1Divisione di Neurologia, Ospedale Pediatrico Bambino GesùIRCCS, Roma, Italy
2Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma, Italy
3Divisione di Riabilitazione Neuromotoria, Casa di Cura San Raffaele Pisana, IRCCS, via della Pisana 235, 00165 Roma, Italy
4Istituto di Neurologia, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma, Italy
Received 25 October 2004; revised 11 February 2005; accepted 17 February 2005; online publish-ahead-of-print 24 March 2005.
* Corresponding author. Tel: +39 06 3015 4187; fax +39 06 3055 535. E-mail address: g.a.lanza{at}inwind.it
See page 946 for the editorial comment on this article (doi:10.1093/eurheartj/ehi242)
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Abstract |
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Methods and results Cortical laser evoked potentials (LEPs) were recorded in 16 SX patients, in 10 patients with refractory angina due to obstructive coronary artery disease (CAD) and in 13 healthy controls. LEPs were recorded during stimulation of chest and right hand dorsum. Three sequences of painful stimuli were applied at each site. Subjective pain rating was assessed by a 0100 mm visual analogic scale (VAS). Basal LEPs did not differ among groups and there were no differences for most LEP components across the repetitions of stimuli. However, the amplitude of the N2/P2 LEP component, specifically reflecting cortical pain processing, decreased across the three sequences of stimuli in controls and CAD patients, but not in SX patients. Compared with the first sequence, the N2/P2 amplitude during the third sequence of stimuli in the three groups was 77±16, 56±24, and 99±34%, respectively, for chest (P=0.001), and 63±31, 72±17, and 98±46%, respectively, for right hand (P=0.03) stimulation. The changes in VAS pain score across the three sequences paralleled those of N2/P2 amplitude.
Conclusion Our data show that in SX patients, central handling of painful stimuli is characterized by inadequate habituation, which might play a role in determining the peculiar clinical characteristics of anginal chest pain of these patients.
Key Words: Syndrome X Pain Cortical laser evoked potentials
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Introduction |
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However, in several SX patients, the severity and refractoriness of chest pain episodes usually contrast with the limited objective evidence of myocardial ischaemia on standard diagnostic techniques,69 suggesting that, in most cases, the latter may not be sufficient to account by itself for patient symptoms. Previous studies in SX patients consistently demonstrated increased painful sensitivity to cardiac stimuli which do not usually cause any sensation in healthy subjects,1013 thus suggesting that an abnormal cardiac nociception might play a major role in the pathophysiology of the syndrome, allowing even to mild myocardial ischaemia to result in a relevant clinical syndrome.
In a recent study, Rosen et al.14 using positron emission tomography showed increased blood flow to the right insular cortex during dobutamine stress test in SX patients. The authors suggested that an increased activity of this cortical region, resulting in a facilitating topdown influence on pain transmission, might be a major mechanism of chest pain in SX patients. However, whether the right insular activation was a primary phenomenon or it was rather the effect of a more peripheral (e.g. cardiac, spinal, or thalamic) nociception abnormality could not be ascertained by that study.
In the present study, we investigated the function of the brain areas specifically devoted to nociception in SX patients, by assessing cortical laser evoked potentials (LEPs) in response to cutaneous CO2 laser pulses. These latter have indeed been shown to be suitable to study the nociceptive pathway function, as they are able to activate selectively the thin myelinated (A) and unmyelinated (C) nociceptive fibres without any concurrent activation of the larger, non-nociceptive afferent fibres.15
Specifically, two main cortical LEP components are recorded during cutaneous CO2 laser stimulation, N1P1 and N2/P2. The N1P1 wave is believed to originate in the secondary somatosensory area (SII) and correlates with the sensory-discriminative aspect of pain.24 The N2/P2 response, on the other hand, is mostly generated by neurons in the cingulate cortex18,19,2527 and is important for the emotional component of sensation.28,29
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Methods |
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In the attempt to limit the possibility that the detection of cortical LEP abnormalities in SX patients might be secondary to recurrent chest pain, rather than an expression of a potential pathogenetic mechanism of the syndrome, we also studied a group of 10 patients with documented severe coronary artery disease (CAD), who presented a chronic clinical pattern of stable angina episodes refractory to maximally tolerated drug therapy (refractory angina), caused by a CAD pattern judged unsuitable for both percutaneous and surgical coronary revascularization. These patients were older than SX patients and controls (age 65.8±10, P<0.01 vs. the other groups), but similar in gender (six men, four women; P=0.53 for comparisons among groups). Furthermore, the frequency of angina episodes in these patients was similar to that of patients with SX (Table 1). Patients with neurological or systemic diseases or with any other chronic painful condition other than angina pectoris were excluded from the study.
