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Laser-Evoked Potentials Habituation in Fibromyalgia
The Journal of Pain, Vol 12, No 1 (January), 2011: pp 116-124 Available online at www.sciencedirect.com
Laser-Evoked Potentials Habituation in Fibromyalgia Marina de Tommaso,* Antonio Federici,y Roberto Santostasi,* Rita Calabrese,* Eleonora Vecchio,* Giovanni Lapadula,z Fiorenzo Iannone,z Paolo Lamberti,* and Paolo Livrea* * Department of Neurological and Psychiatric Sciences, Bari University, Bari, Italy. y Department of Physiology and Pharmacology, Bari University, Bari, Italy. z Department of Internal and Public Medicine, Bari University, Bari, Italy.
Abstract: Abnormalities of central pain processing play an important role in the pathophysiology of fibromyalgia (FM). The aims of the present study were to: 1) evaluate habituation of laser-evoked potentials (LEP) to repeated painful stimulation of 1 tender and 2 nontender points; and 2) determine correlations between LEP abnormalities and major clinical features of FM. Fourteen consecutive FM outpatients and 13 normal controls were included. LEP were recorded from scalp designations Fz, Cz, Pz, T3, and T4. The dorsum of the right hand, the right supra-orbital zone, and the right knee (a tender point in all patients) were subjected to repeated CO2 laser stimuli. For each stimulation site, recordings were obtained for 3 consecutive series of 20 stimuli. The 3 main findings in FM patients were: 1) an increased amplitude of vertex LEP and subjective laser pain; 2) decreased habituation of vertex LEP and subjective laser pain; and 3) a correlation between reduced N2 wave habituation and the severity of self-reported depressive symptoms. As with other chronic pain syndromes, the pathophysiology of FM may involve a generalized increase in the perception of painful stimuli and reduced habituation of the sensory cortex. Perspective: Reduced habituation of cortical responses to laser stimuli in FM patients suggests alterations in the pattern of cortical excitability. This is facilitated by depressive symptoms and abnormalities in central neurotransmission. These findings provide further support for the use of medications with effects on the central nervous system in the management of FM. ª 2011 by the American Pain Society Key words: Fibromyalgia, laser-evoked potentials, habituation.
F
ibromyalgia (FM) is a chronic disorder characterized by widespread pain and tenderness on palpation. Associated symptoms include nonrestorative sleep, fatigue, and cognitive dysfunction.49 Studies have failed to reliably identify any abnormality in the muscle tissue of FM patients.39,44 Abnormalities in pain processing appear to play an important role in the pathophysiology of FM, in particular for deep-tissue impulse input, central sensitization, and disorders of mood.47,48 The abnormal central pain mechanisms implicated in FM include temporal summation of pain (or windup) and central sensitization.48 Received November 15, 2009; Revised April 29, 2010; Accepted June 3, 2010. Supported by the P.R.I.N. project (protocol 20089CZ48N_003) of the Italian Ministry for Universities and Research. Address reprint requests to Prof. Marina de Tommaso, Department of Neurological and Psychiatric Sciences, Neurophysiopathology of Pain Unit, Bari University (Italy), Policlinico, Piazza Giulio Cesare 11, 70124 Bari. E-mail: [email protected] 1526-5900/$36.00 ª 2011 by the American Pain Society doi:10.1016/j.jpain.2010.06.004
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Laser-evoked potentials (LEP) are a useful tool for the selective evaluation of nociceptive pathways in experimental pain models and diseases of the central and peripheral nervous systems.51 These can be recorded from the vertex (‘‘late components,’’ termed N2 and P2) and the temporal region (‘‘early components,’’ termed N1) of the skull using selective activation of Ad (laserevoked potentials [LEP] and C [ultra-late LEP]) mechanothermal nociceptors in the superficial layers of the skin.10 The LEP waveform may also be influenced by nonnociceptive factors such as levels of attention, arousal,4 and anxiety.23 LEP patterns have been used to elucidate mechanisms underlying the generation and modulation of neuropathic and non-neuropathic central pain.20 Research in FM patients has demonstrated a correlation between a decrease in heat pain threshold and enhanced vertex LEP amplitude.22 Enhancement of N1 and P2 amplitudes may indicate peripheral and central sensitization, abnormalities that involve stronger sensory and attentional processing of nociceptive stimuli.31,32 The LEP pattern observed in these studies resembled that
