Joel D. Greenspan

Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus

&NA; Many lines of evidence implicate the somatosensory areas near the lateral sulcus (Sylvian fissure) in the cortical representation of pain. Anatomical tracing studies in the monkey show nociceptive projection pathways to the vicinity of the secondary somatosensory cortex in the parietal operculum, and to anterior parts of insular cortex deep inside the Sylvian fissure. Clinical observations demonstrate alterations in pain sensation following lesions in these two areas in human parasylvian cortex. Imaging studies in humans reveal increased blood flow in parasylvian cortex, both contralaterally and ipsilaterally, in response to painful stimuli. Painful stimuli (such as laser radiant heat) evoke potentials with a scalp maximum at anterior temporal positions (T3 and T4). Several dipole source analyses as well as subdural recordings have confirmed that the earliest evoked potential following painful laser stimulation of the skin derives from sources in the parietal operculum. Thus, imaging and electrophysiological studies in humans suggest that parasylvian cortex is activated by painful stimuli, and is one of the first cortical relay stations in the central processing of these stimuli. There is mounting evidence for closely located but separate representations of pain (deep parietal operculum and anterior insula) and touch (secondary somatosensory cortex and posterior insula) in parasylvian cortex. This anatomical separation may be one of the reasons why single unit recordings of nociceptive neurons are scarce within regions comprising low‐threshold mechanoreceptive neurons. The functional significance (sensory‐discriminative, affective‐motivational, cognitive‐evaluative) of the closely spaced parasylvian cortical areas in acute and chronic pain is only poorly understood. It is likely that some of these areas are involved in sensory‐limbic projection pathways that may subserve the recognition of potentially tissue damaging stimuli as well as pain memory.

Pain sensitivity alterations as a function of lesion location in the parasylvian cortex

Six patients with lesions involving parasylvian cerebral cortex were evaluated for their pain thresholds using contact heat (all six) and sharp probes that evoke pin-prick pain (4/6). Without knowledge of the sensory status of the individuals, two of the authors evaluated the MRIs of these patients, and determined to what extent the following cerebral regions were involved in the lesion: anterior insula, posterior insula, retroinsula, and parietal operculum. Each patients lesion encompassed at least two of these regions. Three individuals demonstrated significant laterality differences in pain sensitivity, with elevated thresholds on the hand contralateral to his/her lesion. The common feature in these cases was the inclusion of the parietal operculum and posterior insula. The three other cases showed no evidence of abnormal pain thresholds. The common feature of these cases was the apparent sparing of the parietal operculum. Thus, this series of cases points to the significance of the parietal operculum, either alone or with adjacent posterior insula, for normal pain thresholds. In comparison, extensive involvement of the anterior insula in two cases was not associated with abnormal pain thresholds. Four of the six patients were also evaluated with a cold pain tolerance test, which presumably involves more affective/motivational aspects of pain than threshold tests. Only two of these patients showed greater tolerance contralaterally versus ipsilaterally, and theirs were the two lesions of the four with involvement of a large part of the insula. This result supports the theory that the insulas involvement in nociceptive processing is related to the affective/motivational aspect of pain.

Reversible pain and tactile deficits associated with a cerebral tumor compressing the posterior insula and parietal operculum

&NA; Extensive psychophysical tests were conducted on a patient with a well circumscribed tumor located just inferior and posterior to the retroinsular cortex of the right hemisphere. Statistically significant laterality differences were observed, with the left hand exhibiting:a higher mechanical pain threshold,a higher heat pain threshold,a greater cold pain tolerance, anda poorer ability to discriminate roughness. The patient was re‐examined 2.5 months after operative removal of the tumor and was found to have regained normal sensitivity in his left hand. Pre‐ and postoperative MRIs showed resolution of the tumors mass effect on the retroinsula and neighboring parietal operculum, which likely included the second somatosensory cortex. This dramatic change in sensory capacity signifies an essential role for the posterior insula and parietal operculum in normal pain and tactile perception.