Laser stimulation and LEP recording
The study protocol was approved by the Ethics Committee of our Institution, and investigational procedures were performed after obtaining written informed consent to participate in the study. All neurophysiological investigation tests were performed by expert neurologists who were blinded to the clinical diagnosis of the subjects. The tests were always performed in the afternoon (from 3:00 to 6:00 PM), in standard conditions, with the subjects lying on a couch in a warm and semi-dark room. In SX and CAD patients, LEP recordings were performed no less than 24 h after the last angina attack. The stimulation site was visualized by a HeNe laser beam. After each stimulus, the laser beam was slightly shifted to a nearby spot to avoid nociceptor sensitization and skin damage. Laser pulses (wavelength 10.6 µm, beam diameter 2 mm, duration 10 ms) were delivered by a CO2 Neurolas (Electronic Engineering, Florence, Italy).
The chest skin and the right hand dorsum were stimulated in all subjects. Chest was chosen because, according to the theory of referred visceral pain, the painful laser stimuli delivered on the chest skin are likely to be processed by the same dorsal horn neurons onto which the nociceptive stimuli coming from the heart converge.16 To make this assumption most likely, laser pulses were individualized being delivered on the chest area where each patient referred the pain during angina episodes. In contrast, the right hand was chosen because the nociceptive pathways from this hand are usually separated from those coming from the heart at both peripheral and spinal levels; in our patients, in particular, this was suggested by the fact that none of them had ever referred pain in the right arm.
For each subject, we first identified the sensory threshold (STh), defined as the lowest stimulus intensity [measured in watts (W)] required to elicit a distinct sensation, and determined by the method of limits in three series of increasing and decreasing stimulus intensities. Then, the stimulus intensity was set at 2.5xSTh, felt as clearly painful by all our subjects and this recording intensity (RI) was used to record LEPs.
All subjects underwent an LEP recording session with two scalp electrodes placed along the midline in the frontal (Fz) and in the vertex (Cz) regions and one electrode in the left temporal region (T3). The electrode positions were defined according to the 1020 International System.17 The reference electrode was placed at the nose and the ground on the forehead (Fpz). Eye movements and eye-blinks were monitored by an electroculography (EOG) derivation, obtained by referring an active electrode above the right eyebrow to the nose. Signals were amplified, filtered (bandpass 0.370 Hz), and stored for off-line average and analysis. The analysis time was 1000 ms with a bin width of 2 ms. An automatic artefact rejection system excluded all trials contaminated by transient signals exceeding the average value by ±65 µV at any recording channel, including EOG.
Experimental protocol
Three consecutive sequences of 30 stimuli, with interstimulus intervals varying randomly from 8 to 12 s, were delivered to the chest and to the right hand dorsum. In each site, the sequences were separated by a 5 min interval, and a 10 min interval elapsed after the stimulation site was changed. The sequence of the stimulation sites was randomly varied across subjects. At the end of each sequence of stimuli, patients were asked to score pain sensation induced by laser pulses according to a 0100 point visual analogic scale (VAS), in which 0 corresponded to no pain and 100 to the highest imaginable pain.
In all subjects, recordings from midline electrodes during peripheral laser stimulation showed a late, high-amplitude, biphasic (negativepositive) complex (N2/P2). The N2/P2 amplitude was measured from the negative to the positive peak of the biphasic complex. Besides this biphasic complex, a negative N1 potential in the temporal region and, at approximately the same latency, a positive P1 potential in the frontal region contralateral to the stimulation site were identifiable in all subjects. These potentials were shorter in latency and lower in amplitude than the N2/P2 responses. As the N1P1 potentials are generated by the same dipolar source in the contralateral second somatosensory area,18,19 the N1P1 amplitude was measured off-line by referring the temporal lead to Fz.20
Statistical analysis
Basal continuous clinical variables were compared by analysis of variance (ANOVA), whereas proportions were compared by 2 test. LEP amplitudes and latencies and VAS pain scores recorded in the three groups during the three successive sequences of laser pulses at each stimulation site were compared by two-way ANOVA with a repeated measure design to assess whether changes were present throughout the three sequences of stimuli and whether the changes differ among groups (groupsequence interaction). F-test results were corrected for identity covariance matrix by the GreenhouseGeisser method to take into account possible intragroup correlations.