de Tommaso et al observed in patients presenting with severe nonorganic (‘‘sine materia’’) pain and hyperalgesia.20 Studies have reported that FM patients display a generalized hypervigilance to multimodal stimuli that was associated with specific hyperattention to painful stimuli and which was particularly manifest during stimulation of tender points.25,31 A study investigating the intensitydependence of auditory-evoked cortical potentials showed that FM patients were hypervigilant to acoustic stimuli and showed reduced inhibition of the response to noxious and intense auditory stimuli, a phenomenon that the authors attributed to serotonergic deficit.9 A recent study found that FM patients showed reduced habituation to painful heat and cold stimuli, and that this was correlated with anxiety, depression, fatigue, and pain.45 Enhanced LEP may, therefore, be a consequence of reduced habituation to painful stimuli. The amplitude of an evoked potential is a quantitative index of the neuronal population that is activated by particular sensory inputs. It tends to decrease during repetitive sensory stimulation as a consequence of a progressive reduction in the neuronal response. The physiological phenomenon of a progressive reduction in the activation of the sensory cortex in response to repetitive stimuli is termed habituation. Thompson and Spencer50 have defined habituation as a decrement in the amplitude of the response of the sensory cortex to repeated presentations of similar stimuli (in the absence of receptor or effector fatigue) to avoid brain over-stimulation. In pain syndromes characterized by a normal or increased amplitude of basal LEP, such asmigraine and cardiac X syndrome,53,55 reduced habituation to repetitive, painful laser stimulation may suggest an abnormal level of activation and excitability in cortical areas, which exacerbates the perceived intensity of painful stimuli.16,53,55 The aims of the present study were to: 1) evaluate LEP habituation to repeated painful stimulation of 1 tender and 2 nontender points in FM patients and corresponding anatomical regions in normal controls; and 2) determine correlations between LEP abnormalities and the major clinical features of FM.
Methods Subjects Fourteen consecutive outpatients (11 females and 3 males; age range 32 to 55; mean age 45.5 6 4.5) presenting for the first time to the Neurophysiopathology of Pain Unit (Neurological and Psychiatric Sciences Department, Bari University) were included in the present study. The inclusion criterion was a diagnosis of FM according to the criteria of the American College of Rheumatology (ACR).58 Thirteen normal controls (10 females and 3 males; age range 31 to 56; mean age 44.9 6 5.5) were also included. Patients and controls were similar in age (ANOVA with age as a factor F = .9 ns). Subjects with a general medical, neurological, or psychiatric disease were excluded from the study. Psychiatric disorders were defined according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed
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Results of One-Way ANOVA With LEP Amplitudes and Subjective Laser Pain Rating, Measured by VAS, as Variables. The Bonferroni Test Was Computed as Post Hoc Test. The Significant Results Are Reported
Table 1.
MAIN FACTORS Diagnosis (FM versus controls) F= DF = P= Sites (Hand versus face versus knee) F= DF = P= Diagnosis sites F= DF = P= Post hoc test (Bonferroni P value) Face versus knee Hand versus knee Hand versus face
N1
N2
P2
N2–P2
VAS
.85 1 ns
14.23 1 .0001
8.81 1 .003
15.15 1 .0001
6.87 1 .009
1.41 2 ns
1.14 2 ns
4.78 2 .009
3.38 2 .036
.72 2 ns
.1 2 ns Sites
.5 2 ns Sites
.35 2 ns Sites
.3 2 ns Sites
.53 2 ns Sites
ns ns ns
.045 ns ns
.003 ns .034
.007 ns .045
ns ns ns
(DSM-IV).2 Patients receiving medications with effects on the central nervous system were also excluded to rule out any medication effects on subjective pain and evoked responses. The ICHD-II criteria24 were applied to identify and exclude patients with migraine, a very frequent comorbid disorder in FM patients,15 since this is characterized by reduced LEP habituation.17 Patients with chronic tension-type headache were also excluded, although a history of episodic tension-type headache was not an exclusion criterion. Headaches were defined according to ICHD-II criteria.24 All subjects provided written informed consent. The study was approved by the Ethics Committee of The Bari Policlinic General Hospital. All patients completed The Fibromyalgia Impact Questionnaire.6 They also completed the Zung Self-Rating Depression (SDS)60 and Anxiety (SAS)61 Scales since these are considered reliable tools for the detection of anxiety and depressive symptoms in the general nonpsychiatricpatient population and have been applied to evaluate headache patients with comorbid FMS.4 The Manual Tender Point Survey (MTPS) was used to rate the severity of pain experienced upon palpation of the 18 tender points defined by the ACR.36,46 In addition, all patients were asked to complete the Short-Form 36 Health Survey (SF36).57 The Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were also evaluated,57as well as the Multidimensional Assessment of Fatigue.3
Laser-Evoked Potentials Recording The relaxed and awake subject was seated in a comfortable chair in a quiet room with a temperature of 21
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Laser evoked potentials amplitudes
face hand knee
14
uV
12 10 8 6 4 2 0 controls
FM patients
controls
N1
FM patients
controls
N2
FM patients P2
Figure 1. Mean values and standard deviations of LEP amplitudes in patients (n 14) and controls (n 13).
to 23 C. The subjects and the experimenters wore protective goggles throughout data acquisition and the subjects were asked to keep their eyes closed. Five scalp electrodes were placed along the midline (Fz, Cz, and Pz positions of the 10–20 International System, referring to the nasion) and at T3 and T4, referring to Fz (impedance below 5000 ohms), with the ground at Fpz. A further electrode was placed above the right eye to record the EOG. Signals were amplified, filtered (.5–100 Hz), and stored on a biopotential analyzer (MICROMED System Plus; MICROMED, Mogliano Veneto, Italy).
Stimulation The stimulation site was visualized with an He–Ne laser beam. Following each stimulus, the laser beam was shifted slightly to avoid nociceptor sensitization and skin damage. The pain stimulus was a laser pulse (wavelength 10.6 mm) generated by a CO2 laser (Neurolas, Electronic Engineering, Florence, Italy). The beam diameter was 2.5 mm and the duration of the stimulus pulse was 25 ms. In all subjects, the laser power and duration were set at a suprathreshold level5 using a 10-point ver-
60
controls FM patients
LEP Analysis
LASER PAIN PERCEPTION
50
VAS
40
30
20
10
0 f ace
hand
bal analogue scale in which 0 corresponded to no sensation, 4 to the Pain Threshold, and 10 to intolerable pain. All subjects perceived the 25-ms duration and 7.5-watt intensity laser stimuli as a painful pinprick, and gave ratings of $6 for more than 50% of 20 stimuli.5 The dorsum of the right hand and the right supraorbital zone were selected as the 2 nontender points. All patients had reported that the right knee was a tender point and so this was selected as the tender point for the present study. Three consecutive series of 20-laser stimuli were delivered to each stimulation site with an interstimulus interval (ISI) of 10 seconds. A 1-minute interval was interposed between each series. The site of stimulation was changed after a 10-minute interval. The order of the stimulation sites was varied at random between subjects. All subjects had been informed about the modality and rating of the stimulation prior to the procedure. At the end of each series of stimulation, all subjects were requested to rate the average pain perceived for the 20-laser stimuli using a 0 to 100 visual analogue pain scale (Laser-pain VAS), in which 0 indicated no pain (white) and 100 indicated the most severe pain imaginable (red).
knee
Figure 2. Mean values and standard deviations of subjective pain induced by laser stimuli, as measured by visual 0 to 100 VAS in patients (n 14) and controls (n 13).
An investigator who was blind to the clinical condition analyzed the LEP recordings for 1 second, with a 100-ms prestimulus time, at a sampling rate of 512 Hz. All runs containing transient signals that exceeded 65 mV on any recording channel were excluded from the average by an automatic artifact rejection algorithm. Other artifacts were inspected visually. An average of at least 15 artifact-free responses was obtained off-line for each stimulation series. For each stimulation site (right hand, right supra-orbital zone, and right knee), an average was obtained across each series of stimuli. LEP were identified on the basis of their latency and distribution, and 3 responses (N1, N2, and P2) were labelled according to Valeriani et al.54 The N2a (termed N2) and P2 components were analyzed at the vertex (Cz) and the N1 component was analyzed at T3-Fz.
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the LEP amplitudes and the VAS values obtained in the third and the first block of evoked responses was computed. This was termed the habituation index (HI). To optimize assessment of habituation, these quotients were also computed between the second and the first, and the third and the second blocks of evoked responses.
N1 habituation controls FM patients
16 14 12 10
uV
119
8
Statistical Analysis
6 4 2 0 I°
II°
III°
I°
II°
f ace
III°
I°
h an d
II°
III°
k n ee
N2 habituation 14 12 10
uV
8 6 4 controls FM patients
2
Results
0 I°
II°
III°
I°
f ace
II°
III°
I°
h an d
II°
III°
k n ee
P2 habituation
25 controls n° 13 FMS patients n° 14
20
uV
15
10
5
0 I°
II°
III°
f ace
The Kolmogorov-Smirnov statistic, with a Lilliefors significance level, was applied to test for normality. The mean VAS values, the N1, N2, and P2 amplitudes and latencies, (computed across the 3 repetitions), and the Habituation Index were used as the variables for a 2-way ANOVA analysis. Diagnosis and the site of stimulation were the main factors. The Bonferroni was applied as a post hoc test for differences across the 3 sites of stimulation. The Spearman correlation test was used to correlate the main LEP abnormalities with clinical features. In view of the large number of correlations and the possibility of spuriously significant results, only correlations with P values of <.01 were considered. To determine correlations, mean LEP and VAS values across the 3 sites of stimulation and the 3 repetitions, and the mean habituation index across the 3 sites of stimulation, were considered.
