Noninvasive disconnection of targeted neuronal circuitry sparing axons of passage and nonneuronal cells

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  • 1 Department of Neuroscience, University of Virginia, Charlottesville, Virginia;
  • | 2 Department of Radiology, Stanford University, Stanford, California;
  • | 3 Department of Neurology, University of Virginia, Charlottesville, Virginia;
  • | 4 Focused Ultrasound Foundation, Global Internship Program, Charlottesville, Virginia;
  • | 5 Department of Medicine, University of Virginia, Charlottesville, Virginia;
  • | 6 Image Guided Therapy, Pessac, France;
  • | 7 Department of Neurosurgery, University of Virginia, Charlottesville, Virginia; and
  • | 8 Center for Brain, Immunology, and Glia, University of Virginia, Charlottesville, Virginia
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OBJECTIVE

Surgery can be highly effective for the treatment of medically intractable, neurological disorders, such as drug-resistant focal epilepsy. However, despite its benefits, surgery remains substantially underutilized due to both surgical concerns and nonsurgical impediments. In this work, the authors characterized a noninvasive, nonablative strategy to focally destroy neurons in the brain parenchyma with the goal of limiting collateral damage to nontarget structures, such as axons of passage.

METHODS

Low-intensity MR-guided focused ultrasound (MRgFUS), together with intravenous microbubbles, was used to open the blood-brain barrier (BBB) in a transient and focal manner in rats. The period of BBB opening was exploited to focally deliver to the brain parenchyma a systemically administered neurotoxin (quinolinic acid) that is well tolerated peripherally and otherwise impermeable to the BBB.

RESULTS

Focal neuronal loss was observed in targeted areas of BBB opening, including brain regions that are prime objectives for epilepsy surgery. Notably, other structures in the area of neuronal loss, including axons of passage, glial cells, vasculature, and the ventricular wall, were spared with this procedure.

CONCLUSIONS

These findings identify a noninvasive, nonablative approach capable of disconnecting neural circuitry while limiting the neuropathological consequences that attend other surgical procedures. Moreover, this strategy allows conformal targeting, which could enhance the precision and expand the treatment envelope for treating irregularly shaped surgical objectives located in difficult-to-reach sites. Finally, if this strategy translates to the clinic, the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.

ABBREVIATIONS

BBB = blood-brain barrier; DCE = dynamic contrast-enhanced; FUS = focused ultrasound; LITT = laser interstitial thermal therapy; MBP = myelin basic protein; MRgFUS = MR-guided FUS; PING = precise, intracerebral, noninvasive, guided surgery; QA = quinolinic acid; ROI = region of interest.

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