Furthermore, as we were specifically interested in assessing between-group differences in the changes of LEP components and of pain rating during the third (final), when compared with the first (initial), sequence of stimuli, the measures of variables during the third repetition in each patient at each stimulation site were also expressed as a per cent of the measure during the first sequence and values were compared by ANOVA. For completeness of analysis, a comparison was also separately done for the changes observed during the second, when compared with the first, sequence of stimuli. Student's t-test with Bonferroni correction was used for multiple comparisons in case of global statistical significance by ANOVA. When significant, between-group differences were also adjusted for age and gender. Correlation analyses were done by Pearson's test. No prior sample size calculation was done for this study owing to the quite rare types of patients included. Data are reported as mean±SD. A two-sided P value <0.05 was always required for statistical significance. The software SPSS 12.0.2 (SPSS Inc., Florence, Italy) was used for statistical analyses.
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Results |
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When compared with pain rating during the initial sequence, the VAS score in controls, CAD patients, and SX patients was 66±30, 73±28, and 114±50%, respectively, during the final sequence of stimuli (P=0.004), whereas it was 103±39, 99±32, and 108±28%, respectively, during the second sequence of stimuli (P=0.81).
There was a significant correlation between the per cent changes in N2/P2 and VAS score during the third (r=0.47; P=0.002), but not during the second (r=0.24; P=0.14), sequence of stimuli.
Right hand stimulation
There were no differences among groups in RI values for stimulation of the right hand (10.6±1.71, 11.1±1.24, and 10.9±1.58 W for SX, CAD, and controls, respectively; P=0.43). Latency and amplitude of LEP components during the first series of stimuli were similar among groups, and the changes in latency and amplitude of the N1P1 component and in latency of the N2/P2 component did not differ among groups across the three sequences of stimuli (Table 3).
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VAS pain rating during the first sequence of CO2 laser chest stimuli was not significantly different among groups (Table 3). There was a significant difference among groups in the changes of VAS score following repeated sequences of laser stimuli (P=0.001). A significant decrease of VAS score across the three sequences of stimuli was indeed observed in controls and in CAD patients (P=0.003 and P=0.034), whereas VAS score paradoxically increased in SX patients (P=0.047).
When compared with pain rating during the first sequence, the VAS score during the final sequence was reduced in controls and in CAD patients, but not in SX patients (77±20, 82±19, and 110±50%, respectively, P=0.036; Figure 3), a difference persisting after correction for age and gender (P=0.04). No differences were present among groups during the second, when compared with the first, sequence of stimuli (103±27, 93±13, and 104±40%, respectively, P=0.64).
No significant correlation between the percent changes in N2/P2 and VAS score was observed during the third sequence (r=0.23; P=0.16), although there was a tendency for a mild correlation during the second sequence (r=0.30; P=0.06) of stimuli.
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Discussion |
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Nociceptive function in SX patients
To assess the nociceptive pathway function, we examined latency and amplitude of all LEP components recorded during a basal sequence of cutaneous stimuli. LEP components recorded after skin stimulation at noxious intensities have been proved to be generated by inputs transmitted by A fibres,15 and abnormalities in LEP latency and/or amplitude were demonstrated in diseases involving the peripheral A
afferents or the central spinothalamic pathway.21
In this study, LEP components were similar in SX patients, CAD patients, and control subjects, thus suggesting no basal abnormalities in peripheral pain threshold. Accordingly, RIs of both chest and right hand skin, and even subjective basal VAS pain rating, did not differ significantly among groups. These findings contrast with some previous uncontrolled data suggesting reduced systemic pain threshold in SX patients.22,23 However, in agreement with our data, the only study which used a controlled blind protocol to assess dental pulp pain threshold failed to find evidence of generalized enhanced pain perception in these patients.11
It remains to be ascertained whether the reduced pain threshold for myocardial stimuli demonstrated in our previous controlled study13 is associated with abnormalities of electrical cortical activity.
