A study of reception with the use of focused ultrasound. II. Effects on the animal receptor structures.
ABSTRACT The possibility of stimulation of receptor structures with focused ultrasound (focused beam of high frequency mechanical waves) was investigated. Stimulation of single Pacinian corpuscle isolated from cat's mesentery resulted in receptor and action potentials. Stimulation of frog's ear labyrinth resulted in evoked potentials recorded from midbrain auditory area, their characteristics being much the same as those for responses to adequate sound stimuli. It is concluded that focused ultrasound is an advantageous agent for stimulation of various mechanoreceptors both isolated and, especially, located deep in the body. Some problems related to sensory specificity are discussed.
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ABSTRACT: We tested the hypothesis that neuropathic tissue is more sensitive to stimulation by intense focused ultrasound (iFU) than control tissue. We created a diffusely neuropathic paw in rats via partial ligation of the sciatic nerve, whose sensitivity to iFU stimulation we compared with sham-surgery and normal control paws. We then applied increasing amounts of iFU (individual 0.2 s pulses at 1.15 MHz) to the rats' paws, assaying for their reliable withdrawal from that stimulation. Neuropathic rats preferentially withdrew their injured paw from iFU at smaller values of iFU intensity (84.2 W/cm(2) ± 25.5) than did sham surgery (97.7 W/cm(2) ± 11.9) and normal control (> 223 W/cm(2)) animals, with greater sensitivity and specificity (85% for neuropathic rats and 50% each of sham surgery and normal control rats). These results directly support our hypothesis as well as Gavrilov's idea that doctors may some day use iFU stimulation to diagnose patients with neuropathies.Ultrasound in medicine & biology 01/2013; 39(1):111-6. · 2.46 Impact Factor
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ABSTRACT: OBJECTIVE.: Potential peripheral sources of pain from subcutaneous tissue can require invasive evocative tests for their localization and assessment. Here, we describe studies whose ultimate goal is development of a noninvasive evocative test for subcutaneous, painful tissue. DESIGN.: We used a rat model of a focal and subcutaneous neuroma to test the hypothesis that intense focused ultrasound can differentiate focal and subcutaneous neuropathic tissue from control tissue. To do so, we first applied intense focused ultrasound (2 MHz, with individual pulses of 0.1 second in duration) to the rat's neuroma while the rat was under light anesthesia. We started with low values of intensity, which we increased until intense focused ultrasound stimulation caused the rat to reliably flick its paw. We then applied that same intense focused ultrasound protocol to control tissue away from the neuroma and assayed for the rat's response to that stimulation. RESULTS.: Intense focused ultrasound of sufficient strength (I(SATA) of 600 +/- 160 W/cm(2) ) applied to the neuroma caused the rat to flick its paw, while the same intense focused ultrasound applied millimeters to a centimeter away failed to induce a paw flick. CONCLUSION.: Successful stimulation of the neuroma by intense focused ultrasound required colocalization of the neuroma and intense focused ultrasound supporting our hypothesis.Pain Medicine 11/2012; · 2.46 Impact Factor
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ABSTRACT: Previous studies have observed that individual pulses of intense focused ultrasound (iFU) applied to inflamed and normal tissue can generate sensations, where inflamed tissue responds at a lower intensity than normal tissue. It was hypothesized that successively applied iFU pulses will generate sensation in inflamed tissue at a lower intensity and dose than application of a single iFU pulse. This hypothesis was tested using an animal model of chronic inflammatory pain, created by injecting an irritant into the rat hind paw. Ultrasound pulses were applied in rapid succession or individually to rats' rear paws beginning at low peak intensities and progressing to higher peak intensities, until the rats withdrew their paws immediately after iFU application. Focused ultrasound protocols consisting of successively and rapidly applied pulses elicited inflamed paw withdrawal at lower intensity and estimated tissue displacement values than single pulse protocols. However, both successively applied pulses and single pulses produced comparable threshold acoustic dose values and estimates of temperature increases. This raises the possibility that temperature increase contributed to paw withdrawal after rapid iFU stimulation. While iFU-induction of temporal summation may also play a role, electrophysiological studies are necessary to tease out these potential contributors to iFU stimulation.The Journal of the Acoustical Society of America 08/2013; 134(2):1521-9. · 1.65 Impact Factor
Brain Research, 135 (1977) 279-285
Elsevier/North-Holland Biomedical Press
A STUDY OF RECEPTION WITH THE USE OF FOCUSED ULTRASOUND.
