Altered regional brain T2 relaxation times in individuals with chronic orofacial neuropathic pain.

The neural mechanisms underlying the development and maintenance of chronic pain following nerve injury remain unclear. There is growing evidence that chronic neuropathic pain is associated with altered thalamic firing patterns, thalamocortical dysrhythmia and altered infra-slow oscillations in ascending pain pathways. Preclinical and post-mortem human studies have revealed that neuropathic pain is associated with prolonged astrocyte activation in the dorsal horn and we have suggested that this may result in altered gliotransmission, which results in altered resting neural rhythm in the ascending pain pathway. Evidence of astrocyte activation above the level of the dorsal horn in living humans is lacking and direct measurement of astrocyte activation in living humans is not possible, however, there is evidence that regional alterations in T2 relaxation times are indicative of astrogliosis. The aim of this study was to use T2 relaxometry to explore regional brain anatomy of the ascending pain pathway in individuals with chronic orofacial neuropathic pain. We found that in individuals with trigeminal neuropathic pain, decreases in T2 relaxation times occurred in the region of the spinal trigeminal nucleus and primary somatosensory cortex, as well as in higher order processing regions such as the dorsolateral prefrontal, cingulate and hippocampal/parahippocampal cortices. We speculate that these regional changes in T2 relaxation times reflect prolonged astrocyte activation, which results in altered brain rhythm and ultimately the constant perception of pain. Blocking prolonged astrocyte activation may be effective in preventing and even reversing the development of chronic pain following neural injury.

Disruption of default mode network dynamics in acute and chronic pain states.

It has been proposed that pain competes with other attention-demanding stimuli for cognitive resources, and many chronic pain patients display significant attention and mental flexibility deficits. These alterations may result from disruptions in the functioning of the default mode network (DMN) which plays a critical role in attention, memory, prospection and self-processing, and recent investigations have found alterations in DMN function in multiple chronic pain conditions. Whilst it has been proposed that these DMN alterations are a characteristic of pain that is chronic in nature, we recently reported altered oscillatory activity in the DMN during an acute, 5  minute noxious stimulus in healthy control subjects. We therefore hypothesize that altered DMN activity patterns will not be restricted to those in chronic pain but instead will also occur in healthy individuals during tonic noxious stimuli. We used functional magnetic resonance imaging to measure resting state infra-slow oscillatory activity and functional connectivity in patients with chronic orofacial pain at rest and in healthy controls during a 20-minute tonic pain stimulus. We found decreases in oscillatory activity in key regions of the DMN in patients with chronic pain, as well as in healthy controls during tonic pain in addition to changes in functional connectivity between the posterior cingulate cortex and areas of the DMN in both groups. The results show that similar alterations in DMN function occur in healthy individuals during acute noxious stimuli as well as in individuals with chronic pain. These DMN changes may reflect the presence of pain per se and may underlie alterations in attentional processes that occur in the presence of pain.

Self-management programmes in temporomandibular disorders: results from an international Delphi process.

Self-management (SM) programmes are commonly used for initial treatment of patients with temporomandibular disorders (TMD). The programmes described in the literature, however, vary widely with no consistency in terminology used, components of care or their definitions. The aims of this study were therefore to construct an operationalised definition of self-management appropriate for the treatment of patients with TMD, identify the components of that self-management currently being used and create sufficiently clear and non-overlapping standardised definitions for each of those components. A four-round Delphi process with eleven international experts in the field of TMD was conducted to achieve these aims. In the first round, the participants agreed upon six principal concepts of self-management. In the remaining three rounds, consensus was achieved upon the definition and the six components of self-management. The main components identified and agreed upon by the participants to constitute the core of a SM programme for TMD were as follows: education; jaw exercises; massage; thermal therapy; dietary advice and nutrition; and parafunctional behaviour identification, monitoring and avoidance. This Delphi process has established the principal concepts of self-management, and a standardised definition has been agreed with the following components for use in clinical practice: education; self-exercise; self-massage; thermal therapy; dietary advice and nutrition; and parafunctional behaviour identification, monitoring and avoidance. The consensus-derived concepts, definitions and components of SM offer a starting point for further research to advance the evidence base for, and clinical utility of, TMD SM.

