Greg M. Murray

Different Pain, Different Brain: Thalamic Anatomy in Neuropathic and Non-Neuropathic Chronic Pain Syndromes

Trigeminal neuropathic pain (TNP) and temporomandibular disorders (TMD) are thought to have fundamentally different etiologies. It has been proposed that TNP arises through damage to, or pressure on, somatosensory afferents in the trigeminal nerve, whereas TMD results primarily from peripheral nociceptor activation. Because some reports suggest that neuropathic pain is associated with changes in brain anatomy, it is possible that TNP is maintained by changes in higher brain structures, whereas TMD is not. The aim of this investigation is to determine whether changes in regional brain anatomy and biochemistry occur in both conditions. Twenty-one TNP subjects, 20 TMD subjects, and 36 healthy controls were recruited. Voxel-based morphometry of T1-weighted anatomical images revealed no significant regional gray matter volume change in TMD patients. In contrast, gray matter volume of TNP patients was reduced in the primary somatosensory cortex, anterior insula, putamen, nucleus accumbens, and the thalamus, whereas gray matter volume was increased in the posterior insula. The thalamic volume decrease was only seen in the TNP patients classified as having trigeminal neuropathy but not those with trigeminal neuralgia. Furthermore, in trigeminal neuropathy patients, magnetic resonance spectroscopy revealed a significant reduction in the N-acetylaspartate/creatine ratio, a biochemical marker of neural viability, in the region of thalamic volume loss. The data suggest that the pathogenesis underlying neuropathic and non-neuropathic pain conditions are fundamentally different and that neuropathic pain conditions that result from peripheral injuries may be generated and/or maintained by structural changes in regions such as the thalamus.

Pain and Plasticity: Is Chronic Pain Always Associated with Somatosensory Cortex Activity and Reorganization?

The somatosensory cortex remodels in response to sensory deprivation, with regions deprived of input invaded by neighboring representations. The degree of cortical reorganization is correlated with ongoing pain intensity, which has led to the assumption that chronic pain conditions are invariably associated with somatosensory cortex reorganization. Because the presentation and etiology of chronic pain vary, we determined whether cortical changes in human subjects are similar for differing pain types. Using functional and anatomical magnetic resonance imaging, we found that, while human patients with neuropathic pain displayed cortical reorganization and changes in somatosensory cortex activity, patients with non-neuropathic chronic pain did not. Furthermore, cortical reorganization in neuropathic pain patients was associated with changes in regional anatomy. These data, by showing that pain per se is not associated with cortical plasticity, suggest that treatments aimed at reversing cortical reorganization should only be considered for use in patients with certain types of chronic pain.

Chronic Pain: Lost Inhibition?

Human brain imaging has revealed that acute pain results from activation of a network of brain regions, including the somatosensory, insular, prefrontal, and cingulate cortices. In contrast, many investigations report little or no alteration in brain activity associated with chronic pain, particularly neuropathic pain. It has been hypothesized that neuropathic pain results from misinterpretation of thalamocortical activity, and recent evidence has revealed altered thalamocortical rhythm in individuals with neuropathic pain. Indeed, it was suggested nearly four decades ago that neuropathic pain may be maintained by a discrete central generator, possibly within the thalamus. In this investigation, we used multiple brain imaging techniques to explore central changes in subjects with neuropathic pain of the trigeminal nerve resulting in most cases (20 of 23) from a surgical event. Individuals with chronic neuropathic pain displayed significant somatosensory thalamus volume loss (voxel-based morphometry) which was associated with decreased thalamic reticular nucleus and primary somatosensory cortex activity (quantitative arterial spin labeling). Furthermore, thalamic inhibitory neurotransmitter content was significantly reduced (magnetic resonance spectroscopy), which was significantly correlated to the degree of functional connectivity between the somatosensory thalamus and cortical regions including the primary and secondary somatosensory cortices, anterior insula, and cerebellar cortex. These data suggest that chronic neuropathic pain is associated with altered thalamic anatomy and activity, which may result in disturbed thalamocortical circuits. This disturbed thalamocortical activity may result in the constant perception of pain.

