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.

1.
Andersen
,
O. K.
,
Felsby
,
S.
,
Nicolaisen
,
L.
,
Bjerring
,
P.
,
Jensen
,
T. S.
, and
Arendt-Nielsen
,
L.
(
1996
). “
The effect of ketamine on stimulation of primary and secondary hyperalgesic areas induced by capsaicin—a double-blind, placebo-controlled, human experimental study
,”
Pain
66
,
51
62
.
2.
Arendt-Nielsen
,
L.
,
Brennum
,
J.
,
Sindrup
,
S.
, and
Bak
,
P.
(
1994
). “
Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system
,”
Eur. J. Appl. Physiol.
68
,
266
273
.
3.
Arendt-Nielsen
,
L.
,
Nielsen
,
J.
,
Petersen-Felix
,
S.
,
Schneider
,
T. W.
, and
Zbinden
,
A. M.
(
1996
). “
Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain
,”
Br. J. Anaesth.
77
,
625
631
.
4.
Arendt-Nielsen
,
L.
,
Petersen-Felix
,
S.
,
Fischer
,
M.
,
Bak
,
P.
,
Bjerring
,
P.
, and
Zbinden
,
A. M.
(
1995
). “
The effect of N-methyl-D-aspartate antagonist (ketamine) on single and repeated nociceptive stimuli: A placebo-controlled experimental human study
,”
Anesth. Analg.
81
,
63
68
.
5.
Arendt-Nielsen
,
L.
,
Sonneborg
,
F. A.
, and
Andersen
,
O. K.
(
2000
). “
Facilitation of the withdrawal reflex by repeated transcutaneous electrical stimulation: An experimental study on central integration in humans
,”
Eur. J. Appl. Physiol.
81
,
165
173
.
7.
Caterina
,
M. J.
,
Leffler
,
A.
,
Malmberg
,
A. B.
,
Martin
,
W. J.
,
Trafton
,
J.
,
Petersen-Zeitz
,
K. R.
,
Koltzenburg
,
M.
,
Basbaum
,
A. I.
, and
Julius
,
D.
(
2000
). “
Impaired nociception and pain sensation in mice lacking the capsaicin receptor
,”
Science
288
,
306
313
.
8.
Chapman
,
A. J.
(
1991
). “
Heat transfer
,” in
Encyclopedia of Physics
, edited by
R. G.
Lerner
and
G. L.
Trigg
(
VCH Publishers
,
New York
), pp.
481
484
.
9.
Dalecki
,
D.
,
Child
,
S. Z.
,
Raeman
,
C. H.
, and
Cartensen
,
E. L.
(
1995
). “
Tactile perception of ultrasound
,”
J. Acoust. Soc. Am.
97
,
3165
3170
.
10.
del Valle
,
M. E.
,
Cobo
,
T.
,
Cobo
,
J. L.
, and
Vega
,
J. A.
(
2012
). “
Mechanosensory neurons, cutaneous mechanoreceptors, and putative mechanoproteins
,”
Microsc. Res. Tech.
75
,
1033
1043
.
11.
Dickenson
,
A. H.
, and
Sullivan
,
A. F.
(
1987
). “
Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation
,”
Neuropharmacology
26
,
1235
1238
.
51.
Dickey
,
T. C.
,
Tych
,
R.
,
Kliot
,
M.
,
Loeser
,
J. D.
,
Pederson
,
K.
, and
Mourad
,
P. D.
(
2012
). “
Intense focused ultrasound can reliably induce sensations in human test subjects in a manner correlated with the density of their mechanoreceptors
,”
Ultrasound Med. Biol.
38
,
85
90
.
12.
Duck
,
F. A.
(
1990
).
Physical Properties of Tissue: A Comprehensive Reference Book
(
Academic
,
London
), pp.
1
346
.
13.
Garcia
,
J. D.
,
Gofeld
,
M.
,
Illian
,
P. R.
,
Loeser
,
J. D.
,
Kliot
,
M.
,
McClintic
,
A. M.
,
Ward
,
A.
,
Yao
,
A.
, and
Mourad
,
P. D.
(
2013
). “
Intense focused ultrasound as a potential research tool for the quantification of diurnal inflammatory pain
,”
Ultrasonics
53
,
84
89
.
14.
Gavrilov
,
L. R.
(
1984
). “
Use of focused ultrasound for stimulation of nerve structures
,”
Ultrasonics
22
(
3
),
132
138
.
15.
Gavrilov
,
L. R.
,
Gersuni
,
G. V.
,
Ilyinksy
,
O. B.
,
Tsirulnikov
,
E. M.
, and
Shchekanov
,
E. E.
(
1977a
). “
A study of reception with the use of focused ultrasound. I. Effects on the skin and deep receptor structures in man
,”
Brain Res.
135
,
265
277
.
16.
