Spatial Context and Fear Learning
Condition: Anxiety Disorders
MeSH terms: Anxiety Disorders
Study type: Observational

Summary: 
      Background:

      - Fear is a normal response to a threat. Learning fear can be helpful sometimes. For people
      with anxiety disorders, fear can be long-lasting and too intense. Researchers want to study
      how people become fearful of situations. They want to understand how the brain learns when it
      is helpful to feel fear and when it is not.

      Objective:

      - To better understand brain processes related to fear and anxiety.

      Eligibility:

        -  Right-handed adults ages 18 50 with generalized anxiety disorder, panic disorder, social
           anxiety disorder, or post-traumatic stress disorder.

        -  Right handed volunteers ages 18-50 without psychiatric disorders.

        -  And free of psychiatric medication for 2 weeks

      Design:

        -  Participants will first be screened under another protocol.

        -  Participants will play a video game inside a magnetic resonance imaging (MRI) scanner.
           The scanner is a metal cylinder It is surrounded by a strong magnetic field.
           Participants will lie on a table that can slide in and out of the scanner. A device
           called a coil will be placed over the head.

        -  During the scan, participants may play a virtual reality video game. Game instructions
           will be explained before they enter the scanner.

        -  While playing the game, participants will wear 2 electrodes on their fingers. These
           measure sweat on the skin. They will also have 2 small electrodes attached to the left
           hand. These can give brief mild electrical shocks.

        -  Participants will be asked questions when playing the game during the scan.

        -  Before and after the scan, participants will fill out questionnaires about their
           emotions. They may complete questionnaires online while at the clinic.
    

Detailed description: 
      Objective:

      To examine the processes involved in distinguishing between threatening and safe conditions,
      we aim to investigate the neural bases of contextual fear learning using functional magnetic
      resonance imaging (fMRI). To do this, we will study behavioral, physiological, and brain
      responses as aversive stimuli are encountered in a virtual environment, and will explore how
      fear-related responses depend on the surrounding environment. In addition, we will examine
      how these responses differ in clinical anxiety.

      We are interested in studying Pavlovian aversive context conditioning in healthy controls and
      patients with anxiety disorders. We will examine the extent to which participants learn to
      discriminate between dangerous and safe virtual contexts, and how this learning maps to the
      neural networks underlying anxiety and context coding. We expect successful learning of the
      contextual fear response in healthy controls, as evidenced by differential skin conductance
      response and neural activation to safe vs. threat context. Accordingly, we anticipate higher
      neuronal activity in the hippocampus, prefrontal cortex, and amygdala. These findings will be
      accompanied with increased hippocampus-prefrontal cortex connectivity during approach and
      exploration of the dangerous context, and increased amygdala activation during anticipation
      of shock in the dangerous context. Physiologically, SCR will increase in threat context
      compared to safe context. However, anxious patients are expected to fail to learn to
      differentiate safe from threat context, exhibiting increased SCR and neural activation in
      both safe and threat contexts, an index of contextual generalization of fear. Particularly,
      the lack of contextual fear discrimination in anxious patients will be associated with weaker
      hippocampal activation to contextual learning. To examine differential context fear
      conditioning, we will use a virtual reality (VR) paradigm. VR provides an optimal way to
      probe spatial navigation and simulates context. The VR task presents an outdoor space, which
      comprises a dangerous (probabilistic electrical shocks) and a safe (no shocks) location.
      Healthy controls and patients with anxiety disorders will be compared on their physiological
      and neural reactivity during task performance. Preliminary psychophysiological data suggest
      that the proposed procedure is an effective way to promote different responses to a safe and
      dangerous spatial location. Hence, we anticipate that this procedure will allow us to examine
      brain correlates of differential contextual fear responses in humans and compare them between
      healthy participants and patients diagnosed with an anxiety disorder.

      Study population:

      Two study populations, healthy volunteers and patients diagnosed with an anxiety disorder
      (generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, and
      post-traumatic stress disorder) will complete the protocol. Participants will be adult males
      and females, aged 18 to 50 years.

      Design:

      This fMRI study will compare performance, physiological and neural measures between healthy
      adults and patients with anxiety disorders, who perform a threat VR task in the scanner.

      The VR task entails navigating in a virtual outdoor environment, which, unbeknownst to the
      participants is divided into a safe and a dangerous context, which are recognizable by
      environmental characteristics (e.g., mountain, clouds). The dangerous context is associated
      with probabilistic shocks, which are never encountered in the safe context. Participants
      learn about these two contexts as they collect flowers (cues), one at a time, in either
      context. In the dangerous context, the flowers are associated with 50% chance of a shock

      Outcome measures:

      The primary outcome measures will be the cerebral fMRI blood-oxygen-level dependent (BOLD)
      responses to three events: (1) shock anticipation: after collecting the cues (flowers) during
      anticipation of a potential shock, (2) context exploration: as participants navigate in the
      threat context or safe context in between trials (which start when a flower appears in the
      environment), and (3) cue approach: during approach towards the flower, in the threat or safe
      context. The secondary outcome measures will consist of the changes in psychophysiological
      responses, such as SCR, heart rate, pupil dilatation, and respiratory rate, which will
      validate fear responses.
    

Observational model: Case-Control
Time perspective: Prospective
Keywords: Anxiety; fMRI; Virtual Reality; Shock Threat; Healthy Volunteer