Corticothalamic influences on transmission of tactile information in the ventroposterolateral thalamus of the cat: effect of reversible inactivation of somatosensory cortical areas I and II

The influence of the corticothalamic projections from somatosensory areas I and II (SI and SII) on the transmission of tactile information through the ventroposterolateral (VPL) thalamus was investigated by examining the effects of cooling-induced, reversible inactivation of SI and/or SII on the responsiveness of 32 VPL neurons to controlled tactile stimulation of the distal forelimb in anaesthetized cats. Both the response levels and spontaneous activity were unaffected in 21 (66%) of the VPL neurons as a result of inactivation of SI or SII singly, or both SI and SII simultaneously. In the remaining 11 neurons, 10 displayed a reduction in response level, an effect observed over the whole of the stimulus-response relations for the neurons studied at different stimulus amplitudes, and one neuron displayed an increase in response level in association with cortical inactivation. When responses in VPL neurons were affected by inactivation of one cortical somatosensory area, they were not necessarily affected by inactivation of the other. Of 14 neurons studied for the effects of the separate inactivation of SI alone and of SII alone, 7 were affected, one from both areas, but the remaining 6 were affected by inactivation of only one of these areas. Phaselocking, and therefore the precision of impulse patterning in the responses of VPL neurons to skin vibration, was unchanged by the cortical inactivation irrespective of whether the response level was affected. The results suggest that SI and SII may exert a facilitatory influence on at least a third of VPL neurons and in this way may modulate the gain of transmission of tactile signalling through the thalamus.

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.

Noxious Lingual Stimulation Influences the Excitability of the Face Primary Motor Cerebral Cortex (Face MI) in the Rat

The mechanisms whereby orofacial pain affects motor function are poorly understood. The aims were to determine whether 1) lingual algesic chemical stimulation affected face primary motor cerebral cortex (face MI) excitability defined by intracortical microstimulation (ICMS); and 2) any such effects were limited to the motor efferent MI zones driving muscles in the vicinity of the noxious stimulus. Ketamine-anesthetized Sprague-Dawley male rats were implanted with electromyographic (EMG) electrodes into anterior digastric, masseter, and genioglossus muscles. In 38 rats, three microelectrodes were located in left face MI at ICMS-defined sites for evoking digastric and/or genioglossus responses. ICMS thresholds for evoking EMG activity from each site were determined every 15 min for 1 h, then the right anterior tongue was infused (20 microl, 120 microl/h) with glutamate (1.0 M, n = 18) or isotonic saline (n = 7). Subsequently, ICMS thresholds were determined every 15 min for 4 h. In intact control rats (n = 13), ICMS thresholds were recorded over 5 h. Only left and right genioglossus ICMS thresholds were significantly increased (< or =350%) in the glutamate infusion group compared with intact and isotonic saline groups (P < 0.05). These dramatic effects of glutamate on ICMS-evoked genioglossus activity contrast with its weak effects only on right genioglossus activity evoked from the internal capsule or hypoglossal nucleus. This is the first documentation that intraoral noxious stimulation results in prolonged neuroplastic changes manifested as a decrease in face MI excitability. These changes appear to occur predominantly in those parts of face MI that provide motor output to the orofacial region receiving the noxious stimulation.

Electromyographic activity of the human lateral pterygoid muscle during contralateral and protrusive jaw movements

