Dysregulation of the descending pain system in temporomandibular disorders revealed by low-frequency sensory transcutaneous electrical nerve stimulation: a pupillometric study

Annalisa Monaco, Ruggero Cattaneo, Luca Mesin, Eleonora Ortu, Mario Giannoni, Davide Pietropaoli, Annalisa Monaco, Ruggero Cattaneo, Luca Mesin, Eleonora Ortu, Mario Giannoni, Davide Pietropaoli

Abstract

Using computerized pupillometry, our previous research established that the autonomic nervous system (ANS) is dysregulated in patients suffering from temporomandibular disorders (TMDs), suggesting a potential role for ANS dysfunction in pain modulation and the etiology of TMD. However, pain modulation hypotheses for TMD are still lacking. The periaqueductal gray (PAG) is involved in the descending modulation of defensive behavior and pain through μ, κ, and δ opioid receptors. Transcutaneous electrical nerve stimulation (TENS) has been extensively used for pain relief, as low-frequency stimulation can activate µ receptors. Our aim was to use pupillometry to evaluate the effect of low-frequency TENS stimulation of μ receptors on opioid descending pathways in TMD patients. In accordance with the Research Diagnostic Criteria for TMD, 18 females with myogenous TMD and 18 matched-controls were enrolled. All subjects underwent subsequent pupillometric evaluations under dark and light conditions before, soon after (end of stimulation) and long after (recovery period) sensorial TENS. The overall statistics derived from the darkness condition revealed no significant differences in pupil size between cases and controls; indeed, TENS stimulation significantly reduced pupil size in both groups. Controls, but not TMD patients, displayed significant differences in pupil size before compared with after TENS. Under light conditions, TMD patients presented a smaller pupil size compared with controls; the pupil size was reduced only in the controls. Pupil size differences were found before and during TENS and before and after TENS in the controls only. Pupillometry revealed that stimulating the descending opioid pathway with low-frequency sensory TENS of the fifth and seventh pairs of cranial nerves affects the peripheral target. The TMD patients exhibited a different pattern of response to TENS stimulation compared with the controls, suggesting that impaired modulation of the descending pain system may be involved in TMD.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Diagram of the Experimental Protocol.
Fig 1. Diagram of the Experimental Protocol.
Before beginning the experimental session, each enrolled subject was prepared with TENS electrodes and connected to a turned-off TENS device. Subsequently, they underwent three experimental phases: Pre TENS stimulation (green); During TENS stimulation (red); and Post TENS stimulation (blue). Pupillometer application and its removal occurred after the acclimation period and at the end of the experimental session, respectively (green). Based on the literature, central nervous system stimulation was obtained by sensory stimulation of cranial nerves V and VII with low-frequency TENS for 21 minutes (red) [–32]. To avoid operator interference, the pupillometer, electrodes and TENS device were removed only at the end of the experimental session.
Fig 2. The Edinger-Westphal Nucleus (EWN) Exerts…
Fig 2. The Edinger-Westphal Nucleus (EWN) Exerts a Tonic Activity on the Pupil Sphincter.
Larson [55] proposed that in anesthetized patients, opioid action can be exerted, blocking the efferents of inhibitory neurons to the EWN. Translating this hypothesis to non-anesthetized patients, it could be suggested that opioids reduce the inhibition of interneurons, increasing the effects of excitatory afferents of the EWN. The final effect was opioid miosis. In the figure, excitatory components of the model are shown in red, while inhibitory components are shown in black.
Fig 3. Mechanism of Endogenous Opioid Action…
Fig 3. Mechanism of Endogenous Opioid Action Induced by LF TENS in Non-Anesthetized Subjects with Pupil Miosis.