Stimulus Features Relevant to the Perception of Sharpness and Mechanically Evoked Cutaneous Pain

Mechanical probes of various sizes and shapes were used to determine thresholds for the perception of pressure, sharpness, and pain on the human finger. As force increased, perception changed from dull pressure to sharp pressure to sharp pain. With the smallest probe (0.01 mm2), sharpness threshold was very close to pressure threshold. As probe size increased, sharpness and pain threshold expressed in terms of force) increased in proportion to probe circumference (not probe area), whereas pressure threshold increased relatively little. Pain and sharpness thresholds also increased as probe angle became obtuse. There was a statistically significant increase in both thresholds with a probe angle change of 15 degrees. Thus, both size and shape are necessary to describe a mechanical stimulus adequately, and pressure (force/area) is not a sufficient metric for pain studies. Thresholds varied at different skin sites on the finger. The dorsal surface had lower thresholds than the volar surface, but the difference between the two areas was not always statistically significant. The compliance of the skin (e.g., the amount of indentation produced by a given force) exhibited no relation to sharpness or pain threshold, whether considered within subjects at various skin sites, or across subjects at the same skin site. Comparison of the perceptual thresholds with the thresholds for nociceptors determined in electrophysiological studies indicates that the sensation of nonpainful sharpness is likely to be mediated by nociceptors. Furthermore, considerably more than threshold activation of nociceptors is necessary for normal pain perception.

Potential Autonomic Risk Factors for Chronic TMD: Descriptive Data and Empirically Identified Domains from the OPPERA Case-Control Study

UNLABELLED Case-control studies have consistently associated psychosocial factors with chronic pain in general, and with temporomandibular disorders (TMD) specifically. Moreover, a handful of prospective studies suggest that preexisting psychosocial characteristics represent risk factors for new onset TMD. The current study presents psychosocial findings from the baseline case-control study of the Orofacial Pain Prospective Evaluation and Risk Assessment (OPPERA) cooperative agreement. For this study, 1,633 TMD-free controls and 185 TMD cases completed a battery of psychosocial instruments assessing general psychosocial adjustment and personality, affective distress, psychosocial stress, somatic awareness, and pain coping and catastrophizing. In bivariate and demographically adjusted analyses, odds of TMD were associated with higher levels of psychosocial symptoms, affective distress, somatic awareness, and pain catastrophizing. Among controls, significant gender and ethnic group differences in psychosocial measures were observed, consistent with previous findings. Principal component analysis was undertaken to identify latent constructs revealing 4 components: stress and negative affectivity, global psychosocial symptoms, passive pain coping, and active pain coping. These findings provide further evidence of associations between psychosocial factors and TMD. Future prospective analyses in the OPPERA cohort will determine if the premorbid presence of these psychosocial factors predicts increased risk for developing new onset TMD. PERSPECTIVE This article reports baseline psychosocial findings from the OPPERA Study, a large prospective cohort study designed to discover causal determinants of TMD pain. Findings indicate significant differences between TMD cases and TMD-free controls across multiple psychosocial constructs, and future analyses will determine whether these psychosocial factors increase risk for new onset TMD.

Gender differences in temporal summation of mechanically evoked pain.

&NA; Several studies indicate that females are more sensitive to experimentally induced pain than males. Moreover, it was recently shown that temporal summation of heat pain is greater in females than males, suggesting that central processing of nociceptive input may be upregulated in women. Temporal summation of pain has been examined principally using thermal or electrical stimuli. The purpose of this study was to investigate the temporal summation to noxious mechanical stimulation, and examine gender differences in temporal summation of mechanically evoked pain. A sharp probe was used to apply brief mechanical stimuli on the fingers of ten healthy females and ten healthy males. Trains of ten repetitive stimuli were applied at an intensity of 1.2–1.3× the individual subjects pain threshold, at interstimulus intervals (ISIs) ranging from 1 to 6 s. The same or different skin sites were stimulated in any single train of stimuli. The pain ratings for the fifth as well as the tenth stimulus were significantly higher than those for the first stimulus. Also, the pain responses for the tenth stimulus were higher than those for the fifth. There was no overall gender difference in pain ratings, however, there was a significant trial #×gender interaction. Males and females provided comparable magnitude estimates for the first stimulus in the train, but females provided higher pain ratings than males for the fifth as well as the tenth stimulus. Temporal summation occurred across all ISIs, but shorter ISIs (1–3 s) elicited significantly greater temporal summation than longer ISIs (4–6 s). Finally, although higher pain ratings were obtained when the ten consecutive stimuli were applied on the same versus different skin areas, the degree of temporal summation was not significantly different. These findings indicate that temporal summation of mechanically evoked pain is higher in females compared to males, is stimulation frequency dependent and is centrally mediated.

