Causal Role of Frontostriatal Circuitry in Goal-directed Behavior
Condition: Executive Function
Study type: Interventional

Summary: 
      The purpose of this clinical trial is to investigate the causal role that frontostriatal
      circuitry plays in goal-directed behavior. The participants will perform a reward-based
      decision-making task. During the task, cross-frequency patterned rhythmic transcranial
      magnetic stimulation (TMS) will be delivered at delta-beta frequency, a control-frequency, or
      an active sham to either the dorsolateral or medial prefrontal cortex (PFC).
      Electroencephalography will be collected concurrent with stimulation. Structural and
      functional magnetic resonance imaging (MRI) will be collected during performance of the
      reward-based decision-making task to localize the stimulation targets.
    

Detailed description: 
      This study is a pilot, four-session, crossover study with transcranial magnetic stimulation
      (TMS), electroencephalography (EEG), and magnetic resonance imaging (MRI) to understand the
      causal role of delta-beta coupling in goal-directed behavior in the dorsolateral prefrontal
      cortex (dlPFC) to dorsal striatum circuit. Participants that request to be in the experiment
      will provide verbal, documented consent to undergo a phone screening to assess that the
      participant meets initial exclusion/inclusion criteria. Participants complete an MRI and TMS
      screening form over the phone to ensure eligibility.

      The first session will be an EEG session with the reward-based decision-making task. At the
      start of the session, the investigators will acquire written informed consent. Then, the
      investigators will administer a pregnancy test if applicable. Participants will complete five
      assessments: the Snaith Hamilton Pleasure Scale, Behavioral Activation System and Behavioral
      Inhibition System, Temporal Experience of Pleasure Scale, the State-Trait Anxiety Inventory,
      and Ruminative Responses Scale. Note that the participants are from a convenient sample and
      are not required to be diagnosed with major depressive disorder. Thus, these assessments were
      selected as they survey various personality traits that might be relevant to performance in
      the task.

      The scalp dimensions of each participant are calculated and an EEG net is applied. Next, the
      participants complete an eyes-open and eyes-closed resting-state recording of EEG. Then, the
      streamlined version of the Expenditure of Effort for Reward Task (S-EEfRT) is completed.
      These data serve as baseline measurement of brain activity without any form of stimulation.
      This session takes approximately 1.5 hours to complete. After each block of the task, the
      task difficulty will increase or decrease based on performance. At the end of the session, if
      the participant chose to perform the hard task greater than 85% of the time or less than 15%
      of the time, then the participant will not be invited to the next session of the experiment.
      Participants that do not dynamically change their response based on the incentive are not
      engaged with the relevant cognitive constructs under investigation in this study.

      The second session takes place at the MRI facility. In the 24 hours prior to this session,
      participants complete an MRI screening form to ensure eligibility based on common
      contraindications for MRI. During the 60 minutes of scanning, a 5-minute structural MR is
      acquired and the remaining time is used to complete as many blocks of the S-EEfRT as
      possible. The minimal number of sessions required to use the data is 5 blocks, which requires
      approximately 25 minutes to collect. If a participant was unable to complete the requisite
      number of sessions, then they will be excluded from the study. Functional MRI data is
      analyzed before the 3rd and 4th session to localize the regions of dorsolateral prefrontal
      cortex (dlPFC) and medial prefrontal cortex (mPFC) for stimulation. In the localization
      analysis, a region of interest mask in the head of the left caudate and in left nucleus
      accumbens are drawn and the region in dlPFC and mPFC with peak functional connectivity in
      task-based functional connectivity to these regions. In a pilot dataset collected by the
      investigators, it was found that the contrast of trails in which there was a decision to
      perform the hard task versus trials in which the easy task was selected was sufficient to
      localize the anterior middle frontal gyrus. The contrast of trials in which high versus low
      incentive was offered was sufficient to localize the medial prefrontal cortex. Thus, the
      investigators will choose regions in these anatomical areas with maximal connectivity to
      their respective nucleus in the striatum.

      The order of regions (dlPFC then mPFC, or mPFC then dlPFC) targeted by TMS in the third and
      fourth session will be randomized and counter-balanced. In the third and fourth session,
      participants will complete a TMS contraindications screening form. The same TMS screening
      form will be administered over the phone and at the start of each of the TMS session. If
      there is any ambiguity in the contraindications for the TMS form, then the medical monitor
      who is an epileptologist is consulted and final approval is acquired. Participants will be
      fitted with a low-profile EEG net. In the third session, the motor threshold of each
      participant will be calculated using single-pulse TMS to the hand knob of the left primary
      motor cortex with real-time monitoring of the motor-evoked potential using electrodes on the
      first dorsal interosseus muscle. Researchers may also use visible twitch to calculate the
      motor threshold. The motor threshold is defined as the percent stimulator output when a
      motor-evoked potential or visible twitch is observed approximately 50% of the time. For the
      fourth session, the same stimulator intensity will be used as in the third session. The
      structural MRI and regions of interest (dlPFC and mPFC) are imported into neuronavigation
      software. The participant wears a three-dimensional stereotaxic tracking headband and their
      head is registered to their structural MRI using canonical coordinates on the scalp. Then,
      the TMS coil is targeted to either mPFC or dlPFC and the position of the coil relative to the
      head is recorded throughout the session. The participant performs the S-EEfRT as the
      patterned trains of TMS are delivered on every trial. Each block of the study is randomized
      to receive either delta-beta patterned (triplets of TMS pulses at 20 Hertz every 3 Hertz),
      theta-gamma patterned (triplets of pulses at 50 Hertz every 5 Hertz), or an arrhythmic
      pattern (same number of pulses and duration with a random inter-pulse interval). After
      stimulation, a questionnaire is provided with common side effects of TMS. Based on the
      results of the stimulation side effects questionnaire, a structured adverse events interview
      is conducted to acquire more information regarding any side effects that were selected to be
      "very high" by the participant. The third and fourth session will each take approximately two
      hours.
    

Intervention name(s): Delta-beta TMS; Theta-gamma TMS; Arrhythmic TMS
Intervention type(s): Device; Device; Device
Intervention description(s): TMS will be delivered in a delta-beta pattern in which triplets of pulses delivered at 20 Hz (50 milliseconds between each pulse) are sent every 3 Hz (333 milliseconds between the start of each triplet).; TMS will be delivered in a theta-gamma pattern in which triplets of pulses delivered at 50 Hz (20 milliseconds between each pulse) are sent every 5 Hz (200 milliseconds between the start of each triplet).; TMS will be delivered in an arrhythmic pattern in which pulses are delivered with a random inter-pulse interval. The number of pulses and duration is matched to that of the Delta-beta TMS and Theta-gamma TMS.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science