Clinical trial NCT03993509: Effect of rTMS on Anxiety
Official title: Examining the Mechanisms of Anxiety Regulation Using a Novel, Sham-controlled, fMRI-guided rTMS Protocol and a Translational Laboratory Model of Anxiety
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Anxiety
Fear
Anxiety and Fear
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2019-06-20
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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

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.

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

Primary outcomes:
measure: Anxiety Potentiated Startle
timeFrame: Pre and 24-hours post stimulation
measure: Fear Potentiated Startle
timeFrame: Pre and 24 hours post stimulation
measure: Sternberg WM Accuracy
timeFrame: Pre and 24 hours post stimulation
measure: TMS-evoked BOLD Responses
timeFrame: Responses are measured within the TMS/fMRI session in response to each TMS pulse and collapsed across trials. There is no sham condition. This session was typically conducted during the washout period, but varied depending upon participant schedule.
Secondary outcomes:
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
References: