software
 (BIOPAC Systems, Inc.).(Appelhans & Luecken, 2006; Choi et al., 2017; Christopoulos, Uy, &
 Yap, 2016; Laine, Spitler, Mosher, & Gothard, 2009; Thayer, Åhs, Fredrikson, Sollers, &
 Wager, 2012; Williams et al., 2001) Baseline SCR and HRV will be measured during a 3-minute
 prior to initiation of a BAT. SCR will be recorded from electrodes attached to the subjects'
 second and third fingers. Average SCRs and peak SCRs at each step will be measured and
 compared to individual baselines. HRV will be calculated from R-R intervals in a lead II
 electrode configuration recording; average HRVs from each step will be compared to individual
 baselines. The steps are as follows:

 1. Stand 5 feet away from tarantula in closed terrarium

 2. Stand 1 foot away from tarantula in terrarium with top removed

 3. Place both hands on the side of terrarium with top removed

 4. Touch nose against the glass of terrarium while looking at the tarantula

 5. Place gloved hand halfway inside terrarium

 6. Place gloved hand inside terrarium with all fingertips touching base of terrarium

 7. Place bare hand inside terrarium with all fingertips touching base of terrarium

 8. Touch the back of the tarantula's leg continuously with a Q-tip

 9. Touch the back of the tarantula's leg continuously with the tip of the index finger

 Prior to beginning the BAT, all participants will be read instructions reporting the
 following: The experiment consists of 9 steps, each lasting 30 seconds. Instructions for each
 step will be read aloud before the participant proceed to the next step. Each step must be
 completed before moving on to the next step, and steps much be completed in sequential order.
 During each step, participant's heart rate and sweating will be recorded via the electrodes
 on participant's chest and finger. After the experimenter reads the instructions for the next
 step and prior to completing the step, the participant will also be asked to rate
 participant's confidence level to complete the step on a scale from 0 to 100 (0= no
 confidence, 25= mild confidence, 50= moderate confidence, 75= high confidence, 100 = complete
 confidence) and participant's anticipatory distress on a scale from 0 to 100 (0=no distress,
 25=mild distress, 50=moderate distress, 75= high distress, 100= severe distress). After
 completion of each step, participants will be asked to rate their maximum level of distress
 during the step on a scale from 0 to 100. Participants are entitled to withdraw at any step
 if they do not wish to continue. At this point participants will have an opportunity to ask
 questions before beginning testing. The first step of the experiment is to stand 5 feet away
 from the tarantula while it is in its closed container for 30 seconds. The final step of the
 experiment is to touch the back of the tarantula's leg with the tip of participant's index
 finger continuously for 30 seconds.

 Before beginning the BAT and after ensuring comprehension of the above instructions, the
 experimenter will ask the participant to rate his/her overall confidence and overall
 anticipatory distress with respect to his/her ability to complete all nine steps (see rating
 scales in above instructions). Before each subsequent step, the participant will be asked to
 rate his/her confidence and anticipatory distress regarding his/her ability to complete that
 particular step. During each step, the experimenter will record the spider's movement on a
 categorical scale (0 = no movement, 1 = a little movement, 2 = a lot of movement). After each
 step, the participant will be asked to rate his/her maximum level of distress while
 completing that particular step. Finally, the experimenter will record the number of steps
 willingly completed for a given participant.

 Next, all participants will engage in a series of exposure practices with a different live
 tarantula from the one they saw during the BAT. Exposure therapy will consist of a series of
 10 identical exposure trials of a 30-second duration with a 30-second pause between trials.
 Participants will be asked to place an ungloved hand in the terrarium (with all fingertips
 touching the base of the terrarium) on the opposite end of the terrarium as the tarantula
 during the trial. Prior to completing the series of exposures, participants will be asked
 about their feared outcome concerning approaching the tarantula (e.g., being bitten).
 Participants are entitled to withdraw at any step during exposures and will not be prevented
 from further continuation in the study.