The locus coeruleus-noradrenergic system (LC) has been suggested to be a key structure in arousal, and its firing frequency tone has been correlated with wakefulness, vigilance, and sensory and pain perception. The size of the pupil correlates with the activity of LC, and light increases the frequency of firing. The action of the LC excites the excitation pathway that directly induces pupil constriction and excites inhibitory interneurons in the inhibitory pathway, exciting the inhibitor of the inhibitor; the net result is a reduction of inhibition and, indirectly, an agonist effect of the excitatory pathway of pupil constriction. Opioids act on the inhibitory pathway, and TENS has been suggested to be activated via the ventral lateral PAG and the opioid pathway. According to Valentino [74] and Curtis [75], opioids reduce the activation of the LC, and corticotropin-releasing hormone (CRH) increases the firing rate. It is possible that low-frequency sensory TENS inhibits LC inhibitory interneurons, increasing the tone of the pupillary constrictor of the LC. TMD patients could suffer from an impairment of the inhibitory pathway stemming from the ventral lateral PAG. Consequently, pupil constriction in response to light is not counterbalanced by inhibition (smaller pupil size under yellow-green light), and low-frequency sensory TENS is unable to further induce pupil constriction. Red, excitation pathway; black, inhibitory pathway.

References

    1. Maixner W, Fillingim R, Booker D, Sigurdsson A. Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain. Pain. 1995;63: 341–351.
    1. Maixner W, Fillingim R, Sigurdsson A, Kincaid S, Silva S. Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain: evidence for altered temporal summation of pain. Pain. 1998;76: 71–81.
    1. Svensson P, List T, Hector G. Analysis of stimulus-evoked pain in patients with myofascial temporomandibular pain disorders. Pain. 2001;92: 399–409.
    1. Eliav E, Teich S, Nitzan D, El Raziq DA, Nahlieli O, Tal M, et al. Facial arthralgia and myalgia: can they be differentiated by trigeminal sensory assessment? Pain. 2003;104: 481–490.
    1. Ayesh EE, Jensen TS, Svensson P. Somatosensory function following painful repetitive electrical stimulation of the human temporomandibular joint and skin. Exp Brain Res. 2007;179: 415–425.
    1. Schmidt JE, Carlson CR. A controlled comparison of emotional reactivity and physiological response in masticatory muscle pain patients. J Orofac Pain. 2009;23: 230–242.
    1. Nebel MB, Folger S, Tommerdahl M, Hollins M, McGlone F, Essick G. Temporomandibular disorder modifies cortical response to tactile stimulation. J Pain. 2010;11: 1083–1094. 10.1016/j.jpain.2010.02.021
    1. Weissman-Fogel I, Moayedi M, Tenenbaum HC, Goldberg MB, Freeman BV, Davis KD. Abnormal cortical activity in patients with temporomandibular disorder evoked by cognitive and emotional tasks. Pain. 2011;152: 384–396. 10.1016/j.pain.2010.10.046
    1. Korszun A, Young EA, Singer K, Carlson NE, Brown MB, Crofford L. Basal circadian cortisol secretion in women with temporomandibular disorders. J Dent Res. 2002;81: 279–283.
    1. Nilsson AM, Dahlström L. Perceived symptoms of psychological distress and salivary cortisol levels in young women with muscular or disk-related temporomandibular disorders. Acta Odontol Scand. 2010;68: 284–288. 10.3109/00016357.2010.494620
    1. Maixner W, Greenspan JD, Dubner R, Bair E, Mulkey F, Miller V, et al. Potential autonomic risk factors for chronic TMD: descriptive data and empirically identified domains from OPPERA case-contrl study. J Pain. 2011: 12(11 Suppl): T75–T91. 10.1016/j.jpain.2011.09.002
    1. Light KC, Bragdon EE, Grewen KM, Brownley KA, Girdler SS, Maixner W. Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. J Pain. 2009;10: 542–552. 10.1016/j.jpain.2008.12.006
    1. Eze-Nliam CM, Quartana PJ, Quain AM, Smith MT. Nocturnal heart rate variability is lower in temporomandibular disorder patients than in healthy, pain-free individuals. J Orofac Pain. 2011;25: 232–239.
    1. Chen H, Nackley A, Miller V, Diatchenko L, Maixner W. Multisystem dysregulation in painful temporomandibular disorders. J Pain. 2013;14: 983–996. 10.1016/j.jpain.2013.03.011
    1. Lumb BM. Inescapable and escapable pain is represented in distinct hypothalamic-midbrain circuits: specific roles for Adelta- and C-nociceptors. Exp Physiol. 2002;87: 281–286.