Understanding of the normal function of the lateral pterygoid muscle is limited. The principal aim here was to determine whether there is a progressive increase in lateral pterygoid activity as the mandibular condyle moves downwards and forwards as would be expected if the muscle is concerned with the precise horizontal positioning of the mandible. In eight humans, recordings were made of the activity of the superior (SHLP) and inferior (IHLP) heads of the lateral pterygoid and the masseter, anterior temporal, posterior temporal and digastric muscles, together with the movement of the palpated lateral condylar pole (JAWS-3D tracking system) during trials of a contralateral and a protrusive jaw movement. Recording sites in SHLP and, in one participant, IHLP were verified by computed tomography. In each participant there was a progressive increase in the rectified and smoothed SHLP and IHLP activity in association with condylar movement during the contralateral and protrusive jaw movement. Further, irregularities in condylar movement, which reflected variations in the rate at which the jaw was moved, were correlated in time with prominent bursts of SHLP and IHLP activity. In all participants there was a consistently high correlation coefficient between the rectified and smoothed SHLP and IHLP activity and condylar displacement during the contralateral or protrusive jaw movements. For example, the mean (+/-SD) correlation between anterior condylar translation during contralateral excursion and SHLP activity was 0.91+/-0.09, and for IHLP 0.96+/-0.02. For the masseter, anterior temporal, posterior temporal and digastric muscles, mean r-values were, respectively, 0.10+/-0.77; -0.14+/-0.72; 0.24+/-0.78; 0.54+/-0.47. When treated as a group the correlation coefficients for SHLP and IHLP were statistically significantly different from the correlation coefficients for the other muscles treated as a group (ANOVA; p < 0.002 for correlation with anterior translation). These observations support the notion that the lateral pterygoid provides the principal driving force for moving the jaw forwards or laterally in protrusive or lateral excursive condylar movements. Further, the data suggest that the muscle plays a part in the fine control of jaw movements.

Functional Heterogeneity in the Superior Head of the Human Lateral Pterygoid

The activity of the superior head of the human lateral pterygoid muscle (SHLP) is controversial. Given the non-parallel alignment of some SHLP fibers, the SHLP may be capable of differential activation. The aims were to clarify SHLP activity patterns in relation to location within SHLP. In 18 subjects, SHLP single motor units were intramuscularly recorded at computer-tomography-verified sites during horizontal (e.g., protrusion) and vertical (e.g., opening) jaw tasks (recorded by a jaw-tracking device) and at resting postural jaw position. None of 92 units was active at the resting postural position. Medially located units (21) showed activity during contralateral movement, protrusion, and opening; 5 were also active on jaw closing. There was a significant association between unit location and the number of units active during vertical tasks (i.e., jaw closing and clenching). Analysis of the data suggests differential activation within SHLP and raises the possibility of functional heterogeneity within SHLP.

The variability of condylar point pathways in open-close jaw movements

STATEMENT OF PROBLEM Clinical assessments of condylar movement often rely on the movement of a single clinically determined or average value condylar point. PURPOSE The aim of this investigation was to study the effect of differences in condylar point location on recorded movement trajectories with an open-close jaw movement. METHODS Recordings were made of the movements of various condylar points in 44 subjects. The points were identified clinically (average value points) and radiographically. RESULTS The trajectory of each condylar point, whether average value or radiographically determined, was different in form and dimension from any other condylar point within a subject for the same open-close jaw movement. CONCLUSIONS Depending on the point chosen in the vicinity of the condyle, quite different interpretations of condylar movement within a subject could be made. The data underscore the caution that must be exercised when interpreting condylar movement from the movement of a single condylar point.

Electromyographic evidence for functional heterogeneity in the inferior head of the human lateral pterygoid muscle: a preliminary multi-unit study

OBJECTIVE Functional heterogeneity, i.e. regional or selective activation of subpopulations of fibres within a muscle, has been described in some jaw and limb muscles. Each head of the lateral pterygoid muscle may also be functionally heterogeneous. The aims of this investigation were to develop a technique to test this hypothesis, and to use this technique to determine whether there is any multi-unit electromyographic (EMG) evidence for functional heterogeneity within the inferior head of the lateral pterygoid (IHLP). METHODS In 3 human subjects without craniomandibular disorders, recordings were made of condylar movement and multi-unit EMG activity from two sites in the IHLP during repeated trials of a contralateral (n = 21) and a protrusive (n = 26) jaw movement. The recording sites within IHLP were approached extraorally (labelled IHLP-extra) and were verified by computer tomography (CT); the other (IHLP-intra) were from sites in IHLP approached intraorally. RESULTS In each subject, the time of occurrence of the peak filtered signal from IHLP-extra was significantly different (P<0.05) from IHLP-intra for all protrusion trials but not for contralateral trials. CONCLUSIONS The data suggest a task-dependent change in motor unit recruitment order within IHLP and that IHLP is functionally heterogeneous.