Vignesh Subramanian ’24

A number of movement disorders and motor neuron diseases, including focal epilepsy, Parkinson’s disease, amyotrophic lateral sclerosis, progressive muscular atrophy, and multiple sclerosis, are recognized as medically intractable or capable of becoming so. Intractable conditions lack known etiologies and have no established courses of treatment, with those in the neurological sphere often characterized by resistance to neural activity-suppressing medications (e.g. muscle relaxants, anticonvulsants, and anticholinergics). Surgical approaches have increasingly been used as alternatives to repair or resect faulty brain circuits (populations of neurons synapsing together to carry out specific functions), but remain underutilized per their risks as invasive procedures. The potential development of iatrogenic infarcts, intracranial hemorrhaging, venous air embolisms, and other surgical complications highlights the need to develop means of eliminating defective circuitry that simultaneously reduce perioperative threats to the brain’s vasculature and structural integrity. With this aim, researchers at the UVA School of Medicine and Stanford University experimented with a new form of brain “surgery” lacking the use of incisions entirely. 

The researchers first injected two dozen Sprague Dawley rats and several comparative descendants bearing cortical dysplasias, or abnormal brain tissue growths, with a microbubble agent. The rats were then placed in a low-intensity, magnetic resonance-guided focused ultrasound system (MRgFUS) to undergo sonication, a process by which sound energy is channeled to agitate and maneuver microparticles. The resultant microbubble movement was used to open up each subject’s blood-brain barrier (BBB), the semipermeable border of cells mediating diffusion of substances from surrounding microvasculature into the brain. Finally, a neurotoxin was intravenously infused to reach select regions of the brain parenchyma and assess whether specific cell populations could be targeted. 

Subsequent MRI analyses indicated that MRgFUS successfully opened subjects’ BBBs in the designated areas, with these focal openings being both precise and reversible. This approach, termed by researchers as ‘PING’, succeeded in lesioning dysplastic and other target neurons while sparing non-neuronal glial cells and axons in the same areas of the striatum and subcortical white matter, revealing the method’s capacity for distinguishing between aberrant circuitry and healthy tissue. These findings contrast PING with existing ablative surgical approaches that involve physical penetration with probes and induce greater collateral damage. The ability of PING to noninvasively permeate the BBB and produce focal neuronal injury where desired ultimately broadens the range of prospective cellular targets that may be newly accessed and extends promise as a potential therapeutic for currently intractable neurodegenerative conditions. 

Works Cited:

[1] Y. Wang, et al., Noninvasive disconnection of targeted neuronal circuitry sparing axons of passage and nonneuronal cells. Journal of Neurosurgery 137, 296-306 (2021). doi: 10.3171/2021.7.JNS21123

[2] Image retrieved from: https://www.flickr.com/photos/tudedude/8555160653