I°
II°
III°
k n eee
I°
II°
III°
h an d
Figure 3. Amplitudes of laser-evoked potentials in the 3 consecutive series of stimulation, showing the course of habituation in patients (n 14) and controls (n 13).
Trace Absolute latencies of the scalp potentials were measured at the highest peak of each response component. The amplitude of each wave was measured from the baseline. Baseline was measured automatically by calculating the average signal on the whole sweep and subtracting it from the trace (ASA- v.4.6 by ANT software; Advanced Neuro Technology, Enschede, The Netherlands). The peak-to-peak amplitude was taken into consideration for the vertex biphasic LEP component (N2–P2). To assess LEP and laser pain habituation, the quotient between
The N1, N2, and P2 latencies were similar for FM patients and controls for all 3 stimulation sites. The N1 amplitude was also similar in patients and controls for all 3 stimulation sites. (Table 1; Fig 1). The amplitudes of N2 and P2 (and consequently of the N2–P2 complex) were increased in FM patients compared to controls (Table 1; Fig 1). The N2 and P2 amplitudes were not significantly different between the patients and controls with respect to the site of stimulation: The N2 amplitude was larger at the face level, in respect to the knee levels, the P2 at the face in respect to both the hand and knee. (Table 1; Fig 1). FM patients reported greater subjective laser pain than controls for all stimulation sites (Table1; Fig 2). In FM patients, no significant difference in subjective laser pain was found across the 3 sites of stimulation. In controls, the N2 and P2 amplitudes were reduced in the second and third blocks of averaged responses for all stimulation sites (Figs 3 and 4). This reduction was particularly pronounced for the N2 wave (Fig 3). In FM patients, the progressive reduction in N2 and P2 amplitudes was less evident at the face and hand levels (Fig 3), whereas a progressive increase in vertex LEP amplitudes emerged across the 3 consecutive series of stimulations at the tender (knee) point (Figs 3 and 4). FM patients showed a significant increase in the habituation index of N2, P2, and the N2–P2 complex, which indicates reduced habituation across the 3 series of stimulation, for all 3 stimulation sites (Table 2; Figs 3 and 4). The VAS scores, which indicate subjective perception of laser pain, also showed reduced habituation across the 3 series of stimulation in FM patients (Table 2). In controls, the N1 wave amplitude showed a tendency toward a progressive reduction in
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Figure 4. Laser-evoked potentials obtained by the right knee in a representative fibromyalgia patient and a normal control. Each trace is the average of 15 responses.
the second and third repetitions (Fig 3). FM patients showed a nonsignificant trend toward an increased N1 habituation index (Table 2; Fig 3). No significant differences in LEP and VAS scores were found across the II versus I and III versus II repetitions, either between groups or across the sites of stimulation. In FM patients, the N2–P2 complex amplitude was positively correlated with VAS scores (Spearman correlation test: .625: P = .009). The N2 amplitude was positively correlated with the duration of FM (Spearman correlation test: .645: P = .008). Higher N2 habituation index values (which indicate reduced habituation) were positively correlated with the severity of self-reported depressive symptoms, as measured by SDS (Spearman correlation test: .701: P = .005; Fig 5). Other correlations between P2 and N2–P2 amplitude habituation indices and main clinical features did not achieve statistical significance.
Results of One-Way ANOVA With LEPs Habituation Index (HI) as Variables. The Significant Results Are Reported
Table 2.
