Pain sensitivity alterations as a function of lesion... : PAIN (original) (raw)
1. Introduction
Several lines of evidence suggest that regions of the parasylvian cerebral cortex process somesthetic information that is relevant to pain perception. Based on primate neuroanatomical studies, nociceptive processing regions of thalamus project axons to the parietal operculum (which includes the second somatosensory cortex: S2, and area 7b), the insular cortex, and its posterior extension, the retroinsula (Burton and Jones, 1976; Jones and Burton, 1976; Mufson and Mesulam, 1984; Mesulam and Mufson, 1985; Burton and Carlson, 1986; Friedman and Murray, 1986; Stevens et al., 1993; Craig, 1995). An analogous relationship exists for human beings, such that nuclei containing nociresponsive neurons in and around the ventral caudal nucleus (VC) (Lenz et al., 1993; Lenz et al., 1994) project to the anterior insular cortex and the posterior parietal operculum (Van Buren and Borke, 1972). Parasylvian cortical regions receive nociceptive input, as measured by scalp recorded evoked potentials (Chatrian et al., 1975; Kunde and Treede, 1993; Bromm and Chen, 1995), cortical-surface recorded evoked potentials (Lenz et al., 1998), and magnetoencephalography (MEG) (Hari et al., 1983; Hari and Kaukoranta, 1985; Kitamura et al., 1995). Positron emission tomography (PET) and functional MRI (fMRI) show regional brain activation within the parietal operculum and the insula in response to painful stimuli (Talbot et al., 1991; Casey et al. 1994, Coghill et al. 1994; Casey et al., 1996; Craig et al., 1996; Davis et al., 1998; Greenspan et al., 1998). In addition, hypalgesia and hypesthesia – sometimes accompanied by central pain – have been observed in people with parasylvian lesions (Davison and Schick, 1935; Biemond, 1956; Obrador et al., 1957; Greenspan and Winfield, 1992; Schmahmann and Leifer, 1992; Horiuchi et al., 1996).
The present study sought to quantitatively evaluate pain sensitivity of several individuals with lesions involving the parasylvian region. Since any one patient is likely to have a lesion encompassing multiple areas of interest, a single case alone is not precisely informative as to the brain region most relevant for pain sensitivity. However, by comparing individuals with different lesions, using a standardized psychophysical protocol, one can specify those regions that are most consistently related to pain perception alterations. Some of these results have been reported in abstract form (Greenspan et al., 1997).
2. Methods
2.1. Subjects
Patients were recruited from the neurosurgery service at SUNY Health Science Center for participation in this project. Criteria for recruitment included: (1) a lesion encompassing the insula and/or the parietal operculum as determined by at least one MRI study depicting the entire brain; (2) normal cognitive function; (3) normal language and speech skills, or only a mild degree of aphasia; and (4) willingness to undergo sensory testing. Over a 2-year period, six people fulfilled these criteria. Each subject signed an informed consent agreement to participate in these experiments. They were paid $10/h of psychophysical testing. This project was approved and reviewed annually by the Institutional Review Board for the Protection of Human Subjects at SUNY Health Science Center, Syracuse.
Subject M.C. (53-year-old female) had a glioblastoma multiforme in her left parasylvian region (Fig. 1, top row). She first showed symptoms of the tumor 6–7 weeks before her psychophysical testing. The initial symptoms included transient (˜1 min) hypesthesias in her right hand and leg with some weakness. Over the next month, these episodes became slightly longer (˜2 min), and included motor discoordination and aphasia. A neurological exam one day prior to her psychophysical testing revealed slurred, but comprehensible speech, and no other indication of aphasia. Muscle strength was normal, although she would drag her right foot slightly when walking. She demonstrated decreased pin-prick and tactile sensitivity on her right side, including face, upper limb, trunk, and lower limb.
Gadolinium-enhanced, T1-weighted MR images of three subjects who demonstrated significant laterality differences in pain threshold. The three coronal images were chosen to be at the level of (1) the anterior insula; (2) the posterior insula; and (3) the retroinsula. The sagittal and horizontal images were chosen to best reveal the pathology. Arrowheads on sagittal images indicate the central sulcus. Note that for subject M.C., the central sulcus is displaced anteriorly at its more lateral extent (arrow on sagittal image).
