Brain development and interneurons

Casanova begins by emphasizing that autism is a neurodevelopmental disorder. Therefore, he states, to create opportunities for curative treatments, we must first understand brain development and focus therapies on the pathology of autism (15:45). The presenter details the formation of the cerebral cortex (16:20) and how development differs in individuals with autism: 

• Neuroblasts (excitatory; precursor cells of neurons) and interneurons (inhibitory) migrate to the cortical plate (17:00)
  • Neuroblasts travel radially along arranged glial fibers
  • Interneurons migrate tangentially (orthogonal to the glial fibers) 

Casanova highlights that the distance traveled by tangentially migrating neuroblasts is much greater than that of the radial pathway. Therefore, tangential migration expands the window of opportunity for disruption of neuroblast migration (16:20 – 21:15).  

• Mini columns (22:05) form at the joining of radial and tangential migratory currents in the cortical plate
  • Cellular associations and functional exchanges between neurons and interneurons occur at the joining locations.
  • When layered on top of one another, those cellular associations form the mini-column, a unit of anatomy and function (21:18).  

Post-mortem studies of mini-columnar morphometry in individuals with autism revealed a significantly reduced area in the peripheral neuronal space (23:20). Casanova emphasizes that the periphery of each mini-column is populated by inhibitory cells that help establish lateral inhibition (inhibition between adjacent columns) (23:52). He presents the analogy (26:45) of a bundle of conductive copper wires (neurons) where each wire is isolated from its neighbors by non-conductive material (interneurons). Deficient insulation (diminished inhibitory cells) allows the copper wires to touch, creating alternate paths for electricity flow (27:15) and a cascade of excitement across mini-columns (24:57). 

• Synchronous recruitment of PV-positive interneurons generates rhythms of gamma oscillation important in cognitive task execution (38:00)
  • PV-positive cells make up around 40% of all interneurons (34:48)
  • Gamma oscillations help us construct a perception of reality based on the elements around us. 

Casanova outlines various studies that found a significant increase in gamma oscillatory activity in individuals with autism (50:29). These findings reflect a decrease in signal-to-noise ratio caused by a reduction in the total number of PV-positive cells or decreased inhibition (41:10). We can thus infer that “…the inhibitory cells in the periphery of the mini-column are diminished in number and function in individuals with autism…and that correcting this deficit could provide a therapeutic target in autism (24:30).” 

To learn more about brain development in autism, view Exploring Monogenic Syndromes with Elevated Rates of Autism, a free webinar presented by Dr. Daniel Vogt, PhD.

Transcranial Magnetic Stimulation (TMS)

Transcranial Magnetic Stimulation (TMS) uses a polar magnetic field created from coiled conductors (43:30) to stimulate currents along the glial lines instead of through them (45:25). Due to the small magnetic field area, TMS can only treat specific parts of the brain (46:08). Because the dorsolateral prefrontal cortex (DLPC) interconnects with many brain areas, correcting inhibition deficits in this area could create a therapeutic cascade that could normalize the functionality of associations across the entire brain  (47:30). 

Casanova outlines his research group studies that found direct relationships between TMS sessions and increased coherence of function across brain regions (51:02), improved error-rate and post-error response time (52:14), normalized autonomic nervous system parameters (57:55), and minimized abhorrent and repetitive behaviors (59:20). He posits that this type of therapy must be investigated as an alternative to neuroleptics as TMS has no known side effects (59:55).  

The presenter stresses that TMS should not be idealized as a possible cure for autism (1:01:00). Although the evidence is hopeful, he emphasizes the need for multi-center trials with sufficient participants to test the efficacy and compare TMS to other treatments and notes that long-term effects are not yet understood (1:02:35). Casanova outlines some of his latest publications before opening the Q&A (1:03:58).