Effect of rTMS on Anxiety

Examining the Mechanisms of Anxiety Regulation Using a Novel, Sham-controlled, fMRI-guided rTMS Protocol and a Translational Laboratory Model of Anxiety

Sponsors

Lead Sponsor: University of Pennsylvania

Source University of Pennsylvania
Brief Summary

Given the overall lack of treatment adherence/efficacy, side effects of drugs, and the substantial burden of anxiety disorders on the individual and on the national healthcare system, there is a critical need for mechanistic research into the CNS mechanisms that underlie these disorders. Accordingly, the objective of this grant is to use noninvasive neuromodulation to causally identify the key neural mechanisms that mediate the cognitive symptoms of anxiety. This project is relevant to public health because it has the potential to lead to novel repetitive transcranial magnetic stimulation treatments for pathological anxiety.

Detailed Description

Although extensive research has explored the involvement of subcortical structures in arousal, arousal symptoms are only one facet of the symptom profile shared across anxiety disorders. Much less is known about the cognitive symptoms (i.e. difficulty concentrating) experienced by anxiety patients. Accordingly, there is a critical need for mechanistic research into the CNS mechanisms that mediate the cognitive symptoms experienced by anxiety patients. Without such research, treatment development for these disorders will continue to make slow progress. The objective of this application is to determine the key neural mechanisms that mediate the cognitive symptoms of anxiety. The central hypothesis is that the right dorsolateral prefrontal cortex (dlPFC) regulates emotion through top-down inhibition of emotion-related regions. The approach will be to use repetitive transcranial magnetic stimulation (rTMS) to study the effect of right dlPFC activity on objective and subjective measures of induced anxiety, anxiety-related working memory deficits (WM), and TMS-evoked blood oxygenation-level dependent (BOLD) responses during simultaneous TMS/fMRI (i.e. target engagement). The rationale for this approach is that by experimentally manipulating right dlPFC activity using rTMS, this research will be able to causally demonstrate involvement of this region in anxiety regulation, which could translate to future targeted rTMS treatments for anxiety. The first aim will be to determine the effect of a 1-week course of rTMS treatment (1 Hz vs. 10 Hz; right dlPFC target) on anxiety using the threat of unpredictable shock paradigm. The second aim will be to determine the effect of a 1-week course of rTMS treatment (1 Hz vs. 10 Hz; right dlPFC target) on anxiety-related WM-deficits using the Sternberg WM paradigm during threat of shock. The third aim will be to demonstrate target engagement by measuring BOLD responses evoked by TMS pulses to the right dlPFC during threat of shock. The work is innovative because it will combine advanced neuromodulatory techniques (fMRI guidance, electric-field modelling, neuronavigation, active-sham control) with a translational threat of shock paradigm. PUBLIC HEALTH RELEVANCE: Once completed, this research should yield direct evidence for a causal role of the right dlPFC in anxiety regulation, complete with evidence of target engagement, and a novel application to anxiety.

Overall Status Active, not recruiting
Start Date October 30, 2019
Completion Date August 1, 2023
Primary Completion Date August 1, 2023
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
Anxiety Potentiated Startle during NPU 24 Hours
Fear Potentiated Startle during NPU 24 hours
Sternberg WM accuracy 24 hours
TMS-evoked BOLD responses 2 seconds (i.e. Latency of BOLD response)
Enrollment 63
Condition
Intervention

Intervention Type: Device

Intervention Name: rTMS to the right dlPFC

Description: A Magventure MagPro 100X stimulator with a B65 active/placebo figure-8 coil will be used. The TMS coil will be placed on the head over the target. rTMS intensity will be 100% of the motor threshold (MT), adjusted for field strength difference at motor cortex and target cortex using the individual E-field model. Subjects will receive 3000 pulses/session.

Eligibility

Criteria:

Inclusion Criteria:

- Subjects must be 18-50 years old

- Able to give their consent

- Right-handed

Exclusion Criteria:

- Non-english speaking

- Any significant medical or neurological problems

- Current or past Axis I psychiatric disorder(s), active or history of active suicidal ideation

- Alcohol/drug problems in the past year or lifetime alcohol or drug dependence

- Medications that act on the central nervous system

- History of seizure

- History of epilepsy

- Increased risk of seizure for any reason

- Pregnancy, or positive pregnancy test

- IQ <80

- Any medical condition that increases risk for fMRI or TMS

- Any metal in their body which would make having an MRI scan unsafe

- Any sort of medical implants

- Hearing loss

- Claustrophobia

Gender: All

Minimum Age: 18 Years

Maximum Age: 50 Years

Healthy Volunteers: Accepts Healthy Volunteers

Location
Facility: University of Pennsylvania
Location Countries

United States

Verification Date

October 2019

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: 1 Hz Arm

Type: Experimental

Description: Subjects will receive a continuous train of 1 Hz stimulation until all 3000 pulses are delivered. Consistent with the 10 Hz condition, TMS will occur during the Sternberg WM paradigm.

Label: 10 Hz Arm

Type: Experimental

Description: Subjects will receive 75, 4 second trains at 10 Hz, separated by a 36 second ITI. Stimulation will occur while subjects are doing the Sternberg WM paradigm. The timing of the Sternberg task will be jittered so that each rTMS train will be administered during the maintenance interval of a WM trial.

Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Crossover Assignment

Intervention Model Description: Aims 1 and 2 will be tested using a between-subjects design where 1 group of healthy volunteers will receive 4-day courses of active and sham 1 Hz stimulation to the right dlPFC, while the other group will receive 4-day courses of active and sham 10 Hz stimulation to the right dlPFC. Aim 1, will test the effects of this stimulation on anxiety during the NPU threat task. Aim 2, will test the effects of this stimulation on anxiety-related working memory (WM) deficits using the Sternberg WM paradigm. Aim 3 will be tested using a within-subjects design where this same group of subjects will receive single-pulse active and sham stimulation to the right dlPFC during the Neutral, Predictable, and Unpredictable (NPU) threat task while in the MRI scanner. BOLD activity to the TMS pulses will be the primary outcome measure.

Primary Purpose: Basic Science

Masking: Triple (Participant, Investigator, Outcomes Assessor)

Masking Description: Both the subject and the TMS operator will be blinded as to the study condition (active vs. sham)

Source: ClinicalTrials.gov