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«Year: 2015 The human brain response to dental pain relief Meier, M L; Widmayer, S; Abazi, J; Brügger, M; Lukic, N; Lüchinger, R; Ettlin, D A ...»

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Year: 2015

The human brain response to dental pain relief

Meier, M L; Widmayer, S; Abazi, J; Brügger, M; Lukic, N; Lüchinger, R; Ettlin, D A

Abstract: Local anesthesia has made dental treatment more comfortable since 1884, but little is known

about associated brain mechanisms. Functional magnetic resonance imaging is a modern neuroimaging

tool widely used for investigating human brain activity related to sensory perceptions, including pain.

Most brain regions that respond to experimental noxious stimuli have recently been found to react not only to nociception alone, but also to visual, auditory, and other stimuli. Thus, presumed functional attributions have come under scrutiny regarding selective pain processing in the brain. Evidently, inno- vative approaches are warranted to identify cerebral regions that are nociceptive specific. In this study, we aimed at circumventing known methodological confounders by applying a novel paradigm in 14 vol- unteers: rather than varying the intensity and thus the salience of painful stimuli, we applied repetitive noxious dental stimuli at constant intensity to the left mandibular canine. During the functional mag- netic resonance imaging paradigm, we suppressed the nociceptive barrage by a mental nerve block. Brain activity before and after injection of 4% articaine was compared intraindividually on a group level. Dental pain extinction was observed to correspond to activity reduction in a discrete region of the left posterior insular cortex. These results confirm previous reports demonstrating that direct electrical stimulation of this brain region-but not of others-evokes bodily pain sensations. Hence, our investigation adds further evidence to the notion that the posterior insula plays a unique role in nociceptive processing.

DOI: 10.1177/0022034515572022 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: http://doi.org/10.5167/uzh-116526 Accepted Version

Originally published at:

Meier, M L; Widmayer, S; Abazi, J; Brügger, M; Lukic, N; Lüchinger, R; Ettlin, D A (2015). The human brain response to dental pain relief. Journal of Dental Research, 94(5):690-696. DOI: 10.1177/0022034515572022 Journal of Dental Research Senior Editor: W.V. Giannobile The human brain response to dental pain relief Michael L Meier1,2*, Sonja Widmayer3, Jetmir Abazi1, Mike Brügger1,4, Nenad Lukic1, Roger Lüchinger4, Dominik A Ettlin1 1) Center of Dental Medicine, University of Zurich, Zurich, Switzerland 2) Balgrist University Hospital, Zurich, Zurich, Switzerland 3) Department of Psychiatry (UPK), University of Basel, Switzerland 4) Institute for Biomedical Engineering, ETH Zurich and University of Zurich, Zurich, Switzerland Corresponding author Michael L. Meier Center of Dental Medicine Plattenstrasse 11 8032 Zurich, Switzerland Phone: +41 44 634 34 70 Mail: Michael.meier@uzh.ch

Abstract

word count: 233 Total word count: 3318

Number of tables:1

Number of figures:1

Number of references:37 Keywords: Pain, Anesthesia, Magnetic Resonance Imaging (MRI), Neuroscience/Neurobiology Abstract Local anesthesia has made dental treatment more comfortable since 1884, but little is known about associated brain mechanisms. Functional magnetic resonance imaging (fMRI) is a modern neuroimaging tool widely used for investigating human brain activity related to sensory perceptions, including pain. Recently, most brain regions that respond to experimental noxious stimuli have been found to react not only to nociception alone, but also to visual, auditory and other stimuli. Thus, presumed functional attributions have come under scrutiny regarding selective pain processing in the brain. Evidently, innovative approaches are warranted to identify cerebral regions that are nociceptivespecific. In this study, we aimed at circumventing known methodological confounders by applying a novel paradigm in 14 volunteers: rather than varying the intensity and thus the salience of painful stimuli, we applied repetitive noxious dental stimuli at constant intensity to the left mandibular canine.

During the fMRI paradigm we suppressed the nociceptive barrage by a mental nerve block. Brain activity before and after injection of 4% articaine was compared intra-individually on a group level.