    1. Ossipov MH. The perception and endogenous modulation of pain. Scientifica. 2012;2012: 561761 10.6064/2012/561761
    1. Kobayashi S. Organization of neural systems for aversive information processing: pain, error, and punishment. Front Neurosci. 2012;6: 136 10.3389/fnins.2012.00136
    1. Bandler R, Keay KA, Floyd N, Price J. Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull. 2000;53: 95–104.
    1. Keay KA, Clement CI, Depaulis A, Bandler R. Different representations of inescapable noxious stimuli in the periaqueductal gray and upper cervical spinal cord of freely moving rats. Neurosci Lett. 2001;313: 17–20.
    1. Heinricher MM, Tavares I, Leith JL, Lumb BM. Descending control of nociception: specificity, recruitment and plasticity. Brain Res Rev. 2009;60: 214–225. 10.1016/j.brainresrev.2008.12.009
    1. Bruehl S, Burns JW, Chung OY, Chont M. Pain-related effects of trait anger expression: neural substrates and the role of endogenous opioid mechanisms. Neurosci Biobehav Rev. 2009;33: 475–491. 10.1016/j.neubiorev.2008.12.003
    1. Graeff FG. New perspective on the pathophysiology of panic: merging serotonin and opioids in the periaqueductal gray. Braz J Med Biol Res. 2012;45: 366–375.
    1. Staud R. Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions. Expert Rev Neurother. 2012;12: 577–585. 10.1586/ern.12.41
    1. Linnman C, Moulton EA, Barmettler G, Becerra L, Borsook D. Neuroimaging of the periaqueductal gray: state of the field. Neuroimage. 2012;60: 505–522. 10.1016/j.neuroimage.2011.11.095
    1. DeSantana JM, Walsh DM, Vance C, Rakel BA, Sluka KA. Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain. Curr Rheumatol Rep. 2008;10: 492–499.
    1. Johnson M, Martinson M. Efficacy of electrical nerve stimulation for chronic musculoskeletal pain: a meta-analysis of randomized controlled trials. Pain. 2007;130: 157–165.
    1. Sluka KA, Walsh D. Transcutaneous electrical nerve stimulation: basic science mechanisms and clinical effectiveness. J Pain. 2003. April 4: 109–121.
    1. Ainsworth L, Budelier K, Clinesmith M, Fiedler A, Landstrom R, Leeper BJ, et al. Transcutaneous electrical nerve stimulation (TENS) reduces chronic hyperalgesia induced by muscle inflammation. Pain. 2006;120: 182–187.
    1. DeSantana JM, Da Silva LF, De Resende MA, Sluka KA. Transcutaneous electrical nerve stimulation at both high and low frequencies activates ventrolateral periaqueductal grey to decrease mechanical hyperalgesia in arthritic rats. Neuroscience. 2009;163: 1233–1241. 10.1016/j.neuroscience.2009.06.056
    1. Sluka KA, Deacon M, Stibal A, Strissel S, Terpstra A. Spinal blockade of opioid receptors prevents the analgesia produced by TENS in arthritic rats. J Pharmacol Exp Ther. 1999;289: 840–846.
    1. Kalra A, Urban MO, Sluka KA. Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS). J Pharmacol Exp Ther. 2001;298: 257–263.
    1. Radhakrishnan R, King EW, Dickman JK, Herold CA, Johnston NF, Spurgin ML, et al. Spinal 5-HT(2) and 5-HT(3) receptors mediate low, but not high, frequency TENS-induced antihyperalgesia in rats. Pain. 2003;105: 205–213.
    1. Jankelson B. Electronic control of muscle contraction—a new clinical era in occlusion and prosthodontics. Sci Educ Bull. 1969;2: 29–31.