11. EFFECTS ON THE ANIMAL RECEPTOR STRUCTURES
LEONID R. GAVRILOV, GRIGORYI V. GERSUNI, OLEG B. ILYINSKY, EFIM M. TSIRUL-
NIKOV and EUGENYI E. SHCHEKANOV
Sechenov Institute of Evol~dtionary Physiologj~ and Biochemistry, Acad. Sci. USSR, Leningrad, (O.B.I.)
Pavlov Institute of Physiology, Acad. Sci. USSR, Lenitigrad and (L.R.C.) Acoustical Institute, Acad.
Sci. USSR, Moscow (U.S.S.R.)
(Accepted February loth, 1977)
The possibility of stimulation of receptor structures with focused ultrasound
(focused beam of high frequency mechanical waves) was investigated. Stimulation
of single Pacinian corpuscle isolated from cat's mesentery resulted in receptor and
action potentials. Stimulation of frog's ear labyrinth resulted in evoked potentials
recorded from midbrain auditory area, their characteristics being much the same
as those for responses to adequate sound stimuli. It is concluded that focused ultra-
sound is an advantageous agent for stimulation of various mechanoreceptors both
isolated and, especially, located deep in the body. Some problems related to sensory
specificity are discussed.
In the preceding paper4 a variety of sensations produced by stimulation of the
human arm with focused ultrasound were described. However, the question remained
as to whether the observed effects are due to excitation of receptors or to direct
stimulation of afferent nerve fibres. The aim of the present work was to investigate
the possibility of stimulation of receptors with focused ultrasound.
The main effective factor in ultrasonic stimuli is a mechanical one2, therefore
it is likely that the best approach appeared to be work on mechanoreceptors. The
Pacinian corpuscle from cat's mesentery, whose reactions to mechanical stimulation
are described in great detail in the literaturels, was judged to be particularly suitable
as one kind of experimental material.
Energy can be concentrated in a given point in deep tissues with the aid of
focused ultrasound. For this work study of the mechanoreceptor structures of laby-
rinth were chosen as particularly valuable. These experiments were carried out on
the frog (Rana temporaria) since ultrasonic energy can be rather easily delivered to
the labyrinth of this animal.
Some of the results of this study have previously been partly published395.
Ultrasound stimulation was done by the use of an ultrasonic generator and
focusing irradiator, the resonant frequency 0.48 MHz (for details, see ref. 4). The
focal region of the irradiator (34 mm long and 6.4 mm across) being larger than both
the Pacinian corpuscle and the labyrinth, the focus easily covered both test objects.
Ultrasonic stimuli were rectangular bursts with duration from 0.1 msec to hundreds
Effects on the Pacinian corpuscle
An isolated receptor along with the nerve fiber attached was placed in the vase-
line oil, over the ultrasonic irradiator, in the center of the focal region. Cotton threads
suspending the receptor were moistened with physiological solution and served as
Effects on the frog's labyrinth
Excitation of receptor structures of the labyrinth was tested by detecting the
overall electrical responses from the midbrain auditory area, torus semicircularis, a
part of the frog's auditory system which has received the most study. Responses to
ultrasound were compared with those to sonic stimuli which were tones of optimal
frequency (i.e. the frequency associated with lowest response thresholds).
An animal was immobilized with diplacin (0.4-0.5 ml of a 0.5 % solution), the
left labyrinth being destroyed. Thereupon the animal was fixed over the irradiator
so as to project the centre of the focal region into the right labyrinth. Potentials were
recorded with tungsten electrodes (tip diameter 10 pm) from the contralateral, left
torus. Water was the coupling medium between the irradiator and the object.