Biomechanics of occlusion--implications for oral rehabilitation.

The dental occlusion is an important aspect of clinical dentistry; there are diverse functional demands ranging from highly precise tooth contacts to large crushing forces. Further, there are dogmatic, passionate and often diverging views on the relationship between the dental occlusion and various diseases and disorders including temporomandibular disorders, non-carious cervical lesions and tooth movement. This study provides an overview of the biomechanics of the masticatory system in the context of the dental occlusion's role in function. It explores the adaptation and precision of dental occlusion, its role in bite force, jaw movement, masticatory performance and its influence on the oro-facial musculoskeletal system. Biomechanics helps us better understand the structure and function of biological systems and consequently an understanding of the forces on, and displacements of, the dental occlusion. Biomechanics provides insight into the relationships between the dentition, jaws, temporomandibular joints, and muscles. Direct measurements of tooth contacts and forces are difficult, and biomechanical models have been developed to better understand the relationship between the occlusion and function. Importantly, biomechanical research will provide knowledge to help correct clinical misperceptions and inform better patient care. The masticatory system demonstrates a remarkable ability to adapt to a changing biomechanical environment and changes to the dental occlusion or other components of the musculoskeletal system tend to be well tolerated.

The effects of catastrophizing on central motor activity.

BACKGROUND: Pain catastrophizing significantly affects an individual's experience of pain. High pain catastrophizing is associated with increased fear avoidance behaviours, pain intensity and disability. The aim of this investigation was to determine the effect of pain catastrophizing on ongoing brain activity and movement-evoked brain activity during acute orofacial muscle pain. METHODS: Thirty-four healthy, pain-free subjects were recruited. In 17 subjects, the effect of catastrophizing on regional brain activity was determined. In 19 subjects, functional magnetic resonance imaging was used to determine the effects of pain catastrophizing on brain activation patterns during jaw movements in the presence of ongoing pain. RESULTS: We found that in the presence of pain, catastrophizing was significantly correlated with activity in multi-sensory integrative brain regions, including the dorsolateral and medial prefrontal cortices. Importantly, this relationship did not exist when subjects were not experiencing pain. In addition, during repetitive open-close jaw movements in the presence of pain, activity in the primary motor cortex, cerebellar cortex and the trigeminal motor nucleus was positively correlated with pain catastrophizing scores. In contrast, in the dorsolateral prefrontal cortex, as pain catastrophizing scores increased, the magnitude of signal intensity change during jaw movements decreased. Again, no such relationships occurred when the individual was not in pain. CONCLUSIONS: These data show that during pain, catastrophic thinking has a significant impact on activity in motor and sensory integrative regions. Reducing negative coping strategies may be an effective means in reducing fear avoidance behaviours and the intensity of ongoing pain.

Anatomical changes within the medullary dorsal horn in chronic temporomandibular disorder pain.

Accumulated evidence from experimental animal models suggests that neuroplastic changes at the dorsal horn are critical for the maintenance of various chronic musculoskeletal pain conditions. However, to date, no study has specifically investigated whether neuroplastic changes also occur at this level in humans. Using brain imaging techniques, we sought to determine whether anatomical changes were present in the medullary dorsal horn (spinal trigeminal nucleus caudalis) in subjects with the chronic musculoskeletal pain. In twenty-two subjects with painful temporomandibular disorders (TMDs) and forty pain-free controls voxel based morphometry of T1-weighted anatomical images and diffusion tensor images were used to assess regional grey matter volume and microstructural changes within the brainstem and, in addition, the integrity of ascending pain pathways. Voxel based morphometry revealed significant regional grey matter volume decreases in the medullary dorsal horn, in conjunction with alterations in diffusivity properties, namely an increase in mean diffusivity, in TMD subjects. Volumetric and mean diffusivity changes also occurred in TMD subjects in regions of the descending pain modulation system, including the midbrain periaqueductal grey matter and nucleus raphe magnus. Finally, tractography revealed altered diffusivity properties, namely decreased fractional anisotropy, in the root entry zone of the trigeminal nerve, the spinal trigeminal tract and the ventral trigeminothalamic tracts of TMD subjects. These data reveal that chronic musculoskeletal pain in humans is associated with discrete alterations in the anatomy of the medullary dorsal horn, as well as its afferent and efferent projections. These neural changes may be critical for the maintenance of pathological pain.

Isotonic resistance jaw exercise alters jaw muscle coordination during jaw movements.

The aim was to investigate the effects of isotonic resistance exercise on the electro-myographic (EMG) activity of the jaw muscles during standardised jaw movements. In 12 asymptomatic adults surface EMG activity was recorded from the anterior temporalis and masseter muscles bilaterally and the right anterior digastric muscle during right lateral jaw movements that tracked a target. Participants were randomly assigned to a Control group or an Exercise group. Jaw movement and EMG activity were collected (i) at baseline, before the exercise task (pre-exercise); (ii) immediately after the exercise task (isotonic resistance at 60% MVC against right lateral jaw movements); (iii) after 4 weeks of a home-based exercise programme; and, (iv) at 8-weeks follow-up. There were no significant within-subject or between-group differences in the velocity and amplitude of the right lateral jaw movements either within or between data collection sessions (P > 0.05). However, over the 8 weeks of the study, three of the tested EMG variables (EMG Duration, Time to Peak EMG from EMG Onset, and Time to Peak EMG activity relative to Movement Onset) showed significant (P < 0.05) differences in the five tested muscles. Many of the significant changes occurred in the Control group, while the Exercise group tended to maintain the majority of the tested variables at pre-exercise baseline values. The data suggest a level of variability between recording sessions in the recruitment patterns of some of the muscles of mastication for the production of the same right lateral jaw movement and that isotonic resistance exercise may reduce this variability.

Expanding the taxonomy of the diagnostic criteria for temporomandibular disorders.

There is a need to expand the current temporomandibular disorders' (TMDs) classification to include less common but clinically important disorders. The immediate aim was to develop a consensus-based classification system and associated diagnostic criteria that have clinical and research utility for less common TMDs. The long-term aim was to establish a foundation, vis-à-vis this classification system, that will stimulate data collection, validity testing and further criteria refinement. A working group [members of the International RDC/TMD Consortium Network of the International Association for Dental Research (IADR), members of the Orofacial Pain Special Interest Group (SIG) of the International Association for the Study of Pain (IASP), and members from other professional societies] reviewed disorders for inclusion based on clinical significance, the availability of plausible diagnostic criteria and the ability to operationalise and study the criteria. The disorders were derived from the literature when possible and based on expert opinion as necessary. The expanded TMDs taxonomy was presented for feedback at international meetings. Of 56 disorders considered, 37 were included in the expanded taxonomy and were placed into the following four categories: temporomandibular joint disorders, masticatory muscle disorders, headache disorders and disorders affecting associated structures. Those excluded were extremely uncommon, lacking operationalised diagnostic criteria, not clearly related to TMDs, or not sufficiently distinct from disorders already included within the taxonomy. The expanded TMDs taxonomy offers an integrated approach to clinical diagnosis and provides a framework for further research to operationalise and test the proposed taxonomy and diagnostic criteria.

Masseter motor unit recruitment is altered in experimental jaw muscle pain.

Some management strategies for chronic orofacial pain are influenced by models (e.g., Vicious Cycle Theory, Pain Adaptation Model) proposing either excitation or inhibition within a painful muscle. The aim of this study was to determine if experimental painful stimulation of the masseter muscle resulted in only increases or only decreases in masseter activity. Recordings of single-motor-unit (SMU, basic functional unit of muscle) activity were made from the right masseters of 10 asymptomatic participants during biting trials at the same force level and direction under infusion into the masseter of isotonic saline (no-pain condition), and in another block of biting trials on the same day, with 5% hypertonic saline (pain condition). Of the 36 SMUs studied, 2 SMUs exhibited a significant (p < 0.05) increase, 5 a significant decrease, and 14 no significant change in firing rate during pain. Five units were present only during the no-pain block and 10 units during the pain block only. The findings suggest that, rather than only excitation or only inhibition within a painful muscle, a re-organization of activity occurs, with increases and decreases occurring within the painful muscle. This suggests the need to re-assess management strategies based on models that propose uniform effects of pain on motor activity.

The effect of food bolus location on jaw movement smoothness and masticatory efficiency.

Masticatory efficiency in individuals with extensive tooth loss has been widely discussed. However, little is known about jaw movement smoothness during chewing and the effect of differences in food bolus location on movement smoothness and masticatory efficiency. The aim of this study was to determine whether experimental differences in food bolus location (anterior versus posterior) had an effect on masticatory efficiency and jaw movement smoothness. Jaw movement smoothness was evaluated by measuring jerk-cost (calculated from acceleration) with an accelerometer that was attached to the skin of the mentum of 10 asymptomatic subjects, and acceleration was recorded during chewing on two-colour chewing gum, which was used to assessed masticatory efficiency. Chewing was performed under two conditions: posterior chewing (chewing on molars and premolars only) and anterior chewing (chewing on canine and first premolar teeth only). Jerk-cost and masticatory efficiency (calculated as the ratio of unmixed azure colour to the total area of gum, the unmixed fraction) were compared between anterior and posterior chewing with the Wilcoxon signed rank test (two-tailed). Subjects chewed significantly less efficiently during anterior chewing than during posterior chewing (P = 0·0051). There was no significant difference in jerk-cost between anterior and posterior conditions in the opening phase (P = 0·25), or closing phase (P = 0·42). This is the first characterisation of the effect of food bolus location on jaw movement smoothness at the same time as recording masticatory efficiency. The data suggest that anterior chewing decreases masticatory efficiency, but does not influence jerk-cost.

The effect of vibration on pain during local anaesthesia injections.

BACKGROUND: The "gate control" theory suggests pain can be reduced by simultaneous activation of nerve fibres that conduct non-noxious stimuli. This study investigated the effects of vibration stimuli on pain experienced during local anaesthetic injections. METHODS: In a preliminary study, subjects were asked to rate anticipated and actual pain from regional anaesthetic injections in the oral cavity. A second study compared, within subjects, pain from injections with and without a simultaneous vibration stimulus. Both infiltration and block anaesthetic injection techniques were assessed. In each subject, two similar injections were given and with one, a vibration stimulus was randomly allocated. Injection pain was assessed by visual analogue scale and McGill pain descriptors. RESULTS: Both infiltration and block injections were painful (mean anticipated intensity: 31.25, actual: 17.82 mm on 100 mm scale). Pain intensity with and without vibration was 12.9 mm (range 0-67) and 22.2 mm (range 0-83) respectively (p = 0.00005, paired T-test), and this effect was seen with both infiltration (p = 0.032) and block anaesthetic (p = 0.0001) injection subgroups. Furthermore, compared to no vibration-stimulus injections, injections with vibration resulted in less pain descriptors chosen (p = 0.004), and the descriptors had a lower pain rating (p = 0.001). CONCLUSIONS: The results suggest that vibration can be used to decrease pain during dental local anaesthetic administration.

How does pain affect jaw muscle activity? The Integrated Pain Adaptation Model.

