Effect of cTBS on Startle and TMS-evoked BOLD

Official title

The Effect of Right dlPFC cTBS on Acute Measures of Anxiety, Functional Connectivity, and TMS-evoked BOLD Responses.

Overview

The right dorsolateral prefrontal cortex (dlPFC) is increasingly being targeted with transcranial magnetic stimulation (TMS) to reduce anxiety expression; however, there is little mechanistic evidence supporting an optimized treatment protocol. Thus, the objective of the current project is to develop an interleaved TMS/fMRI that can assess the effect of neuromodulatory (potentially therapeutic) TMS protocols on neural and behavioral measures related to anxiety expression. PUBLIC HEALTH RELEVANCE: These results will yield direct evidence that 1 Hz and cTBS modulate brain activity associated with anxiety expression and regulation, thus informing novel TMS based anxiety treatments.

Detailed description

The right dorsolateral prefrontal cortex (dlPFC) is increasingly being targeted with transcranial magnetic stimulation (TMS) to reduce anxiety expression in anxiety disorders, depression, and posttraumatic stress disorder (PTSD). However, we lack the basic evidence to determine critical details regarding the optimal stimulation parameters including the dose, target, and protocol. In addition, there is little mechanistic evidence for why any particular right dlPFC target/dose/protocol should be effective for a given set of patients. Indeed, there is little consensus as to whether such mechanistic evidence should generalize across disorders. Accordingly, there is a critical need to understand the mechanisms of action underlying neuromodulatory right dlPFC TMS protocols, yet there is not a standardized protocol to yield such evidence. Without a reliable approach to approach to generate such information, it will be difficult or impossible to develop and optimize novel TMS treatments for disorders like PTSD and anxiety. The objective of the current project is to develop a protocol using interleaved TMS/fMRI that can assess the effect of neuromodulatory (potentially therapeutic) TMS protocols on neural and behavioral measures related to anxiety expression. Our central hypothesis is that inhibition of the right dlPFC via cTBS will also inhibit activity throughout its downstream targets, resulting in reduced anxiety, connectivity, and TMS-evoked responses among these downstream circuits during threat. Accordingly, our approach will be to measure anxious arousal, resting state functional connectivity, and TMS evoked BOLD responses before and immediately after 600 pulses of cTBS or sham stimulation in 100 high anxious individuals using a within-subjects crossover design. For anxious arousal, our primary outcome will be anxiety potentiated startle (APS) recorded with electromyography during the neutral, predictable, and unpredictable (NPU) threat paradigm administered in the lab before and after the scanning session. For the interleaved TMS/fMRI runs, our primary outcome will be TMS-evoked BOLD responses in these same downstream regions. This study is innovative because it is the first to combine these technologies to study the effect of neuromodulatory TMS on threat-related TMS-evoked BOLD responses. This project is significant because it will provide future researchers with an systematic approach for evaluating the effectiveness of neuromodulatory TMS protocols on several neural and behavioral indices of anxiety expression. It will also yield direct evidence that cTBS modulate brain activity associated with anxiety expression and regulation.

Interventions

• Device Active TMS
  Subjects will receive a continuous 1800 pulse cTBS train to the right dlPFC at 100% of motor threshold. The train will consist of 50 Hz bursts, repeated at intervals of 200 ms (5 Hz) for 40 sec.
• Device Sham TMS
  Subjects will receive a series of 100 single pulses to the right dlPFC at 100% of motor threshold. Pulses will be randomly jittered and have an average interpulse interval of 6 ± 4 seconds. Single pulses delivered in such a fashion have been shown to have little or no neuromodulatory effect on subsequent cortical excitability.

Primary outcome measures

• TMS-evoked BOLD responses [Time frame: Subjects will undergo 4 study visits spaced over a 5-week period. On visits 3 (week 2) and 4 (week 5), TMS-evoked BOLD responses will be recorded immediately (within 5 minutes) before and after the intervention.]
• Anxiety Potentiated Startle [Time frame: Subjects will undergo 4 study visits spaced over a 5-week period. On visits 3 (week 2) and 4 (week 5), Anxiety Potentiated Startle will be recorded immediately (within 15 minutes) before and after the intervention.]

Eligibility criteria

Inclusion criteria

• Able to give their consent
• Right-handed
• Individuals receiving therapy for anxiety must be stable on their regimen for at least 4 weeks prior to study enrollment.

Exclusion criteria

• Non-english speaking
• Any significant medical or neurological problems
• Current or past non-anxiety-related psychiatric comorbidity, 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
• 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
• orthostatic hypotension

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Crossover

Masking

Open label

Primary purpose

Basic science

Study locations

United States · 1 center

• University of Pennsylvania — Philadelphia

Identifiers

NCT: NCT07415772 · 860105

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