The potentials were amplified by conventional technique and were photo-
graphed from oscilloscope (10-20 reactions superimposed).
Ultrasonic irradiation of Pacinian corpuscles, with appropriate parameters of
stimulation, produced receptor and peak potentials (Fig. 1) of the usual type. The
amplitude of the receptor potentials gradually increased with intensity of ultrasound
stimuli. Observed were both depolarizing and hyperpolarizing responses, since the
Fig. 1. Responses of isolated Pacinian corpuscles to the focused ultrasound. Top tracing: the oscillo-
gram of responses (action and receptor potentials); bottom tracing: the stimulus. Two different
receptors. At the left: response to a single stimulus 1 msec duration; to the right: responses to double
stimuli, duration, 0.1 msec; interval, 3 msec. Arrows show the receptor potentials. Calibration:
50 pV, 2.5 msec.
rotation of the receptor around its axis could result in the change from one type of
response to the other.
When the receptor potential reached a critical level an action potential was
fired in an all-or-none manner. Action of double stimuli resulted in absolute and
relative refractory periods. Stimulation with long (several msec and longer) stimuli
gave both on- and off-responses. The firing level for action potentials varied between
0.4 and 2.5 W/sq.cm.
The frog's labyrinth
Ultrasound stimulation of the labyrinth structures produced an electrical respon-
Fig. 2. Evoked responses in the midbrain auditory area of the frog. I: stimulation of the labyrinth
with the focused ultrasound (stimulus duration, 1 msec); 11: responses to sonic stimuli of optimal
frequency (100-1600 Hz), 20 msec duration. Stimulus intensity: 20 dB above threshold. Top tracing:
the oscillogram of responses; bottom tracing: the stimulus. Calibration: 100 pV, 25 msec. 1-3: the
se in the midbrain area of the type shown in Fig. 2. In shape, amplitude and latency
the responses were similar to those evoked by sonic stimuli. After destruction of
labyrinth neither ultrasound nor sound were able to cause detectable responses.
Thresholds for detectable responses, with stimulus duration of 1 msec, were in
the range from 0.1 to 1.0 W/sq.cm, decreasing, with stimulus duration of 100 msec,
to 0.01-0.1 W/sq.cm.
Comparative study of a number of characteristics of the responses to ultrasonic
and sonic stimulation was undertaken to be certain that the responses to ultrasound
are due to stimulation of receptor structures of the auditory organ.
Responses to suprathreshold (estimated in dB with respect to the threshold)
ultrasonic and sonic stimuli of equal magnitude were found to be of about the same
size; the latency associated with ultrasound was, in the majority of experiments,
somewhat shorter than the latency of responses to sonic stimuli.
Switching off of a long stimulus (100 msec and longer) resulted in some experi-
ments in an off-response similar in shape and other characteristics with responses
to onset of the stimulus. The off-responses were observed with both ultrasonic and
The full restoration time of the amplitude of responses to a test ultrasonic or
sonic stimulus after, respectively, ultrasonic or sonic conditioning stimulus was much
the same (250-300 msec) for both types of stimulation.
When in a double pulse experiment one of the stimuli was ultrasonic and the
other sonic and vice versa, the amplitude of a response to the test stimulus depended
on a time interval between stimulations (Fig. 3). The restoration of the amplitude of
responses to the test stimulus was in both cases complete in 200-250 msec.
With simultaneous presentation of ultrasonic and sonic near-threshold stimuli
the response interaction was as in the case of central facilitation, i.e. the
amplitude of a response to simultaneous presentation of stimuli was larger than the
sum of responses obtained at separate presentation. With strong suprathreshold
stimuli the interaction followed the pattern seen with occlusion, i.e. the amplitude
Fig. 3. Interaction between responses to sonic and ultrasonic stimuli at consecutive presentation.
