ReviewThe neuroprotective effect of focused ultrasound: New perspectives on an old tool
Introduction
It has been already known that ultrasound (US) play an important role in diagnostic medical imaging which is based on the processing of the echogenic characteristics of the reflected longitudinal sound waves which have been intentionally directed to the target tissue (Jain and Swaminathan, 2015). Besides its important role in diagnostic medical imaging, it has also been recently established that US may also produce diverse biological effects via the thermal, mechanical or electrophysiological properties of sound waves that also may act therapeutically on the target tissue (Jain and Swaminathan, 2015, Yusuf et al., 2010, Harvey, 1929, Dalecki, 2004, Hynynen and Clement, 2007, O’Brien, 2007, Ter, 2007, Dinno et al., 1989, Global Burden of Disease Study, 2015). This opened a new window in the treatment of various non-neurological diseases including cancer, tinnitus, and osteoarthritis through the application of US. In the light of inherent electrical excitability of the neuronal networks as well as the electrophysiological therapeutic effect of sound waves on the non-neuronal tissue, the research has been focused on the US-mediated electrical excitability of the neuronal tissue and evaluated the possible therapeutic role of US in various neurological disorders.
The critical piece of evidence came in 1929, showing that US can stimulate nerve and muscle fibers in neuromuscular preparations (Yusuf et al., 2010, Harvey, 1929). These promising results were replicated in independent groups over the last decade, showing that high/low-intensity US may modulate peripheral nerves, hippocampal slices, cortex, spinal cord and the peripheral somatosensory receptors in humans and animals (Jain and Swaminathan, 2015, Yusuf et al., 2010, Fry et al., 1958, Foster and Wiederhold, 1978, Young and Henneman, 1961, Lele, 1963, Mihran et al., 1990, Tsui et al., 2005, Fry et al., 1950, Velling and Shklyaruk, 1988, Gavrilov et al., 1976, Shealy and Henneman, 1962, Bachtold et al., 1998, Rinaldi et al., 1991). This indicated to a possible neuromodulatory and neurotherapeutic effect of ultrasound in special frequency ranges (Jain and Swaminathan, 2015, Yusuf et al., 2010). Although recent studies have shown that high-intensity US related destructive mechanical/thermal effects limit the noninvasive use of US in the brain-circuit stimulation (Dalecki, 2004, Hynynen and Clement, 2007, O’Brien, 2007, Ter, 2007), following studies have revealed that pulsed US at lower intensities and frequencies produce mechanical effects without leading to tissue damage (Dalecki, 2004, O’Brien, 2007, Ter, 2007, Dinno et al., 1989). These findings suggested that US can be safely applied through skull bone at lower frequency and intensities. In agreement with this further in-vivo and in-vitro studies have revealed that transcranial focused ultrasound at low intensity and low frequency may specifically and noninvasively stimulate small millimeters size of the brain (Yusuf et al., 2010, Yang and Lee, 2012, McDannold et al., 2008, Yang et al., 2009, Yang et al., 2010, Yang et al., 2011a, Yang et al., 2011b, Kroll and Neuwelt, 1998, Choi et al., 2011, Hynynen et al., 2005, Weng et al., 2011, Yulug et al., 2016, Wu et al., 2014a, Tyler et al., 2008). This is in line with further clinical studies showing that transcranial focused ultrasound (tFUS) may non-invasively stimulate neuronal circuits and exert a significant therapeutic effect in of Parkinson’s Disease, essential tremor and neuropathic pain (Magara et al., 2014, Dobrakowski et al., 2014, Schlesinger et al., 2015, Elias et al., 2013, Martin et al., 2009).
In the last years, there are rapidly increasing evidence showing that therapeutic approaches targeting the opening of Blood Brain Barrier (BBB) may prolong the conventional therapeutic time window for delivering efficacious/candidate neuroprotective agents drugs to the target brain region. As expected, studies with special regard to increasing the BBB permeability showed improved US mediated drug delivery to the target brain area which was associated with significant neuroprotective effect (Yang and Lee, 2012, McDannold et al., 2008, Yang et al., 2011a, Yang et al., 2011b, Yang et al., 2010, Yang et al., 2009, Wu et al., 2014a, Raymond et al., 2008a, Jordão et al., 2010a). These findings led to increased interest in the direct parenchymal neuroprotective effect of Focused Ultrasound (FUS) without requiring an additional therapeutic approach to increase the drug transport to the Central Nervous System (CNS) (Yusuf et al., 2010, Jin et al., 2002, Jin et al., 2003, Scarcelli et al., 2014, Burgess et al., 2011, Ziadloo et al., 2012, Reher et al., 1999, Cao et al., 2004, Yuluğ et al., 2010). Considering all these worthful evidence, we reviewed the direct and indirect neuroprotective effects of FUS in various animal models (Table 1).
Section snippets
Stroke
The molecular pathogenesis of stroke is complex and involves increased excitotoxicity, neuroinflammation, toxic free radicals and the disturbance of ionic imbalances (Woodruff et al., 2011, Thompson and Ronaldson, 2014, Yulug et al., 2006, Beker et al., 2015, Yulug et al., 2008Woodruff et al., 2011; Thompson and Ronaldson, 2014; Yulug et al., 2006; Beker et al., 2015; Yulug et al., 2008 Yulug et al., 2006; Beker et al., 2015; Yulug et al., 2008) leading to neuronal cell death. Impaired ionic
Conclusion
Although with limited size, all of these studies reviewed here support that focused ultrasound provides a unique alternative to other invasive techniques. Despite its non-invasive feature, FUS may exert all the advantages of other invasive techniques in terms of accuracy and effectiveness. Besides its major advantages over newly implemented brain stimulation techniques (Douglas et al., 2012), FUS may also be a novel therapeutic option with its dual action on the drug delivery system and
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