Study of Neuroimaging Biomarkers of Social Cognition Deficits in Adolescents (Age 13-17) With Autism Spectrum Disorder and Effects of Gabapentin
Condition: Autism Spectrum Disorder
MeSH terms: Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is increasing in
      prevalence, and is characterized by deficits in social communication and interaction across
      multiple contexts, and restricted, repetitive patterns of behavior, interests, or activities.
      The majority of individuals with ASD have poor outcomes in the area of social functioning;
      however, there are no medical treatments available that target the core social communication
      deficits. The goal of the proposed research is to understand the neurobiological role of an
      imbalance in excitatory (glutamate) and inhibitory (gamma-aminobutyric acid, GABA)
      neurotransmission in the social cognition deficits in ASD, and to develop proton magnetic
      resonance spectroscopy as a measurement of target engagement to measure the ability of a
      medication, gabapentin, to increase cortical GABA levels. Spectrally-edited proton magnetic
      resonance spectroscopy (1H-MRS) provides an ideal method for measuring cortical GABA levels.
      All proposed studies will be in 70 adolescents (male and female) with ASD (age 13 to 17
      years). Specific Aim 1: To measure correlations of 1H-MRS GABA levels in the anterior
      cingulate cortex (ACC) and occipital cortex (OC) with clinical measures of social cognition
      at baseline. Specific Aim 2: To measure the effect of an initial one time dose of gabapentin
      on 1H-MRS GABA levels in the ACC and OC. The hypotheses are 1) that higher social cognition
      ability will be positively correlated with GABA in the ACC but not in the OC (a control,
      non-social cognition-related region) of individuals with ASD, and 2) that gabapentin will
      increase GABA levels in the ACC and OC of youth with ASD.
    

Detailed description: 
      The investigators will complete a 1H-MRS study in 42 adolescents with ASD. Given the low
      burden on patients, it is assumed that 90% of those recruited to participate in baseline
      1H-MRS (Aim 1) will also consent/assent to repeated 1H-MRS after gabapentin administration
      (Aim 2). Projections from the preliminary study were used to select a proposed number of
      subjects that would be both achievable in the time frame of study and adequate to evaluate
      the research hypotheses.

      Psychiatric comorbidity will be assessed based on DSM-5 criteria by clinical interview and
      administration of the Kiddie-Schedule for Affective Disorders and Schizophrenia (Present and
      Lifetime version; K-SADS-PL).

      T1- and T2-weighted high resolution structural imaging (T1- and T2-weighted (MPRAGE)) will be
      acquired. These structural MRI scans will be analyzed using FreeSurfer (Martinos Center for
      Biomedical Imaging, Charlestown, MA) and Statistical Parameter Mapping
      (SPM8-http://www.fil.ion.ucl.ac.uk/spm/software/spm8/) to determine white matter, gray matter
      and CSF contributions to the MRS voxel for partial volume correction. This data will be
      analyzed for variation with age, and used as a co-variate in the statistical analysis plan.

      MRS data will be acquired from the Anterior Cingulate Cortex and Right anterior insula.
      Imaging sessions will be conducted at the Advanced MRI Center (AMRIC) at UMMS, which houses a
      3.0 Tesla Philips Achieva MRI research scanner (Philips Healthcare, Best, Netherlands) and
      32-channel phase-array receiver SENSE head coil. AMRIC is dedicated to research and the MRI
      system has considerable evening and weekend availability. A Board certified neuroradiologist
      associated with the AMRIC at UMMS reviews all MRI scans. In the event of an unexpected,
      clinically important finding, the primary investigator will be informed. The investigator
      will share the finding with the participant and be in contact with the participant's primary
      care physician (PCP) in order to help decide the appropriate follow-up care/work up that is
      needed (consent will be obtained to contact each child's PCP during the study consent
      process).

      GLU+GLN absolute levels will be quantified, and GABA levels will be quantified using the
      total creatine (tCr) peak as a reference. Macromolecule-suppressed editing will be used with
      MEGA-PRESS sequence, including prospective frequency correction to address the impact of
      drift and motion during scans.

      Neurotransmitter levels will be correlated with social cognition measures. In females of
      reproductive age, menstrual cycle charting will be done for 2 months prior to scan, and
      imaging will be timed to target the mid-luteal phase, as cortical GABA levels fluctuate
      during the menstrual cycle and are most similar to levels in males during the luteal phase.
      In analysis of female subject data, menstrual phase will be confirmed on the day of the scan
      by measurement of serum estradiol and progesterone levels, and these levels will be used as
      covariates in the analysis. Exploratory analysis will be used to seek correlations with all
      clinical measures.
    

Intervention name(s): Gabapentin
Intervention type(s): Drug
Intervention description(s): Single dose of gabapentin 900 mg
Intervention MeSH terms: Gabapentin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: magnetic resonance imaging; spectroscopy; GABA; glutamate; social cognition