    1. Katch EM. Application of transcutaneous electrical nerve stimulation in dentistry. Anesth Prog. 1986;33: 156–160.
    1. Cooper BC. International College of Cranio-Mandibular Orthopedics (ICCMO). Temporomandibular disorders: A position paper of the International College of Cranio-Mandibular Orthopedics (ICCMO). Cranio. 2011;29: 237–244.
    1. Chipaila N, Sgolastra F, Spadaro A, Pietropaoli D, Masci C, Cattaneo R, et al. The effects of ULF-TENS stimulation on gnathology: the state of the art. Cranio. 2014;32: 118–130.
    1. Rodrigues D, Siriani AO, Bérzin F. Effect of conventional TENS on pain and electromyographic activity of masticatory muscles in TMD patients. Braz Oral Res. 2004;18: 290–295.
    1. Cooper BC, Kleinberg I. Establishment of a temporomandibular physiological state with neuromuscular orthosis treatment affects reduction of TMD symptoms in 313 patients. Cranio. 2008;26: 104–117.
    1. Monaco A, Sgolastra F, Ciarrocchi I, Cattaneo R. Effects of transcutaneous electrical nervous stimulation on electromyographic and kinesiographic activity of patients with temporomandibular disorders: a placebo-controlled study. J Electromyogr Kinesiol. 2012;22: 463–468. 10.1016/j.jelekin.2011.12.008
    1. Kamyszek G, Ketcham R, Garcia R, Radke J. Electromyographic evidence of reduced muscle activity when ULF-TENS is applied to the Vth and VIIth cranial nerves. Cranio. 2001;19: 162–168.
    1. Murillo R, Crucilla C, Schmittner J, Hotchkiss E, Pickworth WB. Pupillometry in the detection of concomitant drug use in opioid-maintained patients. Methods Find Exp Clin Pharmacol. 2004;26: 271–275.
    1. Fliegert F, Kurth B, Göhler K. The effects of tramadol on static and dynamic pupillometry in healthy subjects—the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status. Eur J Clin Pharmacol. 2005;61: 257–266.
    1. Matouskova O, Slanar O, Chytil L, Perlik F. Pupillometry in healthy volunteers as a biomarker of tramadol efficacy. J Clin Pharm Ther. 2011;36: 513–517. 10.1111/j.1365-2710.2010.01203.x
    1. Monaco A, Cattaneo R, Mesin L, Ciarrocchi I, Sgolastra F, Pietropaoli D. Dysregulation of the autonomous nervous system in patients with temporomandibular disorder: a pupillometric study. PLOS ONE. 2012;7: e45424 10.1371/journal.pone.0045424
    1. Monaco A, Cattaneo R, Mesin L, Fiorucci E, Pietropaoli D. Evaluation of autonomic nervous system in sleep apnea patients using pupillometry under occlusal stress: a pilot study. Cranio. 2014;32: 139–147.
    1. Wilhelm B, Giedke H, Lüdtke H, Bittner E, Hofmann A, Wilhelm H. Daytime variations in central nervous system activation measured by a pupillographic sleepiness test. J Sleep Res. 2001;10: 1–7.
    1. Wilhelm B, Wilhelm H, Widmaier D, Ludtke H, Ruhle K. Therapy control in sleep apnea patients by means of a pupillographic sleepiness test. Sleep. 1998;21: 266.
    1. Yamamoto K, Kobayashi F, Hori R, Arita A, Sasanabe R, Shiomi T. Association between pupillometric sleepiness measures and sleep latency derived by MSLT in clinically sleepy patients. Environ Health Prev Med. 2013;18: 361–367. 10.1007/s12199-013-0331-0
    1. Bär KJ, Schulz S, Koschke M, Harzendorf C, Gayde S, Berg W, et al. Correlations between the autonomic modulation of heart rate, blood pressure and the pupillary light reflex in healthy subjects. J Neurol Sci. 2009;279: 9–13. 10.1016/j.jns.2009.01.010
    1. Keivanidou A, Fotiou D, Arnaoutoglou C, Arnaoutoglou M, Fotiou F, Karlovasitou A. Evaluation of autonomic imbalance in patients with heart failure: a preliminary study of pupillomotor function. Cardiol J. 2010;17: 65–72.