Repetitive noxious stimuli and cerebral cortex excitability
Two main cortical LEP components were recorded during CO2 laser stimulation, N1P1 and N2/P2. Previous studies showed that the middle-latency N1P1 wave is probably generated in the secondary somatosensory area (SII) and may represent the neurophysiologic correlatation of the sensory-discriminative aspect of pain.24 The N2/P2 response, on the other hand, is mostly generated by neurons in the cingulate cortex,18,19,2527 which is part of the limbic system and is important for the emotional component of sensation.28,29
In this study, in agreement with previous data,30,31 healthy controls showed a significant reduction in amplitude of the vertex LEP components N2/P2 during repetitive sequence of stimuli. Although all previous neurophysiological studies suggested that the SII area and the cingulate cortex are sequentially activated after pain stimulation,15 the N2/P2 habituation, in spite of the unmodified N1P1 amplitude during repetitive painful stimuli, likely represents a phenomenon occurring within the cortical areas generating the N2/P2 LEP components.
In patients with cardiac SX, the habituation of the N2/P2 complex was virtually absent, thus suggesting that some cortical areas devoted to pain processing, namely, those generating the N2/P2 potentials, have an abnormal excitability in SX patients.
The dysfunction seems to involve not only the cortical projections coming from the chest, but also those from the right hand, the nociceptive pathways of which are likely separated from those coming from the heart both at peripheral and at spinal levels, thus suggesting a generalized abnormal pain processing occurring at cortical level. However, it is worth noting that differences among groups were more apparent during chest stimulation than during right hand stimulation, which might suggest preferential abnormalities of cortical processing of stimuli coming from specific sites of the body.
Independent of the mechanisms, the cortical LEP abnormalities in SX patients cannot be interpreted as a secondary response to recurrent angina or an unspecific effect of pain as CAD patients with refractory angina showed normal habituation to pain.
The neurophysiological results in our groups were paralleled by similar changes in subjective pain rating, a finding also shown in previous reports.30,31 This finding confirms the strict relation of N2/P2 amplitude with pain perception, also suggesting that pain rating by VAS can be sufficiently reliable, although the poor correlation between N2/P2 amplitude and VAS score suggests that the neural mechanisms underlying these two parameters are, at least in part, different.
Abnormal cortical excitability and pathophysiology of SX
Two major pathophysiological components have been suggested to significantly contribute to cardiac SX, i.e. coronary microvascular dysfunction15 and an abnormal pain perception of cardiac stimuli.1013 The relationship between these two pathophysiological components has not been clarified yet, with hypotheses including independent occurrence in a same patient, common neuro-mediated pathogenetic mechanisms, or even afferent cardiac nerve fibre abnormalities secondary to microvascular dysfunction and scattered ischaemia.32
In the present study, we aimed at obtaining further insights on pain function and processing in SX patients in whom the relevance of microvascular dysfunction was suggested by both exercise-induced ST-segment depression on the ECG and reversible perfusion defects on 201Tl myocardial scintigraphy. Our results tend to deny that this abnormal finding can be related to a reduced central pain threshold, which is in agreement with our demonstration of preferential ventricular issues in abnormal cardiac pain perception in these patients.13 Furthermore, in cardiac SX, the detection of pronounced functional abnormalities of efferent cardiac adrenergic nerve fibres33 suggests the possibility of an impairment of afferent cardiac nerve fibre function,32 as also suggested by the beneficial effects on angina symptoms of spinal cord stimulation, which is believed to mainly act through an enhancement of pain gate control in dorsal horns.34,35
On the other hand, the lack of habituation to pain seems typical of SX patients and might contribute to define some peculiar characteristics of angina, such as prolonged duration, frequent persistence after effort interruption, and recurrence, although a relationship with these features needs to be established.
Therefore, it is conceivable that in SX patients, an abnormal cardiac nociception, possibly due to local vascular or nervous autonomic factors, interacts with an abnormal excitability of the cortical areas devoted to pain processing, to result in the appearance and clinical feature of the disease.
It is worth noting, indeed, that the phenomenon of reduced habituation of vertex LEPs found in cardiac SX is similar to that shown in patients with migraine,36 another chronic painful condition also involving the peripheral vascular system.
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Clinical implications |
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References |
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