Dental pain extinction was observed to correspond to activity reduction in a discrete region of the left posterior insular cortex. These results confirm previous reports demonstrating that direct electrical stimulation of this brain region - but not of others – evokes bodily pain sensations. Hence, our investigation adds further evidence to the notion that the posterior insula plays a unique role in nociceptive processing.

Introduction

In 1884, the Austrian ophthalmologist Carl Koller performed the first operation using local anesthetic on a patient with glaucoma (Koller, 1884). The news about the painless procedure spread rapidly across the globe (n.b. without internet), and in the same year American dentists were the first to use a syringe to apply infraorbital and mandibular nerve blocks (Hall, 1884). Considering the 130 year history of local anesthetics in dentistry remarkably little knowledge exists on their effects on the human brain. A meta-analysis recently summarized the relatively sparse evidence regarding the representation of experimental dental pain in the human brain (Lin et al., 2014). It revealed a cerebral network which mainly includes primary and secondary somatosensory cortices (S1 and S2), insula, thalamus, cingulate cortex and frontal brain regions. This dental pain network overlaps strongly with the neuromatrix (also referred to as “pain matrix”) reported for spinal pain (Iannetti and Mouraux, 2010). Compared to the latter, noxious tooth stimulation may gain an edge because of the extraordinary high proportion of nociceptive afferents in the dental pulp (Byers and Narhi, 1999;





Chatrian et al., 1975). Yet, irrespective of stimulus type and location, pain related brain activity does not necessarily imply nociceptive specificity. Cumulating evidence indicates that brain regions responding to pain are equally involved in processing nociceptive and non-nociceptive stimuli (Iannetti and Mouraux, 2010; Mouraux et al., 2011). Hence, their activation may merely reflect general responses to salient or behaviorally relevant stimuli, such as e.g. non-specific cognitive processes associated with magnitude estimation and/or motor aspects of pain intensity rating (Baliki et al., 2009). Since most pain studies performed categorical comparisons among different stimulus strengths, the functional distinction between salience and nociceptive related aspects of brain activity is precluded (Brugger et al., 2012; Coghill et al., 1999; Meier et al., 2012). Although efforts have been made to control for such effects, e.g. by means of advanced statistical modeling (Oertel et al., 2012), no experimental design has so far been able to unequivocally elucidate pain-specific effects within pain-associated brain regions.

Considering these conceptual challenges, the aim of this study was to develop an alternative approach by circumventing the various confounders of previous study designs. For this purpose we designed a novel functional magnetic resonance imaging (fMRI) paradigm that was based on keeping the dental noxious stimulus strength stable. To evoke pain perception contrasts, the barrage of nociceptive signaling was interrupted by an analgesic nerve block. Using this novel methodology, we hypothesized to 1) observe global dental pain related brain activations that replicate findings of previous neuroimaging studies and 2) to identify differential brain activity between the pain and analgesic states in distinct brain regions, reflecting the neuronal substrate underlying dental nociception.

Methods

Subjects A total of 15 right-handed male subjects were recruited by advertising on an online platform (www.marktplatz.uzh.ch) and enrolled after informed written consent was obtained. One subject was excluded due to technical problems with the stimulation device, leaving a sample of 14 subjects (mean age = 25.14, SD = 4.48). Subjects were compensated with 50 Swiss francs per hour. The study was conducted according to the Declaration of Helsinki and was approved by the local ethics committee of the canton Zurich, Switzerland (KEK-ZH-Nr. 2012-0342).

Exclusion criteria included systemic diseases, history of allergy to the components of the local anesthetic solutions, local anesthesia in the mental region less than 2 weeks prior to the experiment, dental anxiety, acute or chronic pain condition, intake of analgesic medication. Further, on the target mandibular canine: dental sensitivity or caries, large restorations, or periodontal disease. Dental anxiety was assessed by the Dental Anxiety Scale (DAS) questionnaire (Corah, 1969). The mean DAS score was 6.29 (SD = 1.6). Alcohol was prohibited for 12 h before the experiment, and fMRI measurements were performed between 1 p.m. and 9 p.m.