Gavrilov
,
L. R.
,
Gersuni
,
G. V.
,
Ilyinksy
,
O. B.
,
Tsirulnikov
,
E. M.
, and
Shchekanov
,
E. E.
(
1977b
). “
A study of reception with the use of focused ultrasound. II. Effects on the animal receptor structure
,”
Brain Res.
135
,
279
285
.
17.
Gavrilov
,
L. R.
,
Tsirulnikov
,
E. M.
, and
Davies
,
I. I.
(
1996
). “
Application of focused ultrasound for the stimulation of neural structures
,”
Ultrasound Med. Biol.
22
,
172
192
.
18.
Hargreaves
,
K.
,
Dubner
,
R.
,
Brown
,
F.
,
Flores
,
C.
, and
Joris
,
J.
(
1988
). “
A new sensitive method for measuring thermal nociception in cutaneous hyperalgesia
,”
Pain
32
,
77
88
.
19.
Herrero
,
J. F.
,
Laird
,
J. M.
, and
Lopez-Garcia
,
J. A.
(
2000
). “
Windup of spinal cord neurons and pain sensation: Much ado about something?
Prog. Neurobiol.
61
,
169
203
.
20.
Hill
,
C. R.
,
Rivens
,
I.
,
Vaughan
,
M. G.
, and
ter Harr
,
G. R.
(
1994
). “
Lesion development in focused ultrasound surgery: A general model
,”
Ultrasound Med. Biol.
20
,
259
269
.
21.
Hoque
,
M.
, and
Gandhi
,
O. P.
(
1988
). “
Temperature distributions in the human leg for VLF-VHF exposures at the ANSI-recommended safety levels
,”
IEEE Trans. Biomed. Eng.
35
,
442
449
.
22.
Illing
,
R. O.
,
Kennedy
,
J. E.
,
Wu
,
F.
,
ter Haar
,
G. R.
,
Protheroe
,
A. S.
,
Friend
,
P. J.
,
Gleeson
,
F. V.
,
Cranston
,
D. W.
,
Phillips
,
R. R.
, and
Middleton
,
M. R.
(
2005
). “
The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population
,”
Br. J. Cancer
93
,
890
895
.
23.
Ivanusic
,
J. J.
(
2009
). “
Size, neurochemistry, and segmental distribution of sensory neurons innervating the rat tibia
,”
J. Comp. Neurol.
517
,
276
283
.
24.
Jimenez-Andrade
,
J. M.
,
Mantyh
,
W. G.
,
Bloom
,
A. P.
,
Xu
,
H.
,
Ferng
,
A. S.
,
Dussor
,
G.
,
Vanderah
,
T. W.
, and
Mantyh
,
P. W.
(
2010
). “
A phenotypically restricted set of primary afferent nerve fibers innervate the bone versus skin: Therapeutic opportunity for treating skeletal pain
,”
Bone
46
,
306
313
.
25.
Katsarava
,
Z.
,
Ayzenberg
,
I.
,
Sack
,
F.
,
Limmroth
,
V.
,
Dinere
,
H. C.
, and
Kaube
,
H.
(
2006
). “
A novel method of eliciting pain-related potentials by transcutaneous electrical stimulation
,”
Headache
46
,
1511
1517
.
26.
Klinger
,
H. C.
,
Susani
,
M.
,
Seip
,
R.
,
Mauermann
,
J.
,
Sanghvi
,
N.
, and
Marberger
,
M. J.
(
2008
). “
A novel approach to energy ablative therapy of small renal tumours: Laparoscopic high-intensity focused ultrasound
,”
Eur. Urol.
53
,
810
816
.
27.
Mach
,
D. B.
,
Rogers
,
S. D.
,
Sabino
,
M. C.
,
Luger
,
N. M.
,
Schewi
,
M. J.
,
Pomonis
,
J. D.
,
Keyser
,
C. P.
,
Clohisy
,
D. R.
,
Adams
,
D. J.
,
O'leary
,
P.
, and
Mantyh
,
P. W.
(
2002
). “
Origins of skeletal pain: Sensory and sympathetic innvervation of the mouse femur
,”
Neuroscience
113
(
1
),
155
166
.
28.
Mancall
,
E. L.
, and
Brock
D. G.
(
2011
).
Gray's Clinical Neuroanatomy
(
Elsevier
,
Philadelphia
), Sec. I, p.
29
.
29.
McClintic
,
A. M.
,
Dickey
,
T. C.
,
Gofeld
,
M.
,
Kliot
,
M.
,
Loeser
,
J. D.
,
Richebe
,
P.
, and
Mourad
,
P.
(
2013
). “
Intense focused ultrasound preferentially stimulates subcutaneous and focal neuropathic tissue: Preliminary results
,”
Pain Med.
14
,
84
92
.
30.
Mourad
,
P. D.
(
2012
). “
Therapeutic ultrasound, with an emphasis on applications to the brain
,” in
Ultrasonic Transducers–Materials Design and Applications
, edited by
K.