Pain and limitation of movement are two cardinal symptoms of temporomandibular disorders but it is unclear how one influences the other. The relationship between pain and movement is clinically significant but controversial with two major theories having been proposed: the Vicious Cycle Theory and the Pain Adaptation Model. The Vicious Cycle Theory proposes a vicious cycle between pain and muscle activity. This theory has little scientific basis but underpins many management strategies. The Pain Adaptation Model is more evidence-based and proposes that pain causes changes in muscle activity to limit movement and protect the sensory-motor system from further injury. The Pain Adaptation Model has many positive features but does not appear to explain the relation between pain and muscle activity in all situations. We propose that the relationship is influenced by the functional complexity of the sensory-motor system and the multidimensional nature of pain. This new Integrated Pain Adaptation Model states that pain results in a new recruitment strategy of motor units that is influenced by the multidimensional (i.e., biological and psychosocial) components of the pain experience. This new recruitment strategy aims to minimize pain and maintain homeostasis. This model emphasizes the individual reaction to pain and suggests a tailored approach towards management.

Ipsilateral interferences and working-side condylar movements.

UNLABELLED: There is limited knowledge of the effects of the occlusion on temporomandibular joint function. AIM: The aim was to investigate the influence of a working-side occlusal alteration (OA, i.e. interference) on trajectories of working-side condylar points during standardized lateral jaw movements (laterotrusion) tracked by a jaw-tracking system. METHODS: Ten trials of right laterotrusion were repeated under: control 1 (before OA), OA (immediately after placement of a working-side interference) and control 2 (immediately after removal of OA) conditions. RESULTS: During right jaw movement, the paths of the working-side condylar points under OA were significantly more inferior and anterior to those under control at the same amount of mid-incisor-point displacement from the intercuspal position. The OA significantly reduced the rotation of the mandible about the antero-posterior and supero-inferior axes and significantly increased the opening angle. Controls 1 and 2 were not significantly different. CONCLUSIONS: A working-side interference has an immediate, significant effect on working-side condylar movement.

Forces resisting jaw displacement in relaxed humans: a predominantly viscous phenomenon.

Forces opening the relaxed human jaw are resisted by intrinsic restraints, including passive tensions in the jaw-closing muscles. These muscle tensions have been modelled as viscoelastic elements, and static measurements suggest their elastic portions contribute approximately a total of 5 N resistance at wide gape. As the viscous damping properties of muscles which affect the jaw's dynamic behaviour are unknown, we measured the jaw opening force required to reach maximum gape during fast and slow opening in six relaxed subjects. These data were then incorporated in a dynamic mathematical jaw model to determine the damping properties of the masticatory system. During the 3 and 8 s opening trials, forces increased with gape (6.7 +/- 3.3 and 3.9 +/- 2.3 N, respectively, at 50% gape) and reached their maxima at wide gape (19.9 +/- 4.5 and 13.2 +/- 4.4 N, respectively). The muscle damping constant needed by the model to emulate these results was 150 Nsm(-1), approximately 25% lower than the calculated critical damping constant. This study suggests low forces are required to open the jaw in relaxed humans, and that jaw viscosity, not elasticity, provides the major resistance to motion.

Implant angulation: a measurement technique, implant overdenture maintenance, and the influence of surgical experience.

PURPOSE: The purposes of this study were to develop a technique to measure the angulation between two implants and between each implant and reference planes, to analyze the relationship between the maintenance (adjustments and repairs) of ball-attachment mandibular implant overdentures and implant angulation, and to see if there is any correlation between surgeon experience and implant orientation. MATERIALS AND METHODS: Final casts of 41 patients who had received two-implant ball-attachment mandibular overdentures were used to measure implant angulations using digital photographs and plane geometry. The measured angles were compared with the number of adjustments and repairs of the prostheses and analyzed by surgeon experience for any trends. RESULTS: No significant relationships were found between number of adjustments and repairs and the interimplant angles. However, there was a significantly higher number of repairs when the lingual inclination of an implant was > or = 6.0 degrees (P = .033) or if the facial inclination was < 6.5 degrees (P = .036). Less experienced surgeons had a significantly greater tendency to place implants that diverged from each other in the frontal plane (P = .045) and with a facial or lingual inclination in the sagittal plane (P = .035). CONCLUSION: While interimplant angulation did not appear to affect prosthesis maintenance, individual implants with a lingual inclination > or = 6 degrees and a facial inclination < 6.5 degrees were associated with significantly more prosthesis repairs. There was a tendency for implants placed by less experienced surgeons to demonstrate greater inclination.