Evidence for generalized hyperalgesia in temporomandibular disorders patients.

Temporomandibular disorders (TMD) is a collective term including a number of pathological conditions involving the temporomandibular joints (TMJ) and the masticatory musculature, and manifesting with pain and dysfunction of the orofacial apparatus. The most common signs and symptoms of TMD include facial pain, tenderness upon joint and muscle palpation, limited or asymmetric mandibular movement, and TMJ sounds. TMD affect approximately 12% of the population, and are most prevalent among women of reproductive age (Dworkin, 1995). TMD are subdivided into articular and masticatory muscle disorders. Articular disorders include disc displacements, arthralgia, osteoarthritis and osteoarthrosis of the TMJ, while muscle disorders encompass myositis, myospasm, contracture and myofascial pain. Myofascial pain is characterized by pain and tenderness to palpation in the masticatory muscles. Despite extensive research in the past few decades, the pathophysiology of TMD-related chronic myofascial pain remains unknown. In accordance with the research diagnostic criteria for TMD (RDC/TMD; Dworkin and LeResche, 1992), studies indicate that pressure pain thresholds (PPTs) are lower in the masticatory muscles of myogenous TMD patients than pain-free controls (Ohrbach and Gale, 1989; Reid et al., 1994; Farella et al., 2000). Also, several studies have explored the sensitivity of TMD patients to noxious stimuli applied in a remote area, or to cutaneous noxious stimulation of the craniofacial region. These investigations provide valuable information regarding the generalized sensitivity of TMD patients to noxious stimulation, with important implications for the mechanisms underlying TMD. This article reviews the scientific literature on the generalized sensitivity of TMD patients to various experimental noxious stimuli, and discusses relevant pathophysiological mechanisms. MEDLINE was searched for English language studies examining the sensitivity of TMD patients to noxious stimulation in bodily sites remote to the craniofacial region, and cutaneous noxious stimulation in the affected area. The following terms were used: experimental pain, threshold, tolerance, and temporomandibular disorders. Relevant articles mentioned in the reference lists of studies were also included. Fifteen studies were identified and included in this review.

Clinical Findings and Pain Symptoms as Potential Risk Factors for Chronic TMD: Descriptive Data and Empirically Identified Domains from the OPPERA Case-Control Study

Clinical characteristics might be associated with temporomandibular disorders (TMD) because they are antecedent risk factors that increase the likelihood of a healthy person developing the condition or because they represent signs or symptoms of either subclinical or overt TMD. In this baseline case-control study of the multisite Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) project, 1,633 controls and 185 cases with chronic, painful TMD completed questionnaires and received clinical examinations. Odds ratios measuring association between each clinical factor and TMD were computed, with adjustment for study-site as well as age, sex, and race/ethnicity. Compared to controls, TMD cases reported more trauma, greater parafunction, more headaches and other pain disorders, more functional limitation in using the jaw, more nonpain symptoms in the facial area, more temporomandibular joint noises and jaw locking, more neural or sensory medical conditions, and worse overall medical status. They also exhibited on examination reduced jaw mobility, more joint noises, and a greater number of painful masticatory, cervical, and body muscles upon palpation. The results indicated that TMD cases differ substantially from controls across almost all variables assessed. Future analyses of follow-up data will determine whether these clinical characteristics predict increased risk for developing first-onset pain-related TMD PERSPECTIVE: Clinical findings from OPPERAs baseline case-control study indicate significant differences between chronic TMD cases and controls with respect to trauma history, parafunction, other pain disorders, health status, and clinical examination data. Future analyses will examine their contribution to TMD onset.