 Following the series of exposures, participants will undergo TMS treatments using an iTBS
 protocol. Before the first iTBS treatment, the TMS coil will be calibrated to the subject's
 individual resting motor threshold (RMT), or the minimum stimulus intensity necessary to
 elicit a motor response in the right abductor pollicis brevis (APB) or first dorsal
 interosseus (FDI) muscles for ≥ 50% of stimuli applied to the motor cortex. After initial
 calibration, the TMS coil will be placed over the subject's ventral medial prefrontal cortex
 (vmPFC; as determined using position Fpz of the international 10-20 EEG electrode system), a
 TMS target shown to affect phobic response.(Baeken et al., 2010; Guhn et al., 2012, 2014;
 Suarez-Jimenez et al., 2018) Stimulation intensity of 100% of the individual RMT in bursts of
 three pulses at a frequency of 50 Hz every 200 ms on top of a 5Hz carrier wave. Pulse
 delivery is over 2 s and repeated every 10 s, 20 times in succession, for a total of 600
 pulses delivered in 3.33 minutes.(Baeken et al., 2010; Bulteau et al., 2017; Guhn et al.,
 2014) This specific protocol was selected based on the assumption that it should impact fear
 circuitry top-down from prefrontal to subcortical networks (particularly the amygdala) as
 seen in prior work.(Baeken et al., 2010; Bulteau et al., 2017; Guhn et al., 2014) Control
 iTBS will consist of the same stimulation parameters over the subject's midline central
 sulcus or vertex (as determined using position Cz, of the international 10-20 EEG electrode
 system). This placement was chosen for control as its position over the vertex will minimize
 amount of cortex stimulated and the stimulated area is not associated with the circuitry
 examined in this experiment.(Duecker & Sack, 2015) It is a commonly-used control site in TMS
 studies because it is associated with no known effects and has a similar risk profile to
 other TMS sites. (Foltys et al., 2001; Jung, Bungert, Bowtell, & Jackson, 2016; Rossi et al.,
 2009; Weiss, Sparing, Fink, Tomasino, & Dafotakis, 2008) It is generally associated with
 lower rates of scalp discomfort and no clinically-observed behavioral or mood effects.(Jung
 et al., 2016; Rossi et al., 2009) Some work has demonstrated a possible decrease in
 activation of the default mode network, though this has not been found to be
 clinically-significant.(Jung et al., 2016)

 DAY 2 As described above, this visit will occur one to two days after Day 1. All participants
 will return to the laboratory to engage in a second series of exposure practices with the
 same tarantula from exposures at the first visit. They will undergo 10 identical exposure
 trials for durations of 30 seconds each, with a 30-second pause between trials. During each
 exposure trial, they will again be asked to place an ungloved hand in the terrarium (with all
 fingertips touching the base of the terrarium) on the opposite end of the terrarium as the
 tarantula during the trial. Prior to completing the series of exposures, participants will be
 asked about their feared outcome concerning approaching the tarantula (e.g., being bitten).
 Participants are entitled to withdraw at any step during exposures and will not be prevented
 from further continuation in the study.

 Following the series of exposure practices, participants will undergo a TMS treatment using
 an iTBS treatment protocol in the same location that they received stimulation on Day 1
 (vmPFC vs. vertex).

 DAY 3 This visit will be identical to Day 2, and will occur one to two days after Day 2.

 DAY 4 This visit will occur five to seven days after Day 3. All participants will complete
 the Spider Phobia Questionnaire (SPQ; Klorman et al, 1974) and Fear of Spiders Questionnaire
 (FSQ; Szymanski & O'Donohue, 1995), uploaded in Section 10.1, Item 1.0, to test for change in
 arachnophobia fear/avoidance symptoms as a function of TMS treatment received. Next, all
 participants will complete an identical BAT to that completed at their first visit with the
 same tarantula (see DAY 1 above). Self-report and physiological (i.e., SCR) data will again
 be collected. After completion of these forms, participants will be debriefed by an
 un-blinded member of the study team and informed to which group they are assigned. They will
 be encouraged to discuss whatever questions or concerns they have regarding the study at that
 time.

 After completion of Day 4, participants will be compensated for their time with one credit
 per hour of study participation.