Prediction of the outcome of a phase 3 clinical trial of an antischizophrenic agent (quetiapine fumarate) by simulation with a population pharmacokinetic and pharmacodynamic model.

A completed phase 3 trial result was simulated 100 times on the basis of a simulation model of quetiapine fumarate (Seroquel), an antischizophrenic agent. The simulation was executed by analysts who were completely blinded from results of the actual trial until after the simulations were submitted to the holder of the trial results. Data from two clinical investigations of quetiapine in patients with schizophrenia were analyzed by use of nonlinear mixed effects modeling to derive a population pharmacokinetic- and pharmacodynamic-based simulation model. The time course of quetiapine concentrations was described by use of a one-compartment open linear pharmacokinetic model with first-order absorption and elimination. The combination of an inhibitory maximum effect pharmacodynamic model for the active treatment effect and a linear function of time for the placebo effect characterized the observed time course of change in the Brief Psychiatric Rating Scale. Simulation results were compared with those in the actual trial to evaluate how well the simulations predicted the outcome. The actual trial results for all doses except the placebo group fell within the predicted Brief Psychiatric Rating Scale scores +/- 1 SE. Unlike the phase 2 trial, from which the pharmacokinetic/pharmacodynamic model was developed, the placebo group in the actual phase 3 trial showed deterioration of Brief Psychiatric Rating Scale scores with time. We conclude that variable placebo responses observed in short-term studies of schizophrenia provide an inadequate basis for the modeling and simulation of placebo subjects in clinical trials. Knowledge of the range of placebo response observed in other studies may have provided an improved basis for the placebo effect model. The model for active drug produced adequate predictions of the actual trial outcomes.

Dynamic simulation of muscle and articular properties during human wide jaw opening.

Human mandibular function is determined in part by masticatory muscle tensions and morphological restraints within the craniomandibular system. As only limited information about their interactions can be obtained in vivo, mathematical modeling is a useful alternative. It allows simulation of causal relations between structure and function and the demonstration of hypothetical events in functional or dysfunctional systems. Here, the external force required to reach maximum jaw gape was determined in five relaxed participants, and this information used, with other musculoskeletal data, to construct a dynamic, muscle-driven, three-dimensional mathematical model of the craniomandibular system. The model was programmed to express relations between muscle tensions and articular morphology during wide jaw opening. It was found that a downward force of 5 N could produce wide gape in vivo. When the model's passive jaw-closing muscle tensions were adjusted to permit this, the jaw's resting posture was lower than that normally observed in alert individuals, and low-level active tone was needed in the closer muscles to maintain a typical rest position. Plausible jaw opening to wide gape was possible when activity in the opener muscles increased incrementally over time. When the model was altered structurally by decreasing its angles of condylar guidance, jaw opening required less activity in these muscles. Plausible asymmetrical jaw opening occurred with deactivation of the ipsilateral lateral pterygoid actuator. The model's lateral deviation was limited by passive tensions in the ipsilateral medial pterygoid, which forced the jaw to return towards the midline as opening continued. For all motions, the temporomandibular joint (TMJ) components were maintained in continual apposition and displayed stable pathways despite the absence of constraining ligaments. Compressive TMJ forces were presented in all the cases and increased to maximum at wide gape. Dynamic mathematical modeling appears a useful way to study such events, which as yet are unrecordable in the human craniomandibular system.