Page 44 - Volume 8, Issue 4 - Winter 2012

At very high doses, another threshold is passed and nerve damage becomes irreversible. Eventually, complete ablation occurs.
The neurolytic mechanism at high doses is thermal coagulation, but the low-dose mechanisms are unknown and are labeled here as a unified “second” mechanism. This graph is based on work by Vaitekunas,6 and is consistent with work by Takagi7 Young,8 and Colucci9 demonstrating reversible blocking of ex vivo frog sciatic nerves, Foley10 demonstrating neurolysis of in vivo rabbit sciatic nerves, and Jabbary5 demonstrating reversible blocking of ex vivo lobster ventral nerves.
Different fibers within a nerve respond differently to the same incident ultrasound beam
A peripheral nerve is composed of several layers. The outermost layer is the epineurium, made of tough connec- tive tissue. The perineurium is the middle matrix of con- nective tissue surrounding fascicles and blood vessels. The fascicles are composed of individual neural fibers (axons) embedded in the endoneurium matrix of connective tissue. The individual axons are typically myelinated, that is, wrapped with Schwann cells rich in glycolipids and glyco- proteins. The epineurium and perineurium are composed of regular bands of collagen fibers with periodicities as wide as 170 microns,11 with a potential for acoustic interference above 10 MHz.
Nerves can contain sensory (afferent) and motor (effer- ent) fibers together. For example, the vagus (cranial nerve X) contains sensory and motor fibers, whereas the hypoglossal
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Gasser system (Aα, Aβ, Aγ, Aδ, B, and C). Originally based on conduction velocities of action potentials (the fastest Aα at 120 m/s through the slowest C at 0.6 m/s), the thickness of the fibers (25 microns down through 0.1 microns) was soon
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correlated with the velocities. The different fibers have
greater or lesser sensitivity to various stimuli. Type A, the coarsest fibers, are the most susceptible to pressure. Type C, the finest fibers, are the most susceptible to local anesthetic. The ultrasonic dose required for conduction blocking in fibers appears to be proportional to the cross-sectional diam- eter of the fibers;13 thus, to elicit a similar response, type A fibers require a higher dose than do type C fibers.
The difference in sensitivity allows the possibility of dif- ferential conduction blocking. Monteith14 is exploiting this in trigeminal neuralgia therapies. The finest fibers tend to carry signals from pain receptors. Thus it is possible for a skilled practitioner to differentially damage a nerve, that is, to adjust the therapeutic ultrasound dose to block conduction of the finer pain fibers but retain sensation and motor control car- ried by the coarser fibers.
The mechanisms of bioeffective insonification of nerves at sub-ablation ultrasonic doses are not fully characterized
The intractability of the problem of identifying the mechanisms responsible for the sub-ablation bioeffects on
the nervous system is perhaps best illustrated by repeating a phrase from the opening of this article: work has proceeded for 100 years. The first decade of work led to the identifica- tion of the three broad classes of interaction of ultrasound with biological tissue: thermal, mechanical (bubbles or strain-related effects), and radiation force.
Added to this are the various acoustical parameters avail- able for adjustment, e.g., carrier frequency band, incident intensity, waveform shape (pulse width and pulse repetition frequency), and beam shape (unfocused, focal length, spher- ical, cylindrical, and complex shapes from phased arrays). There are the safety indicators, mechanical index (MI) and thermal index (TI), heating for which the Pennes bioheat transfer equation15 is well understood, and some advances in defining inertial cavitation dose;16 otherwise, the concept of dose is itself fuzzy.
Compounding the possibilities are the many types of nerves and their varied locations and functions.
Finally, there are many ways in which the nerves can respond. The site of the interaction of the ultrasonic energy and the tissue can be the integrins, the membranes per se, the internal organelles (e.g., phase changes in the cytoskeleton), streaming which changes local ion concentrations, triggering of genetic expressions and apoptosis, demyelination,10 enhanced blood flow to the nerve from indirect heating (as with physiothermy), sonoporation, and other mechanisms. Expressions of the nerves can include an increase or decrease in action potential threshold, inhibition, increased or decreased spontaneous firing rate, and entrainment to the ultrasound pulses.
Conclusions
The sensitivity of the peripheral nervous system to inci- dent ultrasound is remarkable. That sensitivity, which varies among the fibers within a nerve, and the ability to influence a nerve by insonifying just a small portion of it, and to stim- ulate, inhibit, or irreversibly damage a nerve by increasing the intensity or time of exposure, provide a complex set of possible clinical applications, and a rich set of intellectual challenges. AT
References
1 L. R. Gavrilov and E. M. Tsirulnikov, “Focused ultrasound as a tool to input sensory information to humans (review),” Acoust. Phys. 58, 1–21 (2012).
2 G. Thomas, M. H. Shishehbor, E. L. Bravo, and J. V. Nally, “Renal denervation to treat resistant hypertension: Guarded optimism,” Cleveland Clinic J. Med. 79, 501–510 (2012).
3 F. H. Martini and W. C. Ober, Visual Anatomy & Physiology (Benjamin Cummings, New York, 2011).
4 Y. Sinelnikov, S. McClain, Y. Zou, D. Smith, and R. Warnking, “Renal denervation by intravascular ultrasound: Preliminary in vivo study,” in 11th International Symposium on Therapeutic Ultrasound (New York, New York, USA, April 2011), pp. 337- 344.
5 S. Jabbary, “Effect of high intensity focused ultrasound on neu- ral compound action potential: An in vitro study,” M.Sc. Thesis (Paper 590), Ryerson University (2011).
6 J. J. Vaitekunas, “Focused ultrasound for pain reduction,” U.S.
(cranial nerve XII) contains only motor fibers.
The individual fibers are classified by the Erlanger-
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