Cortical Metrics in Intervention Trials With Autism Spectrum Disorders

The cortical metric is a single numeric measurement that is calculated using a
multi-parametric mathematical approach from a series of measurements of the speed,
intensity, diameter, and distance between two vibrations with which a person reacts to and
can distinguish vibrations from small brushes that touch the top side of fingers on the left
hand under multiple conditions designed to elicit cortical adaptation The cortical metric is
based on the neurobiological principle that the nerves in the fingertips project to adjacent
groups of neurons that work together to continuously optimize perceptions of touch under
varying conditions. Such perceptual optimization reflects the shifting excitatory and
inhibitory actions of individual neurons. We hypothesize that the brain's processing of
vibration is similar to its processing of other kinds of information. We also hypothesize
that in people with ASD adjacent groups of neurons work together less well to process
information.

Specific Aim 1: Obtain evidence regarding the ability of the "cortical metric" to
distinguish between 8-12 year-olds with typical development and with high functioning autism
spectrum disorders (ASDs).

Hypothesis 1: The cortical metric of children with ASD will differ from that of age matched,
typically developing children. This difference will be consistent with lower than normal
local functional connectivity.

Specific Aim 2: Validate the test-retest reliability of the cortical metric by examining its
stability of over an average of 3 weeks with no intervening interventions in both groups of
children.

Hypothesis 2: Test-retest reliability will be highly correlated in both groups of children.

Specific Aim 3: Obtain preliminary proof of mechanism data that the cortical metric assesses
the excitatory: inhibitory balance of intra-cortical connections by examining the effect of
acute exposure to dextromethorphan (DXM), which transiently blocks one type of excitatory
neurotransmission

Hypothesis 3: DXM will alter the cortical metric consistent with reduced adaptation.

The completion of these aims will be essential to design a larger federally funded trial to
validate the cortical metric as an outcome measure in a more heterogeneous pediatric ASD
sample. Specifically, we will aim to demonstrate that 1) the cortical metric differs between
children with ASD and with normal development, 2) that the cortical metric has minimal
variability over time in the absence of fno major changes in brain function, and 3) that the
cortical metric changes in response to a specific, temporary reduction in excitatory
stimulation caused by a single DXM dose.

A larger grant could focus on determining how sensitive and clinically relevant changes in
the cortical metric are.

If we are not able to demonstrate the potential for the cortical metric to be changed by
agents that reduce excitatory stimulation acutely or if the variability of the cortical
metric over 3 weeks is too great, no further examination of the cortical metric as an
outcome measure in ASD trials would be pursued. If there are not differences in the cortical
metric of children with and without ASD, we would be less interested in further examining
the cortical metric.

Group 1 Typically Developing Youth: We will recruit 30 typically developing boys 8-12
years old to participate in a screening visit, and two tactile perception sessions (visit
1 and 2).

Inclusion Criteria:

- Healthy Male Boys ages 8-12

- Normal developmental milestones and school performance

- Primary caretaker is able to participate in study appointments as is indicated

Exclusion Criteria:

- Significant lifetime medical history including non-febrile seizures, neurological
problems, psychiatric problems or learning disabilities

- Any sensory impairment (i.e. deafness or blindness)

- 1st or 2nd degree family members with a history of ASD

- 1st or 2nd degree family members with ADHD or other developmental problems

- Adverse reaction to dextromethorphan

- Inability to successfully complete and fully understand the reaction time subtest
(cortical metrics)

Group 2 Youth with ASD: 8-12 years old: > 30 boys will be recruited who have a known or
suspected diagnosis of ASD confirmed by DSM-5 checklist and the ADOS-2 at screening.

Inclusion Criteria:

- Male Boys ages 8-12 with ASD (confirmed by DSM-5 checklist and the ADOS-2)

- IQ's should be within the normal range (≥ 70) (by prior testing or Stanford Binet 5
at screening)

- Primary caretaker is able to participate in study appointments as is clinically
indicated

- Ability of child to participate in all aspects of the protocol per investigator
clinical judgment

Exclusion Criteria:

- New educational or behavioral intervention within 4 weeks of baseline

- History of non-febrile seizures, other neurological disorders, psychosis, bipolar
disorder, or Tourette Syndrome.

- Any sensory impairment (i.e. deafness or blindness)

- Adverse reaction to dextromethorphan

- Inability to successfully complete and understand the reaction time subtest (cortical
metrics)

- Changes in psychiatric medications within 4 weeks of baseline visit

- Taking epileptic medication (including but not limited to carbamazepine,
phenobarbital, Depakote, lamictal, oxycarbazepine, topiramate)