    1. Jain S, Siegle GJ, Gu C, Moore CG, Ivanco LS, Jennings JR, et al. Autonomic insufficiency in pupillary and cardiovascular systems in Parkinson’s disease. Parkinsonism Relat Disord. 2011;17: 119–122. 10.1016/j.parkreldis.2010.11.005
    1. Muppidi S, Adams-Huet B, Tajzoy E, Scribner M, Blazek P, Spaeth EB, et al. Dynamic pupillometry as an autonomic testing tool. Clin Auton Res. 2013;23: 297–303. 10.1007/s10286-013-0209-7
    1. Gutstein HB, Akil H. Opioid analgesics In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 2006. pp. 547–590.
    1. Verster JC, Veldhuijzen DS, Volkerts ER. Effects of an opioid (oxycodone/paracetamol) and an NSAID (bromfenac) on driving ability, memory functioning, psychomotor performance, pupil size, and mood. Clin J Pain. 2006;22: 499–504.
    1. Larson MD. Mechanism of opioid-induced pupillary effects. Clin Neurophysiol. 2008;119: 1358–1364. 10.1016/j.clinph.2008.01.106
    1. Ichesco E, Quintero A, Clauw DJ, Peltier S, Sundgren PM, Gerstner GE, et al. Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: a pilot study. Headache. 2012;52: 441–454. 10.1111/j.1526-4610.2011.01998.x
    1. Younger JW, Shen YF, Goddard G, Mackey SC. Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems. Pain. 2010;149: 222–228. 10.1016/j.pain.2010.01.006
    1. Dworkin SF, LeResche L. Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique. J Craniomandib Disord. 1992;6: 301–355.
    1. Tarjan R. Depth-first search and linear graph algorithms. SIAM J Comput. 1972;1: 146–160.
    1. Monaco A, Sgolastra F, Pietropaoli D, Giannoni M, Cattaneo R. Comparison between sensory and motor transcutaneous electrical nervous stimulation on electromyographic and kinesiographic activity of patients with temporomandibular disorder: a controlled clinical trial. BMC Musculoskelet Disord. 2013;14: 168 10.1186/1471-2474-14-168
    1. Hayashi N, Someya N, Fukuba Y. Effect of intensity of dynamic exercise on pupil diameter in humans. J Physiol Anthropol. 2010;29: 119–122.
    1. Ishigaki H, Miyao M, Ishihara S. Change of pupil size as a function of exercise. J Hum Ergol. 1991;20: 61–66.
    1. Preuschoff K, ‘t Hart BM, Einhäuser W. Pupil dilation signals surprise: evidence for noradrenaline’s role in decision making. Front Neurosci. 2011;5: 115 10.3389/fnins.2011.00115
    1. Gabay S, Pertzov Y, Henik A. Orienting of attention, pupil size, and the norepinephrine system. Atten Percept Psychophys. 2011;73: 123–129. 10.3758/s13414-010-0015-4
    1. Murphy PR, O’Connell RG, O’Sullivan M, Robertson IH, Balsters JH. Pupil diameter covaries with BOLD activity in human locus coeruleus. Hum Brain Mapp. 2014;35: 4140–4154. 10.1002/hbm.22466
    1. Alnaes D, Sneve MH, Espeseth T, Endestad T, van de Pavert SHP, Laeng B. Pupil size signals mental effort deployed during multiple object tracking and predicts brain activity in the dorsal attention network and the locus coeruleus which represents one of the most important center of arousal. J. Vision. 2014;14: 1–20.
    1. Aston-Jones G. Brain structures and receptors involved in alertness. Sleep Med. 2005;6(Suppl 1): S3–S7.
    1. Aston-Jones G, Cohen JD. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol. 2005;493: 99–110.
    1. Stone EA, Lin Y, Sarfraz Y, Quartermain D. The role of the central noradrenergic system in behavioral inhibition. Brain Res Rev. 2011;67: 193–208. 10.1016/j.brainresrev.2011.02.002
    1. Berridge CW, Schmeichel BE, España RA. Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev. 2012;162: 187–197.
    1. Berridge CW, Waterhouse BD. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev. 2003;42: 33–84.
    1. Szabady E. Modulation of physiological reflexes by pain: role of the locus coeruleus. Front Inegr Neurosci. 2012;6: 94.