Bottom tracing, the oscillogram of potentials; top tracing, the stimulus. a: the first stimulus -
ultrasound; the second -
sound. b: the first stimulus -
to a single test stimulus; 2-5: double stimuli. Time intervals between the stimuli: 2, 50msec; 3, 100
msec; 4, 200 msec; 5, 300 msec. Calibration: 100 pV, 50 msec.
sound; the second -
ultrasound. 1 : response
Fig. 4. Interaction between responses to sonic and ultrasonic stimuli at simultaneous presentation.
Top tracing: the oscillogram of potentials, bottom tracing: the stimulus. 1 : responses to ultrasound;
2: responses to sound; 3: responses to simultaneous presentation of sonic and ultrasomic stimuli.
To the left of the oscjllograms is shown stimulus intensity above threshold in dB. Calibration: 100 pV,
of a response to simultaneous presentation was less than the sum of responses to
separate presentation of ultrasonic and sonic stimuli (Fig. 4).
The fact that the receptor and peak potential appear in response to the action
of the focused ultrasound on the Pacinian corpuscle indicates that this agent can be
used for stimulation of mechanoreceptors. This fact also explains the capability of
the focused ultrasound to evoke the tactile sensations.
Thresholds for the Pacinian corpusles excitation varied from 0.4 to 2.5 W/sq.cm,
which corresponded to displacement amplitudes from 0.02 to 0.06 pm. These threshold
displacements are in good agreement with values available in the literature, according
to which the threshold displacement for a mechanically induced impulse activity
in the Pacinian corpuscle comprises parts per hundred ,um7J2.
Thresholds for the tactile sensations in the finger skin of the hand evoked with
focused ultrasound of the same frequency (0.48 MHz) are within 8-10 W/sq.cm
(displacement amplitudes 0.1-0.12 pm). Comparison of these values with thresh-
olds for excitation of Pacinian corpuscles shows that these receptors can well be
responsible for threshold tactile sensations during ultrasonic stimulation. These facts
are in line with the current concepts concerning the part played by Pacinian corpuscles
in threshold tactile sensationsl0Jl.
The frog's labyrinth
The fact that the destruction of the labyrinth leads to the disappearance of
responses evoked by ultrasonic stimuli indicates that there is a connection between
these responses and the stimulation of the labyrinth structures with focused ultra-
sound. Similarity in shape and other characteristics of responses to ultrasound and
sound suggests that it is the activity of the auditory sensory structures that produces
these responses. Taking into account the results obtained on Pacinian corpuscles,
i.e. that ultrasonic stimuli are capable of stimulating mechanoreceptors, it may be
assumed that the sensory structures in question are the auditory mechanoreceptors.
Thresholds for response detection at stimulation of the labyrinth by focused
ultrasound were 0.01-0.1 W/sq. cm, which gives displacements of 40-120A. (No
allowance was made for attenuation of ultrasound in the tissues on the way to the
labyrinth receptors which is likely to have given overrated displacement values.) The
threshold displacement associated with sonic stimulation of frog's auditory receptors
is unknown. In the last few years, however, a number of works have been published
where the amplitude of vibration of the basilar membrane in the mammalian cochlea
in response to sonic stimuli has been measured (for review see ref. 15) in which the
displacement amplitude varied from tens to hundreds A. This value is of the same
order of magnitude as that for the threshold displacements associated with ultrasonic
stimulation of frog's labyrinth.
From the results presented above it may be concluded that focused ultrasound
can be used for stin~ulation of mechanoreceptors both isolated from organism and
deep in the organism, either the tissue ones or those in specialized structures, that is
the sense organs.
It has previously been shown2 that the displacement of the medium in the focal
region is the main acting factor of ultrasound stimuli. This conclusion also holds -
true for the Pacinian corpuscle and receptors in the ear labyrinth since the threshold
ultrasonic displacements involved are of the same order of magnitude as those pro-
ducing the response of the same structures under natural conditions.
