Study of Neuroimaging Biomarkers of Social Cognition Deficits in Adolescents (Age 13-17) With Autism Spectrum Disorder and Effects of Gabapentin



Status:Recruiting
Conditions:Neurology, Psychiatric, Psychiatric, Autism
Therapuetic Areas:Neurology, Psychiatry / Psychology
Healthy:No
Age Range:13 - 17
Updated:7/21/2018
Start Date:September 14, 2017
End Date:June 1, 2021
Contact:David Cochran, MD, PhD
Email:david.cochran@umassmemorial.org
Phone:508-856-5096

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Imaging Biomarkers of Social Cognition and Pharmacologic Target Engagement in Autism Spectrum Disorder

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.

The investigators will complete a 1H-MRS study in 70 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 Occipital cortex. 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.

Inclusion Criteria:

1. Age 13-17 years

2. English as primary language (both child and legal guardian)

3. DSM-5 criteria for Autism Spectrum Disorder

4. IQ >85 per Weschler Abbreviated Scale of Intelligence (WASI)

5. Informed assent for the study (The guardian must also give written informed consent).

Exclusion Criteria:

1. Any neurological disorder (e.g., cerebral palsy, fetal alcohol syndrome, cerebral
neoplasm, bacterial meningitis, epilepsy, etc.)

2. Genetic disorders (e.g., Fragile X, Rett Syndrome, etc.)

3. Preterm (<36 weeks)

4. Failure to thrive within first year of life

5. Contraindications for MRI, such as metallic or electronic implants in the body, or
severe claustrophobia

6. History of head trauma with loss of consciousness for more than 30 minutes

7. Unstable psychiatric illness, history of psychotic disorder, or psychiatric illness
that would prevent the subject from being able to complete study protocol

8. Clinically significant suicidal ideation as assessed by the Columbia Suicide Severity
Rating Scale

9. IQ < 85

10. History of intolerance to gabapentin or pregabalin

11. Current substance use (including nicotine)

12. Pregnancy at time of 1H-MRS or gabapentin administration

13. Current treatment with gabapentin

14. History of Renal Dysfunction

15. Changes in any psychotrophic medication within 4 weeks prior to screening (8 weeks for
changes in fluoxetine dosing), and subjects will be removed from study if medication
changes are made between screening and the completion of protocol

16. Subjects who weigh less than 25 kg
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