Neurobiology of Functional Movement Disorder and Non-Epileptic Seizures
Condition: Movement Disorders
MeSH terms: Seizures; Movement Disorders; Conversion Disorder; Hysteria
Study type: Interventional
Phase: Early Phase 1

Summary: 
      This study is part of a series of studies that will explore how the mind and the brain work
      to cause episodes of uncontrollable shaking in people who have no known underlying brain or
      medical disorder. The study is conducted at NIH and at the Brown University Rhode Island
      Hospital.

      Healthy volunteers and people with functional movement disorders (FMD) or non-epileptic
      seizures (NES) who are 18 years of age or older may be eligible for this study.

      Patients with NES have 3 teaspoons of blood drawn. The blood is tested for two genes that are
      normally found in healthy individuals to see if they are found more frequently in patients
      with uncontrolled shaking.

      Patients with FMD have blood drawn for testing and also undergo functional magnetic resonance
      imaging (fMRI) to look at how the brain functions while the subject performs a specific task.
      MRI uses a strong magnetic field and radio waves to obtain images of body organs and tissues.
      During the scan, the subject lies on a table that can slide in and out of the scanner, a
      metal cylinder. The scan lasts about 60 to 90 minutes, during which the subject may be asked
      to lie still for up to 10 minutes at a time and to perform tasks, such as identifying the
      gender of faces shown on a screen.

      Healthy volunteers may have blood drawn for genetic testing or fMRI or both.
    

Detailed description: 
      Objectives:

      The study investigates the neurobiological correlates of conversion disorder (CD). The
      primary objectives are to investigate in CD patients:

        -  The role of emotional valence in an implicit emotional processing task (COMPLETE)

        -  The frequency of the 5HTTLPR S/S genotype

        -  Structural differences in grey matter of the brain as detected by voxel-based
           morphometry (VBM)

        -  The neural correlates of fear conditioning and fear extinction in a fear learning fMRI
           task

        -  The neural correlates of interoceptive activity in a Interoceptive Attention fMRI task

        -  Identifying the cortical physiology correlated with making a movement following a go
           command.

        -  Identifying the cortical physiology correlated with not making a movement following a
           no-go command.

        -  Identifying the cortical physiology correlated with planning to move or not move
           following a choose go-no go command.

      Exploratory objectives are to investigate in CD patients:

        -  The frequency of several gene polymorphisms that are implicated in stress and affective
           disorder, including 5HTTLPR S/S (serotonin receptor), COMT (catechol-o-methyltransferase
           enzyme), Val/Met BDNF (brain-derived neurotrophic factor) and FKBP5 rs1360780 genotypes,
           as well as other polymorphisms or mutations to be determined later. Additionally,
           epigenetic data will be explored.

        -  The levels of salivary cortisol as a measure of stress.

        -  The heart rate variability, as a measure of autonomic nervous system function.
           (COMPLETE)

        -  Structural differences in white matter of the brain as detected by diffusion tensor
           imaging (DTI)

        -  The resting state BOLD fMRI signal

        -  The impact of the caregiver's attitude on the patients' symptoms

        -  The relationship between hemodynamic responses in regions implicated in interoception
           and self-reported measures of interoceptive attention, as well as behavioral and motor
           symptom severity

      Study population:

      We intend to study adult patients with diagnoses of functional movement disorders (FMD) seen
      by the Human Motor Control Section clinic (HMCS), patients with diagnoses of psychogenic
      non-epileptic seizures (PNES) seen by the Epilepsy clinic and healthy volunteers. Up to 12
      healthy volunteers will be for the EEG-EMG sub-study. The PNES patient group will include
      patients seen at Rhode Island Hospital. Additionally, we would like to study caregivers of
      patient's with FMD who are enrolled un protocol 07-N-0190.

      Design:

      An assessment for psychiatric diagnoses and measurement scales will be administered to the
      FMD and PNES patients, healthy volunteer controls and caregivers.

        -  Functional MRI (fMRI): emotional processing will be studied using a gender
           identification task with differing emotional valences. (COMPLETE) Limbic processing will
           also be studied using a fear learning fMRI task. Resting state BOLD fMRI signal will
           also be obtained.

        -  Anatomical MRI: VBM and DTI will be performed using anatomical MRI sequences collected
           during the fMRI scanning or subsequent dedicated anatomical MRI sessions.

        -  Genetics: blood will be collected for testing.

        -  Stress biomarkers: saliva will be collected for testing. [EVALUATION IN HEALTHY
           VOLUNTEERS COMPLETE].

        -  Autonomic nervous system function: electrocardiogram (EKG) will be obtained to determine
           heart rate variability. [COMPLETE].

        -  Event related potentials: 64-channel EEG and surface EMG will be recorded during a go ,
           no-go and choose go-no go behavioral task.

        -  EEG will be recorded during the resting state condition (five minutes with eyes open and
           five minutes with eyes closed).

      Outcome measures:

        -  fMRI study: blood oxygenation level dependent (BOLD) signal in the regions of interest
           during a gender identification task (primary) [COMPLETE], in regions of interest during
           a fear learning task (primary), as well as resting state BOLD signal (exploratory). EEG
           resting state data will be compared and correlated with the fMRI resting state data.

        -  Anatomical MRI: VBM (primary) and DTI (exploratory)

        -  Genetics: (a) S/S genotype of the serotonin transporter promoter region polymorphism.
           (primary) (b) Polymorphism frequency of several genes related to affective disorders
           and/or stress (exploratory)

        -  Stress biomarkers: salivary cortisol levels (exploratory). [EVALUATION IN HEALTHY
           VOLUNTEERS COMPLETE]

        -  Autonomic nervous system function: heart rate variability as measured by EKG
           (exploratory). [COMPLETE]

        -  Psychological profile scales: scores exploratory.

        -  The relationship between hemodynamic responses in regions implicated in interoception
           and self-reported measures of IA, motor symptoms and behavioral ratings (exploratory)

        -  EEG-EMG study: Characteristics of event related cortical potentials correlated with
           simple behavioral motor tasks in healthy volunteers. Differences between go and no-go
           potentials will be identified and quantified. This analysis will allow planning a
           properly powered study for patients with functional movement disorders.
    

Intervention name(s): MRI
Intervention type(s): Device
Intervention description(s): The imaging study will use a block design to (i) optimize amygdala activation to emotionally valenced images, (ii) to optimize analysis of PPI and (iii) to optimize the go/no-task design. G. T2-sensitive functional images will be obtained on a MRI system with a 1.5 Tesla superconducting magnet and a standard head coil. An echo planar image sequence (TR=2500msec, TE=33 msec, 90 flip angle) with 30 contiguous 2mm thick coronal oblique slices with 1 mm interslice gap centered over the amygdala, tilted 30 to the anterior, to improve susceptibility artifact. Three-dimensional anatomical images will be taken for the co-registration of the functional images.
Allocation: Non-Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Conversion Disorder; Psychogenic Movement Disorders; Non-Epileptic Seizure; Functional Magnetic Resonance Imaging (fMRI); Genetic Polymorphisms