Subject K.H. (29-year-old female) had an anaplastic oligodendroglioma in her left parasylvian region (Fig. 1, middle row). She had a 1-year history of increasing headache and a 2-month history of clumsiness with walking prior to her testing. One month prior to her testing, she experienced a grand mal seizure. On clinical exam, she showed reduced sensitivity to pin prick on the entire right side, while appearing normal for light touch and position sense.
Subject B.B. (33-year-old male) had a cavernous hemangioma with a sub-acute intraparenchymal hemorrhage in the right parietal lobe (Fig. 1, bottom row). In addition, his MRI study showed three other small hemangiomas (<5 mm across), including one in the left parietal lobe, homolateral to the large one. He had a 3-year history of partial complex seizures with ‘numbness and tingling’ in his left arm and hand, and ‘confusion’. On clinical exam, he demonstrated ‘mildly’ reduced pin prick and light touch sensitivity on the left side, including face, hand, and foot.
Subject K.B. (37-year-old female at time of testing) had an anaplastic astrocytoma in her right parasylvian region (Fig. 2, top row). She had a 4-month history of simple sensory seizures, some with secondary generalization. These seizures began with sensations of numbness, tingling, or burning throughout her left side. On clinical exam, she showed no abnormality in pin prick or tactile sensitivity.
T2-wighted (K.B.) and T1-weighted (C.M. and J.E.) MR images of three subjects who demonstrated no pain threshold abnormality. Images were chosen with the same criteria as for Fig. 1. Arrowheads on the horizontal images denote the central sulcus. Sagittal images were not available for K.B. or C.M.
Subject C.M. (29-year-old male at time of testing) had a grade I/II astrocytoma in his right insula (Fig. 2, middle row). He had a 7-month history of sensory seizures, which evoked warm sensations referred to his left side. On clinical exam, he showed no abnormality in pin prick or tactile sensitivity.
Subject J.E. (37-year-old female) had a low-grade astrocytoma in her left insula (Fig. 2, bottom row). She had an 8-month history of partial complex seizures. Two weeks prior to her psychophysical testing, she experienced her first seizure producing right-sided numbness and hemiplegia. On clinical exam, she showed no abnormality in pin prick or tactile sensitivity.
At the time of testing, all subjects were taking high doses of anti-seizure medication, and all but two (B.B. and K.B.) were taking Decadron.
2.2. MRI analysis
In all cases, only the MRIs created for clinical purposes were available (Figs. 1 and 2). These were T1-weighed images with gadolinium enhancement. Each image represented a brain slice 5 mm thick. Regions of low signal intensity on these images were interpreted as tumor mass or associated peritumoral edema (Hasso et al., 1992). High signal intensity on these images was interpreted as hemorrhage (e.g. patients B.B. and K.H., Bradley, 1992). T2-weighted images were used to define the lesion extent for one case in which the T1-weighted image provided a less definitive picture of the lesion boundaries (patient K.B.).
One critical feature was identification of the central sulcus, which was accomplished using two methods: On sagittal images, the marginal branch of the cingulate gyrus was taken to the posterior margin of the paracentral lobule. The vertically oriented sulcus within this lobule was taken to be the central sulcus, and was traced through more lateral images (Steinmetz et al., 1990; Naidich et al., 1995). On axial images, the superior frontal sulcus terminated posteriorly at the precentral sulcus. The next sulcus posteriorly is the central sulcus, which was traced through successive images (Naidich, 1991; Naidich and Brightbill, 1996).
The position of the central sulcus at its most lateral point was used as a landmark to divide the insula into anterior and posterior components. The parietal operculum was defined as that part of the superior operculum that was coextensive in the anterior–posterior (A–P) axis with the posterior insula. The retroinsula was defined as that cortical region within the Sylvian fissure that lay posterior to the insular gyri.
2.3. Sensory testing procedures
All subjects were tested with a contact heating probe (1.2 cm2) to determine their heat pain threshold at the thenar eminence, and at least one other body site: the dorsal aspect of the forearm, the lateral aspect of the calf, or the plantar surface of the foot. A multiple staircase procedure was used to derive pain thresholds, and in some cases, cool perception thresholds. Details of the equipment and the procedures are described in Taylor et al. (1993)and Greenspan et al. (1993).
Three of the subjects also participated in a cold pain tolerance test, in which they were asked to keep a hand in cold water (either 10° or 0°C) for ‘as long as you can tolerate it’. The duration of their voluntary immersion was recorded as the tolerance measure.
