Reward Circuit Targeted iTBS

Study Overview
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Brief Summary
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The objective of this study is to examine the effect of intermittent theta-burst transcranial magnetic stimulation (iTBS) targeting the reward circuit.

Detailed Description
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The study will examine the effect of medial prefrontal cortex (MPFC)-iTBS on the reward circuit, reward sensitivity, and anhedonia. The reward circuit will be assessed using functional MRI (fMRI) connectivity and activation during the Doors Task. Reward sensitivity will be assessed using an event-related potential called the reward positivity or RewP. The RewP will be measured using electroencephalography (EEG) during the Doors Task. Anhedonia will be measured using the Dimensional Anhedonia Ratings Scale (DARS). The Doors Task was designed to examine reward processing in a simple, well-controlled paradigm. On each trial, participants select one of two doors. Gain (50 cents) or loss (25 cents) feedback is provided. Gains elicit a positive potential referred to as the RewP, while losses elicit a negative potential referred to as the feedback reward negativity (FRN). Gains also show increased activation in reward-related brain areas (e.g. ventral striatum) relative to losses in the fMRI signal. Each participant will complete a baseline session including structural MRI, fMRI and EEG during the Doors task, and transcranial magnetic stimulation (TMS) motor thresholding. The ventral striatum (VS) will be identified on the structural MRI. The MPFC will be identified as a rostral-medial cortical area in prefrontal cortex with high connectivity to the VS. A control site, inion, will be identified using visual inspection of the skull. Each participant will complete 2 weeks of iTBS sessions. Each week will target a different site (experimental: MPFC; control: inion). iTBS will be performed once a day for 5 consecutive days at each site, with order counter-balanced across participants in a cross-over design. 1 week of washout will follow each week of iTBS. At the end of each week, participants will perform the Doors task while being measured with EEG, and complete the DARS. At the end of the iTBS weeks, participants will also perform the Doors task while being measured with fMRI. fMRI activation of the MPFC target and VS, and VS-MPFC fMRI connectivity will be compared at baseline, following the MPFC-iTBS week, and following the control-iTBS week. Changes specific to MPFC-iTBS will provide evidence of the effect of MPFC-iTBS on the reward circuit. The RewP and DARS will be compared at baseline, and after each week, respectively. Changes specific to MPFC-iTBS will provide evidence of the effect of MPFC-iTBS on the reward sensitivity and anhedonia. Changes that persist following washout will provide an indication of a lasting effect of MPFC-iTBS.

Official Title
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Manipulating the Reward Circuit With TMS

Conditions
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Transcranial Magnetic Stimulation

Intervention / Treatment
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* Device: transcranial magnetic stimulation
* Device: transcranial magnetic stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Right-handed Native English speaker or fluent by the age of 6 Elevated self-reported anhedonia Exclusion Criteria: Left-handed Metal in head Brain tumor, stroke, aneurysm, multiple sclerosis Active substance use disorder in last 3 months Dementia or other cognitive disorder making unable to engage in treatment History or diagnosis of schizophrenia, schizoaffective disorder, delusional disorder, or other psychiatic illness that precludes safe participation in trial Suicidal risk that precludes safe participation obsessive-compulsive disorder Inability to stop taking any mediation that significant lowers the seizure threshold (e.g. tricyclic antidepressants, clozapine, etc.) Severe traumatic brain injury Non-English speaker

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MPFC-iTBS<br>Transcranial magnetic stimulation delivered to the medial prefrontal cortex. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days. | Device: transcranial magnetic stimulation<br>* Transcranial magnetic stimulation delivered to the scalp targeting medial prefrontal cortex<br>|
| Active Comparator: Inion-iTBS<br>Transcranial magnetic stimulation delivered to the inion. 600 pulses delivered in 50 Hz bursts every 5 Hz for 2 seconds followed by 8 seconds of no stimulation repeated 20 times at 80% of resting motor threshold. Repeated daily for 5 consecutive days. | Device: transcranial magnetic stimulation<br>* Transcranial magnetic stimulation delivered to the inion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Anhedonia post-intervention | change in self-reported anhedonia from baseline immediately following the intervention measured using the score on the Dimensional Anhedonia Rating Scale (DARS); score range is 0-68 with higher scores meaning better outcomes (less anhedonia) | baseline, 1 hour post-intervention | 
| Change in Anhedonia post-washout | change in self-reported anhedonia from baseline following a week of washout post-intervention measured using the score on the Dimensional Anhedonia Rating Scale (DARS); score range is 0-68 with higher scores meaning better outcomes (less anhedonia) | baseline, 1 week post-intervention | 
| Change in RewP post-intervention measured via EEG | change in reward positivity from baseline immediately following the intervention assessed via the EEG event-related potential (ERP) to feedback over FCz in microvolts | baseline, immediately post-intervention | 
| Change in RewP post-washout measured via EEG | change in reward positivity from baseline immediately following a week of washout post-intervention assessed via the EEG event-related potential (ERP) to feedback over FCz in microvolts | baseline, 1 week post-intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Reward activation measured via fMRI | change in reward-related activation in the ventral striatum assessed via the fMRI blood-oxygenation level dependent (BOLD) signal following feedback (this measure has no units) | baseline, 15 minutes post-intervention | 
| Change in Reward connectivity measured via fMRI | change in fMRI connectivity between ventral striatum and medial prefrontal cortex assessed via correlations in the fMRI blood-oxygenation level dependent (BOLD) signal between these areas (this measure has no units) | baseline, 15 minutes post-intervention |