    1. Brightwell JJ, Taylor BK. Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain. Neuroscience. 2009;160: 174–185. 10.1016/j.neuroscience.2009.02.023
    1. Valentino RJ, Van Bockstaele E. Opposing regulation of the locus coeruleus by corticotropin-releasing factor and opioids. Potential for reciprocal interactions between stress and opioid sensitivity. Psychopharmacology. 2001;158: 331–342.
    1. Curtis AL, Bello NT, Valentino RJ. Evidence for functional release of endogenous opioids in the locus ceruleus during stress termination. J Neurosci. 2001;21: RC152
    1. Mazei-Robinson MS, Nestler EJ. Opiate-induced molecular and cellular plasticity of ventral tegmental area and locus coeruleus catecholamine neurons. Cold Spring Harb Perspect Med. 2012;2: a012070 10.1101/cshperspect.a012070
    1. Valentino RJ, Van Bockstaele E. Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur J Pharmacol. 2008;583: 194–203. 10.1016/j.ejphar.2007.11.062
    1. Hou RH, Freeman C, Langley RW, Szabadi E, Bradshaw CM. Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers. Psychopharmacology. 2005;181: 537–549.
    1. Nikolaou A, Schiza SE, Giakoumaki SG, Roussos P, Siafakas N, Bitsios P. The 5-min pupillary alertness test is sensitive to modafinil: a placebo controlled study in patients with sleep apnea. Psychopharmacology. 2008;196: 167–175.
    1. Ishimatsu M, Williams JT. Synchronous activity in locus coeruleus results from dendritic interactions in pericoerulear regions. J Neurosci. 1996;16: 5196–5204.
    1. Tachado SD, Akhtar RA, Abdel-Latif AA. Activation of beta-adrenergic receptors causes stimulation of cyclic AMP, inhibition of inositol trisphosphate, and relaxation of bovine iris sphincter smooth muscle. Biochemical and functional interactions between the cyclic AMP and calcium signalling systems. Invest Ophthalmol Vis Sci. 1989;30: 2232–2239.
    1. Steinhauer SR, Siegle GJ, Condray R, Pless M. Sympathetic and parasympathetic innervation of pupillary dilation during sustained processing. Int J Psychophysiol. 2004;52: 77–86.
    1. Topalkara A, Karadas B, Toker MI, Kaya T, Durmus N, Turgut B. Relaxant effects of beta-adrenoceptor agonist formoterol and BRL 37344 on bovine iris sphincter and ciliary muscle. Eur J Pharmacol. 2006;548: 144–149.
    1. Patil PN, Weber PA. In vivo functional implications of isoproterenol-mediated relaxation of isolated human iris sphincter. J Ocul Pharmacol. 1991;7: 297–300.
    1. Ploner M, Lee MC, Wiech K, Bingel U, Tracey I. Flexible cerebral connectivity patterns subserve contextual modulations of pain. Cereb Cortex. 2011;21: 719–726. 10.1093/cercor/bhq146
    1. Ploner M, Lee MC, Wiech K, Bingel U, Tracey I. Prestimulus functional connectivity determines pain perception in humans. Proc Natl Acad Sci U S A. 2010;107: 355–360. 10.1073/pnas.0906186106
    1. Suvinen TI, Reade PC, Kemppainen P, Könönen M, Dworkin SF. Review of aetiological concepts of temporomandibular pain disorders: towards a biopsychosocial model for integration of physical disorder factors with psychological and psychosocial illness impact factors. Eur J Pain. 2005;9: 613–633.
    1. Konchak PA, Thomas NR, Lanigan DT, Devon RM. Free way space measurement using mandibular kinesiograph and EMG before and after TENS. Angle Orthod. 1988;58: 343–350.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