 Dependent variables (DVs) will be quantitative self-reports and behavioral symptoms of fear
 and avoidance of spiders both pre- and post-treatment, including SCR (difference between
 baseline and average level during BAT anticipation period, and number of peaks during BAT),
 total number of steps completed during the BAT, self-reported distress, anticipatory
 distress, and maximum distress per BAT step, and total score on the SPQ. BAT measures will be
 collected for each step and therefore minima, maxima, and means will be compared between the
 two groups. Primary outcomes examined will be number of steps completed during BAT,
 self-reported distress during BAT, number of SCR peaks during BAT, SPQ score, and FOS score.
 All other variables examined will be secondary outcomes. Additionally, for feasibility and
 tolerability assessment, attendance to TMS treatment sessions and early termination of TMS
 treatment sessions will be recorded. The primary independent variable examined will be the
 treatment group (iTBS vs. control iTBS). The sample size will be 40 participants (20 per
 group). Pre-comparison ANOVA will be performed to limit type 1 error due to multiplicity of
 comparisons.

 Hypotheses will be tested using between-group two-tailed t-tests given that investigators are
 testing not only for magnitude of an effect, but also direction of an effect. Investigators
 expect that comparisons of efficacy will demonstrate increased confidence during BAT
 approach, decreased endorsed fear of spiders as measured by SPQ and FSQ, and reduced
 physiologic response to stimulus (reduced HRV and SCR) with active iTBS and exposure when
 compared to control iTBS and exposure. Investigators expect that comparisons of feasibility
 and tolerability will show no significant difference between attendance to, early termination
 of, or subjective tolerability ratings of TMS treatment sessions between treatment groups.

 ADVERSE EVENT MANAGEMENT Study personnel administering the BAT and exposure treatments will
 be bachelors-level trained or current UCLA students. These personnel have not been identified
 at this time, but will be added to the IRB and protocols as they are identified. They will be
 trained by personnel from Anxiety and Depression Research Center (ADRC; personnel under the
 supervision of Dr. Michelle Craske) in both how to properly administer the BAT and exposure
 treatments, as well as how to address any questions, concerns, or unexpected events that
 arise from these treatments (including acute episodes of psychological distress, escape of
 spiders, etc.). These personnel have ample experience in training others how to administer
 these treatments.

 Three Chilean Rose Tarantulas (Grammostola rosea) will be stored in individual terrariums
 with weighted lids in a locked room within the ADRC (Life Sciences 5347), under the
 supervision of Dr. Michelle Craske and her laboratory personnel. All BATs and exposure
 treatments will take place in a controlled closed room without windows, open vents, or other
 large openings, to minimize the likelihood of a tarantula escape. At the beginning and end of
 every study session, study personnel will confirm the presence of the tarantula within the
 terrarium and confirm complete closure of the terrarium. After termination of testing for the
 day, study personnel will again confirm of the presence of the spider and the terrarium
 closure before departing.

 In the event that a spider should escape from its terrarium, the participant will be removed
 from the room and study personnel will immediately re-close the room, search for the
 tarantula, and transfer it back to the terrarium in a manner safe for both the personnel and
 the spider when found. This will involve coaxing the spider to a sealable pre-dampened
 carrier, temporarily sealing it, and opening it inside the spider's terrarium. Though the
 risk posed by a tarantula bite or hair projection is low and the risk of occurrence is low,
 study personnel will don gloves, eye protection, and a long-sleeved labcoat (all three of
 which will be provided) before attempting transfer to minimize this risk. If not found after
 a thorough search, the room will remain closed, and other laboratory personnel and the PI
 will be notified, and further action will be taken to locate the spider.

 Any injury sustained in the process of a spider escape or containment, such as a spider bite,
 will be reported as an adverse event. Should such an event emerge, study personnel present at
 the time of the event will be asked to contact the PI or a study clinician, who will assess
 the severity of the event. If the PI is not contacted in real-time, personnel will contact
 the PI within 24 hours of the event, and the PI will then report the adverse event within 24
 hours of being informed.

