Autism is a pervasive developmental disorder of childhood characterized by deficits in social interaction, language, and stereotyped behaviors and restricted range of interests. Recent studies on postmortem tissue suggest that autism is associated with cortical cytoarchitectural abnormalities. In brief, reports on independent populations have shown a reduction in the neuropil space at the periphery of the minicolumn. This is the compartment where lateral inhibition sharpens the borders of minicolumns and increases their definition. The primary source of for this inhibitory effect is derived from axon bundles of double-bouquet cells. The axons of double bouquet cells arrange themselves in essentially repeatable patterns varying between 15 ?m and 30 ?m wide, perpendicular to the cortical surface. This grant attempts to preferentially strengthen the inhibitory surround of minicolumns by taking advantage of the geometry of double bouquet cells. We will use the principle of induction to induce electrical currents in double bouquet cells by applying a coil of wire energized by a capacitor (Transcranial Magnetic Stimulator or TMS) to provide a magnetic field orthogonal to the plane of the coil. Slow or low frequency TMS will enhance interneuron inhibition which in turn will enhance spatial contrast needed to optimize functional discrimination in minicolumnar units. The trial will recruit 70 autistic patients and 30 controls matched for age, sex, IQ, and socio-economic class. Outcome measures will include behavioral and electrophysiological measures. Overall, our project will link behavioral, clinical, and neurophysiological (qEEG, ERP) responses during cognitive tests and TMS treatment outcomes with an underlying neuropathology model (minicolumnar pathology and lateral inhibition deficits) derived from investigations in our laboratory. The results of the proposed study will help understand the specific social communication and cognitive deficits associated with developmental abnormalities of functions within cortical circuitry, and thereby contribute to understanding the brain substrates of behavioral dysfunctions typical for autism. The proposal represents a new development in combining TMS with functional outcome measures (cognitive ERP, EEG), using TMS as a theory-guided psychiatric therapy in autism.

Public Health Relevance

In this grant proposal we describe a potential therapeutic intervention for autism using transcranial magnetic stimulation (TMS). Therapy would not change a person's way of thinking, but is aimed at specific symptoms related to processing sensory information from the environment, which have proven disabling in some patients. The intervention, if proven effective for autism, would also be of value to patients with Asperger syndrome or Rett syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086784-04
Application #
8267109
Study Section
Special Emphasis Panel (ZMH1-ERB-L (05))
Program Officer
Gilotty, Lisa
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$219,780
Indirect Cost
$71,280
Name
University of Louisville
Department
Psychiatry
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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Williams, Emily L; El-Baz, Ayman; Nitzken, Matthew et al. (2012) Spherical harmonic analysis of cortical complexity in autism and dyslexia. Transl Neurosci 3:36-40
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Casanova, Manuel F; El-Baz, Ayman; Elnakib, Ahmed et al. (2011) Quantitative analysis of the shape of the corpus callosum in patients with autism and comparison individuals. Autism 15:223-38
Sokhadze, Estate; Baruth, Joshua; El-Baz, Ayman et al. (2010) Impaired Error Monitoring and Correction Function in Autism. J Neurother 14:79-95
Baruth, Joshua M; Casanova, Manuel F; El-Baz, Ayman et al. (2010) Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Evoked-Gamma Frequency Oscillations in Autism Spectrum Disorder (ASD). J Neurother 14:179-194
Williams, E L; Casanova, M F (2010) Potential teratogenic effects of ultrasound on corticogenesis: implications for autism. Med Hypotheses 75:53-8
Sokhadze, Estate; Baruth, Joshua; Tasman, Allan et al. (2010) Low-frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related potential measures of novelty processing in autism. Appl Psychophysiol Biofeedback 35:147-61