This study was supported by Key Projects in the National Science & Technology Pillar Program during the Twelfth Five-Year Plan Period (2012 BAI13 B00) and Fundamental Research Funds for Jilin University (201103082). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the article.
Neurologic diseases ranging from epilepsy to movement disorders continue to evade effective medical management for many patients. When conventional pharmacotherapeutic approaches have been exhausted for such disorders, surgery becomes a potential modality of choice. For example, patients with temporal lobe epilepsy that is refractory to various combinations of anti-epileptic drugs become candidates for surgical resection of part or all of the temporal lobe. This type of surgery can be highly invasive and require the removal of substantial amounts of cortical tissue. Complications can include bleeding, infection, blood clots, stroke, seizures, swelling of the MLN 8237 and nerve damage (McClelland et al. 2011). Moreover, persistent functional deficits in memory, language comprehension and visual processing may occur (Helmstaedter et al. 2004). Importantly, this type of surgery is quite effective in improving epilepsy in upward of 70% of patients (Wiebe et al. 2001). Alternatives to major invasive procedures include minimally invasive laser ablation (Willie et al. 2014) and non-invasive radiosurgery (Quigg and Barbaro 2008). Finally, non-invasive, high-intensity focused ultrasound is under development as another non-invasive surgical tool for epilepsy and other disorders (Elias et al. 2013; Martin et al. 2009; Monteith et al. 2013). One limitation of magnetic resonance (MR)–guided focused ultrasound (MRgFUS) is that its ablation effect requires the deposition of a significant amount of energy in the brain tissue. This critical amount of energy deposition can be achieved only when the gain of the focused beam is high enough to overcome the dissipation effect of the skull. The resulting treatment envelope includes tissues located a greater distance from the skull (e.g., thalamus), whereas structures located nearer to bone (e.g., hippocampus) are more challenging to treat (Aubry et al. 2003; Hynynen and Sun 1999; Lu et al. 2006; Marquet et al. 2009; Pinton et al. 2012).
It therefore remains critical to identify alternative approaches that lessen the complications of major invasive surgery, do not require the ablation of large areas of the brain and minimize injury to functional circuitries, but still provide effective outcomes. This is true not only for the aforementioned example of temporal lobe epilepsy, but for a variety of neurologic disorders involving circuitry dysfunction. Seeking to develop a means of selectively disrupting impaired neuronal circuitry in a non-invasive and targeted manner, in the present study we took advantage of certain key features of FUS and a centrally acting neurotoxin. First, FUS at adequately low intensities does not produce thermal lesions (Choi et al. 2007; Hynynen et al. 2001; McDannold et al. 2005). Second, when combined with systemic (intravenous) injection of microbubbles, low-intensity FUS is capable of transiently disrupting the blood–brain barrier (BBB) without producing sustained injury to the BBB or brain (Hynynen et al. 2001). A major benefit of introducing microbubbles into the circulation is that the intensity of ultrasound beam needed to disrupt the BBB is reduced significantly, which minimizes both thermal effects and persistent disturbance of the tissue (Konofagou et al. 2012). Third, magnetic resonance imaging can be used to guide and selectively target the site of sonification (Cline et al. 1992). Thus, MRgFUS allows planned and spatially restricted modification of BBB permeability. Finally, the neurotoxin quinolinic acid (QA) poorly penetrates the intact BBB. The neurotoxic effects of QA are dependent primarily on direct access to neural N-methyl-D-aspartate receptors. Consequently, systemic administration of QA is relatively innocuous (Foster et al. 1984). Even when very high dosages are administered over a sustained period, only moderate central nervous system changes are observed (Beskid et al. 1997). Exploiting these characteristics, the current proof-of-concept study examined the concept that a systemically administered neurotoxin can be delivered to a specific and restricted area of the brain to destroy target neurons and disrupt central nervous system circuitry.