Four subjects were evaluated for three distinct mechanically evoked sensations – perception of pressure, sharpness, and pain – using a modified ascending method of limits protocol as described in Greenspan and McGillis (1991). Small cylindrical probes with flat surfaces (0.05 or 0.10 mm2 skin contact area) were used to apply forces ranging from 1–100 g. Stimuli were applied on the dorsal surface of digits two and three.
The mechanical and thermal threshold values derived from these subjects were compared to a data set derived from healthy, neurologically intact subjects tested in the same manner (Taylor et al., 1993; Greenspan and McGillis, 1994). As described in these earlier studies, the range of threshold values across any group of people can be relatively large. However, laterality differences in thresholds provide a much narrower distribution of values, and can more readily identify significant unilateral abnormalities in sensory threshold. Accordingly, we used a value of two standard deviations above the mean laterality difference in the normative database as the criterion of an abnormal laterality difference.
3. Results
3.1. Subjects demonstrating elevated thresholds: MC, KH, BB
Three subjects showed elevated thresholds to mechanically evoked pain and two of those also showed elevated thresholds to heat evoked pain, contralateral to their lesion. Subject M.C. showed the most extensive sensory deficits, reporting virtually no sensations associated with any of the mechanical stimuli applied to her contralateral hand, while showing ipsilateral thresholds well within the normative range (Fig. 3). She also demonstrated the greatest heat pain threshold elevation in the group, most notably for her hand (Fig. 3). Non-painful heat stimuli were occasionally described as warm or hot on her contralateral side, but they were usually not detected. In addition, she uniformly failed to recognize cool stimuli applied to her contralateral hand (temperature change of up to −8.0°C), while showing a cool detection threshold of −0.8°C ipsilaterally.
Sensory thresholds for subject M.C. Top: Threshold values for the various modalities derived from sites contralateral and ipsilateral to the neuropathologic lesion. Note that this subject failed to detect any mechanical stimuli on her right (contralateral) hand, so thresholds are scored as above the ceiling value of 100 g. The dotted lines denote the median (mechanical probe data) or the mean (heat pain data) of thresholds derived from a similarly tested, same sex group of healthy subjects (Greenspan and McGillis, 1991; Taylor et al., 1993; Greenspan and McGillis, 1994). Bottom: Laterality differences in thresholds for the various sensory modalities. The shaded bars represent the range of normative laterality differences, calculated as the mean±2 standard deviations, derived from a group of healthy subjects.
Subject K.H., with a similarly placed but smaller lesion than M.C., showed less extensive, but still significant laterality differences in mechanical and heat pain thresholds, as well as innocuous pressure perception threshold (Fig. 4; no cold pain data collected). Subject B.B., with an even smaller lesion, demonstrated contralateral threshold elevations to mechanical stimuli, including innocuous pressure and pain threshold, but no indication of a heat pain deficit (Fig. 5). However, he failed to recognize cool stimuli applied to his contralateral hand (temperature change of up to −8.0°C), while showing a cool detection threshold of −1.6°C ipsilaterally. A common feature in these cases is the clear involvement of the posterior parietal operculum and the posterior insula in all three lesions (Fig. 1, Table 1).
Sensory thresholds for subject K.H. See Fig. 3 for legend details.
Sensory thresholds for subject B.B. See Fig. 3 for legend details.
Lesion location and sensory testing summarya
It is noteworthy that in all instances of significant laterality differences in thresholds, the ipsilateral threshold is below the normative mean, sometimes very much below (e.g. MC and KH heat pain thresholds for the hand). These low thresholds, however, are less than two standard deviations below the mean of the normative threshold values, and thus cannot be considered automatically abnormally low.
3.2. Subjects demonstrating normal thresholds: KB, CM, JE
Three subjects showed no indication of abnormal pain sensitivity. Subject K.B. was extensively tested, and demonstrated no abnormal values for any mechanical or heat pain tests (Fig. 6). In her case, heat pain testing was done on several body sites. Her MRI images demonstrated a lesion restricted to the retroinsular region, with no visible encroachment into the posterior insula or parietal operculum (Fig. 2).
Sensory thresholds for subject K.B. See Fig. 3 for legend details.
The other two subjects were only tested for heat pain thresholds, due to their limited availability for testing. Neither one showed any indication of a threshold elevation contralaterally (Fig. 7). In both cases, the lesions encompassed an extensive portion of the anterior and mid-insula. C.M. also showed some involvement of the posterior insula, but in neither case was the parietal operculum involved.