Thus, for all receptor structures studied, mechanical displacement stands out
as a factor of decided importance. The displacement to give the threshold response
varies with different receptors. The appearance of a particular response, however,
is due not only to displacement itself but also to its accompanying conditions: the
temperature of surrounding medium, the location of a particular receptor structure,
etc. For instance, stimulation of one and the same cutaneous spot resulted in the
feeling of either cold or warmth depending on the surrounding temperature. It is
reasonable to suggest that one and the same receptor structure might be involved
in producing both warmth and cold sensations*. This, in turn, leads to the suggestion
that the character of an elementary sensation (warmth, cold, pain, etc.) is determined
by the specificity of a receptive system as a whole rather than by the specificity of only
the receptor structures, conduction paths or by central analysis, as was formerly
1 Bing, H. J., On the physiology of the cutaneous sensory modalities, Actaphysiol. scand., 46 (1959)
2 Gavrilov, L. R., Gersuni, G. V., Ilyinsky, 0. B., Popova, L. A., Sirotyuk, M. G. andTsirulnikov
E. M., Stimulation of human peripheral neural structures by focused ultrasound, Sov. Phys.
Acoust, 19 (1974) 332-334.
3 Gavrilov, L. R., Gersuni, G. V., Ilyinsky, 0. B., Sirotyuk, M. G., Tsirulnikov, E. M. and Shche-
kanov, E. E., Action of focused ultrasound on skin and deep nerve structures of human arm.
In Symp. Tissue Reception, Leningrad, 1974, pp. 33-53 (in Russian).
4 Gavrilov, L. R., Gersuni, G. V., Ilyinsky, 0. B., Tsirulnikov, E. M. and Shchekanov, E. E., A
study of reception with the use of focused ultrasound. I. Effects on the skin and deep receptor
structures in man, Brain Research, 135 (1977) 265-277.
5 Gavrilov, L. R., Tsirulnikov, E. M. and Shchekanov, E. E., Reactionsoffrog's midbrain auditory
centers to the labyrinth stimulation with focused ultrasou~id, Sechenov Physiol. J. U.S.S.R, 61
(1975) 213-221 (in Russian).
6 Von Frey, M., Beitrage zur Sinnesphysiologie der Haut, Ber. Verhand. Gesellsch. Wissensch.
Math.-phys. Leipzig, 47 (1895) 166-184.
7 Gray, J. A. B., Mechanical into electrical energy in certain mechanoreceptors. In Progr. Biophys.
Biophys. Chem., Pergamon Press, London, 9, 1959, pp. 285-324.
8 Hensel, H., Cutaneous thermoreceptors. In A. Iggo (Ed.), Handbook of Sensory Physiology, Vol. 2,
Somatosensory System, Springer-Verlag, Berlin, 1973, pp. 79-1 10.
9 Hensel, H., Thermoreceptors, Ann. Rev. Physiol., 36 (1974) 233-249.
10 Lindblom, U., Touch perception threshold in human glabrous skin in terms of displacement
amplitude on stimulation with single mechanical pulses, Brain Research, 82 (1974) 205-210.
11 Lindblom, U. and Lund, J., The discharge from vibration-sensitive receptors in the monkey foot,
Exp. Neurol., 15 (1966) 401-417.
12 Loewenstein, W. R., Facets of a transducer process, Cold Spr. Harb. Symp. qnant. Biol., 30 (1965)
13 Loewenstein, W. R., Mechano-electric transduction in the Pacinian corpuscle. Initiation of sen-
sory impulses in mechanoreceptors. In W. R. Lowenstein (Ed.), Handbook of Sensory Physiology,
Vol. I, Principles of Receptor Physiology, Springer-Verlag, Berlin, 1971, pp. 269-290.
14 Nafe, J. P., Neural corlelates of sensation. In D. R. Kenshalo (Ed.), The Skin Senses, Springfield,
Ill., U.S.A., 1968, pp. 5-14.
15 Wilson, J. P. and Johnstone, J. R., Basilar membrane and middle-ear vibration in guinea-pig
measured by capacitive probe, J. acoust. Soc. Amer., 57 (1975), 705-723.