Allodynia in patients with post-stroke central pain (CPSP) studied by statistical quantitative sensory testing within individuals

&NA; The disinhibition hypothesis of post‐stroke central pain (CPSP) suggests that ‘the excessive response (dysesthesia/hyperalgesia/allodynia) is accompanied by a…loss of sensation’ resulting from a lesion of a ‘lateral nucleus’ of thalamus or of ‘cortico‐thalamic paths’ [Brain 34 (1911) 102]. One recent elaboration of this hypothesis proposes a submodality specific relationship, such that injury to a cool‐signaling lateral thalamic pathway disinhibits a nociceptive medial thalamic pathway, thereby producing both burning, cold, ongoing pain and cold allodynia. The current study quantitatively evaluated the sensory loss and sensory abnormalities to discern submodality relationships between these sensory features of CPSP. The present results were statistically tested within individuals so that sensory loss and sensory abnormality are directly related by occurrence in the same individual. The results demonstrate that individuals with CPSP and normal tactile detection thresholds experience tactile allodynia significantly more often than those with tactile hypoesthesia. Most patients (11/13) exhibited hypoesthesia for the perception of cool stimuli, but few of these (2/11) showed cold allodynia. The most dramatic case of cold allodynia occurred in a patient who had a normal detection threshold for cold. Individuals with cold hypoesthesia, strictly contralateral to the cerebro‐vascular accident (CVA or stroke), were often characterized by the presence of burning, cold, ongoing pain, and by the absence, not the presence, of cold allodynia. Overall, these results in CPSP suggest that tactile allodynia occurs in disturbances of thermal/pain pathways that spare the tactile‐signaling pathways, and that cold hypoesthesia is neither necessary nor sufficient for cold allodynia.

Why Look in the Brain for Answers to Temporomandibular Disorder Pain

Temporomandibular disorder (TMD) patients often exhibit widespread clinical pain, as well as greater sensitivity to experimental pain than pain-free controls, suggesting a role of central pathophysiologic mechanisms in TMD. Moreover, TMD is more prevalent among women, which may be related to the higher sensitivity of women to experimental pain. Women also exhibit greater temporal summation of heat pain compared to men. Temporal summation, the increase in pain intensity upon repetitive noxious stimulation of constant intensity, at a high frequency is centrally mediated. Thus, greater temporal summation in women indicates that their central nociceptive processing is upregulated compared to men. Recent studies in our research center sought further evidence for upregulation of central nociceptive processing in females compared to males and in TMD patients compared to healthy controls, assessing group differences in temporal summation of mechanically evoked pain, and aftersensations following repetitive noxious stimulation. Sixteen series of 10 repetitive, sharp, mechanical stimuli were applied to the fingers of 25 female TMD patients, 25 healthy women, and 25 healthy men, with a computer-controlled small probe. All subjects rated the pain intensity or the unpleasantness evoked by the 1st, 5th and 10th stimulus in the series, and the aftersensations 15 s and 1 min after the last stimulus on visual-analog scales. TMD patients exhibited greater temporal summation of pain and unpleasantness, stronger aftersensations, and more frequent painful aftersensations than controls. Healthy females showed greater temporal summation of pain intensity and unpleasantness, higher intensity and unpleasantness of aftersensations, and more frequent painful aftersensations than males. Greater temporal summation of pain and aftersensations from digital stimulation of TMD patients than controls suggest a generalized hyperexcitability of the central nociceptive system in this patient group. Such hyperexcitability may contribute to the development and/or maintenance of chronic TMD pain. Moreover, greater temporal summation of pain and aftersensations in healthy females than males indicate that their central processing of nociceptive input may be more easily upregulated into pathological hyperexcitability, possibly accounting for the predominance of TMD among women.