Sensory thresholds for subjects J.E. (left) and C.M. (right). These subjects were only available for heat pain testing. See Fig. 3 for legend details.
3.3. Cold pain tolerance
Four of these subjects were tested for cold pain tolerance. M.C. demonstrated a clear, contralateral cold pain hypalgesia by tolerating a 10°C water bath four times longer with her right versus left hand (ipsilateral=.9 s; contralateral=32.2 s; single trail). C.M. also showed an increased cold pain tolerance contralateral to his lesion (ipsilateral=49.3 s; contralateral=maximum limit of 60 s; single trail). In contrast, neither B.B. nor K.B. showed any evidence of a laterality difference in latency to withdraw from a 0°C water bath (B.B.: ipsilateral=10.8 s, contralateral=9.4 s, means of three trials; K.B.: ipsilateral=11.3 s; contralateral=11.3 s; single trial).
4. Discussion
4.1. The posterior parietal operculum
The fundamental correlation observed in this series of patients was that lesions involving the posterior parietal operculum were associated with contralateral threshold elevations while lesions sparing this region showed no pain threshold alterations. The significance of the posterior parietal operculum for pain perception has been suggested previously by evidence of nociceptive input (evoked potentials, MEG), and by hemodynamic measures of regional activation (PET and fMRI) associated with the application of painful stimuli.
Nociresponsive neurons have been documented in the monkey parietal operculum with evoked potentials (Chudler et al., 1985; Chudler et al., 1986) and single unit recordings (Robinson and Burton, 1980; Dong et al., 1989; Dong et al., 1994). The detailed anatomical reconstruction of recording sites in these studies indicate that most of the parasylvian nociresponsive neurons are in the 7b region of the parietal operculum – nearby, but not within S2. In fact, it has been argued that S2 is a mechanoreceptive integrative region, and only involved with tactile perception (Burton, 1986; Burton et al., 1993).
In man, both innocuous and pain-related activity has been identified in the parietal opercular region with evoked potentials (Chatrian et al., 1975; Bromm and Chen, 1995; Lenz et al., 1998), MEG (Hari et al., 1983; Hari and Kaukoranta, 1985; Kitamura et al., 1995), and PET signals (Talbot et al., 1991; Casey et al., 1994; Casey et al., 1996; Coghill et al., 1994; Craig et al., 1996). The spatial resolutions of these techniques do not allow for the same precise localization as with the monkey studies, so it is not possible to determine whether separate loci of activity are associated with painful versus innocuous stimulation. Functional MRI studies in human subjects do allow for greater anatomical precision in localizing stimulus-related brain activation. Recent reports have shown that coincident regions in the parietal operculum are activated with both tactile and noxious stimuli (Davis et al., 1998), including both noxious mechanical and noxious heat stimuli (Greenspan et al., 1998). Thus, one might expect damage to this region to produce effects upon both tactile and pain perception, as was observed here.
Hypalgesia has been reported in patients with cerebral lesions involving the parietal operculum, posterior insula, and/or underlying white matter. Davison and Schick (1935) described two patients exhibiting unilateral hypalgesia, hypothermesthesia, and hypesthesia. Autopsy revealed an infarct of the insula and parietal operculum, but sparing the thalamus, internal capsule, and most of the post-central gyrus (S1). Biemond (1956) described two hypalgesic patients with CVA resembling those of Davison and Schick's patients. Only the most lateral and inferior portions of the parietal lobe were affected, thus sparing most of S1. Obrador et al. (1957) described a patient with a small infarct just beneath the insula, which affected part of the claustrum and adjacent white matter, but appeared to spare the parietal cortex and thalamus. This person experienced spontaneous pains and hyperpathia primarily in the face and distal upper limb, but also demonstrated hypalgesia and hypothermesthesia in the lower abdomen and lower limb, contralateral to the lesion. Schmahmann and Leifer (1992) studied six people who developed hemibody pain following parietal lobe lesions. All showed clinically observable reductions in pin prick and thermal sensation, and the common region of all lesions was the contralateral, posterior parietal operculum. Recently, Horiuchi et al. (1996) described a case in which a sudden hemibody reduction in tactile and pain sensitivity was associated with a small infarct located within the inner bank of the contralateral parietal operculum, while apparently sparing the insula. The present report demonstrates that lesions of parietal operculum, but not insula alone, are sufficient for significant contralateral elevations of pain threshold.