Nakamura
and
S.
Ueha
(
Woodhead
,
Cambridge, UK
), pp.
454
571
.
31.
Myers
,
M. R.
(
2006
). “
Tissue deformation induced by radiation force from Gaussian transducers
,”
J. Acoust. Soc. Am.
119
,
3147
3152
.
32.
Nagakura
,
Y.
,
Okada
,
M.
,
Khoara
,
A.
,
Kiso
,
T.
,
Toya
,
T.
,
Iwai
,
A.
,
Wanibuchi
,
F.
, and
Yamaguchi
,
T.
(
2003
). “
Allodynia and hyperalgesia in adjuvant-induced arthritic rats: Time course of progression and efficacy of analgesics
,”
J. Pharmacol. Exp. Ther.
306
,
490
497
.
33.
Nie
,
H.
,
Arendt-Nielsen
,
L.
,
Andersen
,
H.
, and
Graven-Nielsen
,
T.
(
2005
). “
Temporal summation of pain evoked by mechanical stimulation in deep and superficial tissue
,”
J. Pain
6
,
348
355
.
34.
Nightingale
,
K. R.
,
Nightingale
,
R. W.
,
Palmeri
,
M. L.
, and
Trahey
,
G. E.
(
2000
). “
A finite element model of remote palpation of breast lesions using radiation force: Factors affecting tissue displacement
,”
Ultrason. Imaging
22
,
35
54
.
35.
Nightingale
,
K. R.
,
Palmeri
,
M. L.
,
Nightingale
,
R. W.
, and
Trahey
,
G. E.
(
2001
). “
On the feasibility of remote palpation using acoustic radiation force
,”
J. Acoust. Soc. Am.
110
,
625
634
.
36.
Nightingale
,
K. R.
,
Soo
,
M. S.
,
Nightingale
,
R. W.
, and
Trahey
,
G. E.
(
2002
). “
Acoustic radiation force impulse imaging: In vivo demonstration of clinical feasibility
,”
Ultrasound Med. Biol.
28
,
227
235
.
37.
Park
,
M. Y.
,
Jung
,
S. E.
,
Cho
,
S. H.
,
Piao
,
X. H.
,
Hahn
,
S. T.
,
Han
,
J. Y.
, and
Woo
,
I. S.
(
2009
). “
Preliminary experience using high intensity focused ultrasound for treating liver metastasis from colon and stomach cancer
,”
Int. J. Hyperthermia
25
,
180
188
.
38.
Parker
,
K. J.
(
1985
). “
Effects of heat conduction and sample size on ultrasonic absorption measurements
,”
J. Acoust. Soc. Am.
77
,
719
725
.
39.
Poliachik
,
S. L.
,
Chandler
,
W. L.
,
Mourad
,
P. D.
,
Ollos
,
R. J.
, and
Crum
,
L. A.
(
2001
). “
Activation aggregation and adhesion of platelets exposed to high intensity focused ultrasound
,”
Ultrasound Med. Biol.
27
,
1567
1576
.
40.
Price
,
D. D.
,
Mao
,
J.
,
Frenk
,
H.
, and
Mayer
,
D. J.
(
1994
). “
The N-methyl-D-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man
,”
Pain
59
,
165
174
.
43.
Staud
,
R.
,
Cannon
,
R. C.
,
Mauderli
,
A. P.
,
Robinson
,
M. E.
,
Price
,
D. D.
, and
Vierck
,
C. J.
(
2003
). “
Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome
,”
Pain
102
,
87
95
.
46.
ter Haar
,
G. R.
, and
Coussios
,
C.
(
2007
). “
High intensity focused ultrasound: Physical principles and devices
,”
Int. J. Hyperthermia
23
,
89
104
.
47.
Tych
,
R. E.
,
Gofeld
,
M.
,
Jarvik
,
J. G.
,
Kliot
,
M.
,
Loeser
,
J. D.
,
McClintic
,
A. M.
,
Ollos
,
R. J.
,
Pederson
,
K. D.
,
Sparks
,
R. E.
,
Terman
,
G. W.
, and
Mourad
,
P. D.
(
2013
). “
Neuropathic tissue responds preferentially to stimulation by intense focused ultrasound
,”
Ultrasound Med. Biol.
39
(
1
),
111
116
.
49.
Woolf
,
C. J.
(
2011
). “
Central sensitization: Implications for the diagnosis and treatment of pain
,”
Pain
152
(
3
), Suppl.,
S2
15
.
50.
Wright
,
A.
,
Graven-Nielsen
,
T.
,
Davies
,
I. I.
, and
Arendt-Nielsen
,
L.
(
2002
). “
Temporal summation of pain from skin, muscle and join following nociceptive ultrasonic stimulation in humans
,”
Exp. Brain Res.
144
,
475
482
.
You do not currently have access to this content.