 Investigators will employ the following strategy to manage suicidality and other serious
 adverse events (SAEs). All exposure and TMS procedures will be performed during normal
 working hours while there is a psychiatrist on duty at the Clinical TMS Service. Should
 participants become acutely distressed during a study visit, the attending psychiatrist on
 duty will take any steps necessary to address any clinical issues that emerge. The PI will
 follow up with all participants by phone 12-24 hours after all exposure treatments to ensure
 that they are not suffering from ongoing distress, and participants will be given contact
 information for the PI to reach out sooner should they desire. The PI will involve licensed
 clinicians as appropriate. At the initial study visit, subjects will complete the PHQ2
 (reflex to PHQ9), GAD7, and HamD suicidality item and review their responses with a research
 assistant and clinician. All subjects also will be reminded at each visit about the
 availability of a clinician should the subject develop any event of concern, including
 suicidality or adverse events. Should such an event emerge, the subject will be instructed to
 contact the PI or a study clinician, who will assess the presentation as per their standard
 clinical protocol. This assessment will categorize the SAE as emergent or nonemergent. For
 non-emergent events, the clinicians will manage as they see fit. Rapid consultation with the
 Principal Investigator is available; should the clinician contact the PI, he or she will then
 be responsible for reporting the event as an SAE. If a consultation with the PI is not
 pursued in real-time, the clinician will inform the PI of the event within 24 hours of having
 identified the event. For emergent events, such as the worsening of suicidality or
 self-injurious behavior, the clinician will instruct the subject to go to the nearest
 emergency room possible. Should the clinician be concerned about the subject's imminent
 safety, he or she may contact the individual named by the subject in the consent form as the
 emergency contact, so that the contact person may help the subject get to an emergency room.
 If such an action is not feasible, the clinician may petition the subject to be brought
 involuntarily to the nearest emergency room possible, as provided for under state mental
 health laws in California where the study is being conducted. Consultation at any time is
 available by contacting the PI or a study clinician. Should the PI be contacted in real-time,
 he will then be responsible for initiating the SAE reporting. If the PI is not contacted in
 real-time, the clinician will contact the PI within 24 hours of the event, and the PI will
 then complete SAE reporting within 24 hours of being informed. All reports of adverse events
 will be reviewed by the PI and reported to the UCLA Institutional Review Board in accordance
 with its policies.
Inclusion Criteria:

 1. At least 18 years of age

 2. English-speaking

 3. Spider phobia as determined by a Spider Phobia Questionnaire (SPQ; Klorman et al 1974)
 score of at least 17/30

 Exclusion Criteria:

 1. Subject is mentally or legally incapacitated, unable to give informed consent.

 2. Subjects with psychosis (psychotic depression, schizophrenia, or schizoaffective
 diagnoses (lifetime)); bipolar disorder (lifetime); dementia (lifetime); delirium
 within the past 6 months; eating disorder within the past year; obsessive-compulsive
 disorder (lifetime); post-traumatic stress disorder within the past year; acute risk
 for suicide or self-injurious behavior. Patients with diagnostic uncertainty or
 ambiguity (e.g. rule-out pseudodementia of depression) will be excluded.

 3. Subjects with a HamD suicidality item score of '3' or '4,' corresponding to "suicidal
 ideas or gestures" or "attempts at suicide," will be excluded.

 4. Subjects with exposure to ECT within the past 6 months, previous TMS treatment for any
 condition, or VNS treatment (lifetime).

 5. Past history of skull fracture; cranial surgery entering the calvarium; space
 occupying intracranial lesion; stroke, CVA, or TIAs; cerebral aneurysm; Parkinson's or
 Huntington's disease; or Multiple Sclerosis.

 6. Any history of intracranial implant including cochlear implant, implanted
 electrodes/stimulators, aneursym clips or coils, stents, bullet fragments; implanted
 cardiac pacemaker, defibrillator, vagus nerve stimulator, deep brain stimulator; or
 other implanted devices or objects contraindicated by product labeling.

 7. Neurological conditions including epilepsy, cerebrovascular disease, dementia,
 increased intracranial pressure, history of repetitive or severe head trauma, or with
 primary or secondary tumors in the CNS.

 8. current pregnancy or breast feeding. The effects of TMS on pregnant and breastfeeding
 patients has not been systematically studied.

 9. Infection or loss of integrity of skin over the forehead, where the device will be
 positioned.

 10. Increased risk of seizure as indicated by: a) history (or family history) of seizure
 or epilepsy; b) history of stroke, head injury, or unexplained seizures; c) concurrent
 medication use such as tricyclic antidepressants, neuroleptic medications, or other
 drugs that are known to lower the seizure threshold; d) secondary conditions that may
 significantly alter electrolyte balance or lower seizure threshold; e) no quantifiable
 motor threshold such that TMS dosage cannot be accurately determined.

 11. Known bee, insect, or arachnid allergy

 12. Other medical contraindications to any of the study procedures.