Christopher C. Peck

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.

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 models passive jaw-closing muscle tensions were adjusted to permit this, the jaws 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 models 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.

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.

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.

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.

Chronic Neuropathic Pain: It's about the Rhythm.

The neural mechanisms underlying the development and maintenance of chronic neuropathic pain remain unclear. Evidence from human investigations suggests that neuropathic pain is associated with altered thalamic burst firing and thalamocortical dysrhythmia. Additionally, experimental animal investigations show that neuropathic pain is associated with altered infra-slow (<0.1 Hz) frequency oscillations within the dorsal horn and somatosensory thalamus. The aim of this investigation was to determine whether, in humans, neuropathic pain was also associated with altered infra-slow oscillations within the ascending “pain” pathway. Using resting-state functional magnetic resonance imaging, we found that individuals with orofacial neuropathic pain have increased infra-slow oscillatory activity throughout the ascending pain pathway, including within the spinal trigeminal nucleus, somatosensory thalamus, thalamic reticular nucleus, and primary somatosensory cortex. Furthermore, these infra-slow oscillations were temporally coupled across these multiple sites and occurred at frequencies similar to calcium waves in activated astrocytes. The region encompassing the spinal trigeminal nucleus also displayed increased regional homogeneity, consistent with a local spread of neural activity by astrocyte activation. In contrast, no increase in oscillatory behavior within the ascending pain pathway occurred during acute noxious stimuli in healthy individuals. These data reveal increased oscillatory activity within the ascending pain pathway that likely underpins increased thalamocortical oscillatory activity, a self-sustaining thalamocortical dysrhythmia, and the constant perception of pain. SIGNIFICANCE STATEMENT Chronic neuropathic pain is associated with altered thalamic firing and thalamocortical dysrhythmia. The mechanisms responsible for these changes remain unknown. In this study, we report in individuals with neuropathic pain increased oscillatory neural activity within the ascending pain pathway with evidence that these changes result from altered neural–astrocyte coupling. We propose a series of neural and glial events after nerve injury that result in the generation of altered thalamocortical activity and a persistent neuropathic pain state. Defining the underlying mechanisms responsible for neuropathic pain is critical if we are to develop more effective treatment regimens.

Differential brain activity in subjects with painful trigeminal neuropathy and painful temporomandibular disorder

Summary Chronic neuropathic and chronic nonneuropathic pain are associated with differential patterns of ongoing cerebral and brain stem blood flow, indicating differential underlying neural mechanisms. ABSTRACT Human brain imaging investigations have revealed that acute pain is associated with coactivation of numerous brain regions, including the thalamus, somatosensory, insular, and cingulate cortices. Surprisingly, a similar set of brain structures is not activated in all chronic pain conditions, particularly chronic neuropathic pain, which is associated with almost exclusively decreased thalamic activity. These inconsistencies may reflect technical issues or fundamental differences in the processing of acute compared with chronic pain. The appreciation of any differences is important because better treatment development will depend on understanding the underlying mechanisms of different forms of pain. In this investigation, we used quantitative arterial spin labeling to compare and contrast regional cerebral blood flow (CBF) patterns in individuals with chronic neuropathic orofacial pain (painful trigeminal neuropathy) and chronic nonneuropathic orofacial pain (painful temporomandibular disorder). Neuropathic pain was associated with CBF decreases in a number of regions, including the thalamus and primary somatosensory and cerebellar cortices. In contrast, chronic nonneuropathic pain was associated with significant CBF increases in regions commonly associated with higher‐order cognitive and emotional functions, such as the anterior cingulate and dorsolateral prefrontal cortices and the precuneus. Furthermore, in subjects with nonneuropathic pain, blood flow increased in motor‐related regions as well as within the spinal trigeminal nucleus.

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.

Novelty Enhances Visual Salience Independently of Reward in the Parietal Lobe

Novelty modulates sensory and reward processes, but it remains unknown how these effects interact, i.e., how the visual effects of novelty are related to its motivational effects. A widespread hypothesis, based on findings that novelty activates reward-related structures, is that all the effects of novelty are explained in terms of reward. According to this idea, a novel stimulus is by default assigned high reward value and hence high salience, but this salience rapidly decreases if the stimulus signals a negative outcome. Here we show that, contrary to this idea, novelty affects visual salience in the monkey lateral intraparietal area (LIP) in ways that are independent of expected reward. Monkeys viewed peripheral visual cues that were novel or familiar (received few or many exposures) and predicted whether the trial will have a positive or a negative outcome—i.e., end in a reward or a lack of reward. We used a saccade-based assay to detect whether the cues automatically attracted or repelled attention from their visual field location. We show that salience—measured in saccades and LIP responses—was enhanced by both novelty and positive reward associations, but these factors were dissociable and habituated on different timescales. The monkeys rapidly recognized that a novel stimulus signaled a negative outcome (and withheld anticipatory licking within the first few presentations), but the salience of that stimulus remained high for multiple subsequent presentations. Therefore, novelty can provide an intrinsic bonus for attention that extends beyond the first presentation and is independent of physical rewards.