Experimental Material

Dental splint Mandibular splints were fabricated from impressions made of Blu-Mousse (Blu-Mousse is a fastsetting vinyl polysiloxane material produced by Parkell, Inc., 300 Executive Drive, Edgewood, NY 11717, USA) (Brugger et al., 2011; Brugger et al., 2012; Meier et al., 2014). Stainless steel electrodes were embedded in each splint at the labial and lingual centers of the left mandibular canine. They served as anode and cathode, respectively, during electrical stimulation of the tooth. To minimize electrical resistance during stimulation, a small portion of a specifically prepared contact hydrogel was placed on the anode and cathode. Care was taken that the splints did not evoke pain or discomfort.

Electrical stimulation

A modified “Compex Motion” system (Compex Médical SA, Ecublens, Switzerland) was used. This type of electrical stimulation system has been demonstrated to evoke reliable sharp and pricking pain sensations with minimal adaptive changes in sensory perception (Brugger et al., 2011; Brugger et al., 2012; Keller et al., 2002; Meier et al., 2014). The Presentation® software (http://www.neurobs.com/presentation) was used to control the experimental protocol. Shielded wires were used to avoid radiofrequency contamination by the stimulation current.

Local anesthetic

For the mental nerve block, a solution of 4% articaine (4-methyl-3-[2-(propylamino)-propionamido]thiophene-carboxylic acid, methyl ester hydrochloride) containing 1:200,000 epinephrine was used (Ultracain D-S Forte®) which is currently the most common local dental anesthetic in Europe and has a long history of success (Cowan, 1977). Articaine blocks nociceptive input by binding reversibly to sodium channels and subsequently reducing sodium influx (Becker and Reed, 2012). Since small trigeminal fibers are generally more susceptible to local anesthetic solutions than thickly myelinated fibers, differential sensitivities are commonly observed in clinical dentistry as patients may remain disturbed by a sense of pressure despite complete analgesia (Becker and Reed, 2012).

Experimental procedure Pretest 3-6 weeks prior to the fMRI experiment Prior to the fMRI experiment, subjects were familiarized with the experimental procedure for minimizing arousal/anxiety effects and to secure a response to the local articaine 4%. Sensory detection threshold (SDT), pain detection threshold (PDT) and noxious stimulus intensity (NI; NRS 5/10) were individually determined by applying electrical stimuli of 1ms duration with increasing strength to the left lower canine (1mA steps; ascending method of limits). The NI was determined by increasing the stimulus strength until the subject rated a “5” (corresponding to a painful, but tolerable perception) on a verbally instructed 11-point numeric rating scale (NRS). The NRS left and right anchors were “no pain” and “worst pain imaginable", respectively. Furthermore, pain quality was assessed by the verbal descriptors of “pricking,” “dull” and “pressing.” These three descriptors have demonstrated discriminative properties to distinguish between Aδ- and C-fiber-mediated pain (Beissner et al., 2010). 0.6 ml Articaine was subsequently injected at the left mental foramen according to the technique described by Schwenzer & Ehrenfeld (Schwenzer, 2009). Subject’s analgesic responses were reported by indicating pain offset.

MR experiment

While subjects were lying in the MR scanner, SDT, PDT and NI were determined again by the ascending method of limits. Subjects were asked to indicate the SDT, PDT and NI by pressing the alarm bell of the MR system. All three threshold determinations (SDT, PDT and NI) were repeated thrice, and the mean current to achieve NI was applied during the subsequent stimulation.

In the pain phase, the lower left canine was stimulated 30 times at NI with randomized intervals of 8 to 12 s. For the purpose of the injection, the original MR scanner bed position was memorized by the MR system. To secure a constant brain position for both experimental phases, the subjects’ head was immobilized in the MR coil by means of foamed cushions (Newmatic Medical, Caledonia, Michigan, USA) that filled the gap between coil and head. Additionally, participants were instructed to pay careful attention not to move their heads during scanner bed repositioning and the injection procedure, respectively. The articaine solution was submucosally injected above the left mental foramen. The injection procedure including the exact re-positioning of the scanner bed was kept below one minute.

Thereafter, subjects continued receiving repetitive electrical stimuli at the NI level. The subjects were asked to report pain offset (complete analgesia) by pressing the MR alarm bell once and twice in case of nil stimulus perception (complete anesthesia).

Image acquisition



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