For the cases in which the posterior parietal operculum is involved, encroachment of the post central gyrus (e.g. S1 cortex) cannot be ruled out entirely. This is most evident for subject M.C., who had the largest lesion that involved the parietal operculum. However, functional imaging and evoked potential studies indicate that the hand representation of S1 cortex is located superior to any of the lesions that approach the postcentral gyrus in this group of patients.
4.2. Mechanical versus thermal pain
In one case (B.B.) we observed a significant laterality difference in mechanical pain threshold, but not even a slight difference in heat pain threshold or cold pain tolerance. This individual had the smallest lesion of those involving the parietal operculum. While this is only one case, this clear difference between mechanical and heat pain effects suggests that the two types of information can be processed differentially to some extent in this cortical region. It may be relevant that within somatosensory areas of lateral thalamus, some neurons are responsive to noxious mechanical, but not to noxious thermal stimuli, both in monkey (Kenshalo et al., 1980; Chung et al., 1986) and man (Lenz et al., 1994). In man, these neurons are functionally distinguishable from those that are responsive to noxious heat (Lenz et al., 1993).
4.3. Ipsilateral effects
An unexpected observation was that those people with significant laterality differences in pain threshold had lower than normal thresholds ipsilateral to their lesion. Indeed, in some cases the ipsilateral threshold was as far from the normative mean/median as the contralateral threshold. This apparent ipsilateral hyperalgesia must be viewed with caution, since the range of normative thresholds is large enough to include those values. However, the fact that in all cases, subjects with significant laterality differences showed lower than normal thresholds ipsilaterally suggests that an ipsilateral change resulted from these lesions. A callosal connection has been identified between the two homolateral hand areas of the S2 region of monkey cortex (Manzoni et al., 1984), the function of which remains to be determined (Burton, 1986; Innocenti, 1986). If the transcallosal interaction is inhibitory as far as nociceptive input is concerned, then a unilateral lesion may be expected to produce a contralateral hypalgesia and an ipsilateral hyperalgesia, as observed here.
4.4. The insular cortex
Although early brain stimulation studies suggested that the insula had some role in somesthetic perception (Penfield and Faulk, 1955), its function lay largely unexplored until recently. The renewed interest is attributable to several PET studies that documented a significant and consistent activation in multiple regions of the insula in response to thermal and painful stimulation (Talbot et al., 1991; Casey et al., 1994; Casey et al., 1996; Coghill et al., 1994; Craig et al., 1996). In these studies, two separable areas within the insula have been found to produce significant signal with heat pain stimuli: one anteriorly and another more posteriorly – the latter perhaps continuous with a posterior parietal opercular region of activation. The lesions of C.M. and J.E. appear to have encompassed the more anterior region of insula that is activated by painful thermal stimuli, yet these lesions had no effect upon heat pain thresholds.
Berthier et al. (1987) described six patients with insular cortex lesions, documented with computer tomography images. These patients were described as having asymbolia to pain with a flat affect. Three of these patients were tested for pain threshold with electrocutaneous stimuli. Their thresholds were not significantly different from a group of control subjects, although, laterality differences were not addressed.
Four of the subjects in this study were evaluated for cold pain tolerance, which presumably involves more affective/motivational aspects of pain than threshold tests. Two of these subjects (M.C. and C.M.) showed a greater cold pain tolerance contralateral to their lesions, and they were the ones whose lesions had large involvement of the insula. Our results and Berthier's results support the idea that the insula's role in nociceptive information processing is not related to pain threshold. Rather, the insula is more likely to have a role in the more affective and motivational aspects of pain (Coghill et al., 1994).
Acknowledgements
We thank Jeffrey M. Winfield, MD, Ph.D., formerly of the Neurosurgery Department of SUNY Health Science Center, Syracuse, for his assistance in identifying subjects for this project. We also thank Sandra L.B. McGillis, for her assistance in conducting the sensory testing. This project was supported by NIH grant R01-NS28559 (JDG), and P01-NS32386 (FAL).
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Keywords:
Pain; Parasylvian cortex; Second somatosensory cortex; Insula; Heat pain; Cutaneous pain; Brain lesion
© 1999 Lippincott Williams & Wilkins, Inc.