MAIN FACTORS Diagnosis (FM versus controls) F= DF = P= Sites (Hand versus face versus knee) F= DF = P= Diagnosis sites F= DF = P= Post hoc test (Bonferroni) Hand versus knee Face versus knee Hand versus face
N1 HI
N2 HI
P2 HI
N2 P2 HI
VAS HI
2 1 ns
7.45 1 .009
4.45 1 .043
4.48 1 .042
4.7 1 .034
.59 2 ns
1.29 2 ns
.38 2 ns
1.16 2 ns
2.73 2 ns
.54 2 ns Sites
1.28 2 ns Sites
.46 2 ns Sites
.13 2 ns Sites
2 2 ns Sites
ns ns ns
ns ns ns
ns ns ns
ns ns ns
ns ns ns
Discussion The present study yielded 3 main results: 1) patients with FM showed increased amplitude of vertex LEP and increased laser pain for all stimulation sites; 2) they showed decreased habituation of both the vertex LEP and subjective laser pain; and 3) the reduction in N2 habituation was more pronounced in patients with higher self-reported levels of depression. The first finding (1) partly replicates the results of previous studies. Gibson et al22 found an increase in the amplitude of vertex LEP in response to stimulation of tender and nontender points, suggesting a greater activation of central nervous system (CNS) pathways in response to noxious input. In contrast to the findings of the present study, Lorenz et al32 observed an increase in the amplitude of the N170, which corresponds to the N1 wave, in response to painful laser stimulation. Research has demonstrated that this occipito-temporal negative component is involved in focussed attention and spatial discrimination,41 and it is thought to originate in the opercular cortex.21 One study found that the N1 amplitude was normal or even reduced in patients with migraine, who, in common with FM patients, display greater activation of the central nociceptive system and an increase in the amplitude of the vertex waves, particularly during an attack.17 In the present study, the amplitude of the vertex complex was increased in FM patients. This complex appears to express the attentive orientation toward noxious stimuli (specifically stimulus-driven orienting processes) and the salience of the evoking stimulus.28-30,32 It is thought to originate in the posterior insula and anterior cingulate cortex,21 which are areas that elaborate the attentive and emotional components of pain.37 Noxious stimuli may, therefore, induce greater activation of specific cortical areas in FM patients. Nevertheless, virtually identical factors modulate the negative (N1, N2) and positive (P2) components of LEP.33 However, the small amplitude of the N1 may result in high variability between subjects51 and thus conflicting results across studies. In one study of FM patients, increased N2–P2 amplitude was found to correspond to an increase in pain sensitivity to laser stimuli.8 This corresponds with the finding of abnormalities of pain perception in FM
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Correlation between N2 habituation index and depression levels 60 55
SDS
50 45 40 35 30
0
0,5
1
1,5
2
2,5
3,5
3
4
Habituation index (x 100)
Correlation between N2 amplitude and fibromyalgia duration 45 40
duration (years)
35 30 25 20 15 10 5 0
0
5
10
15
20
25
30
N2 amplitude (uV) Correlation between N2-P2 amplitude and laser VAS (0-100) 100 90 80 70
VAS
60 50 40 30 20 10 0
0
5
10
15
20
25
30
35
40
45
50
N2-P2 amplitude (uV)
Figure 5. Relationship between (A) N2 habituation index, computed as the ratio between the N2 wave amplitude obtained in the third series and that obtained in the first series of stimulation in the FM patients: The mean habituation index across the 3 different sites of stimulation is considered. (B) N2 mean amplitude across the 3 sites of stimulation and illness duration. (C) N2–P2 mean amplitude across the 3 sites of stimulation and laser VAS.
patients reported from studies that have applied various methods of sensory testing.47 Abnormalities of LEP and pain perception appeared to be widespread rather than restricted to the tender point. This confirms that there is a general increase in the activation of cortical areas devoted to the processing of pain stimuli in FM patients, irrespective of the site of stimulation.22,29 In accordance with other studies of LEP in normal subjects,52 controls in the present study were found to have increased amplitudes of vertex LEP at the face level compared with the amplitude of LEP obtained from stimulation of other sites. No significant differences in LEP
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amplitudes were observed between the hand and knee levels, as has been described in previous studies for stimulation of the foot.52 The more proximal location of the knee stimulation point used in the present study would have reduced the difference in amplitude between LEP obtained at the hand and the leg in both patients and normal controls. The observation of increased LEP amplitudes in response to stimulation of hyperalgesic sites may provide support for the hypothesis that FM pain is functional in nature, since reduced LEP amplitudes have been reported in pain of neuropathic origin.20 These findings confirm that LEPs are a useful tool for elucidating the mechanisms that underlie chronic pain syndromes.11 The results of the present study correspond with fMRI findings of significantly greater activation in the anterior insula and the cingulate cortex in response to painful stimuli.38 This enhanced activation of cortical areas that are devoted to the processing of nociceptive stimuli appears to contradict the findings of some voxel-based morphometry studies, which have reported a decrease in grey matter volume in the prefrontal cortex, the amygdala, and the anterior cingulate cortex (ACC) in FM patients.7,59 However, studies that have controlled for clinical features such as the presence of an affective disorder have not replicated these morphological findings.26 It is plausible that in FM and other forms of chronic pain, structural changes may differentially affect brain regions involved in pain modulation, resulting in an altered balance between cerebral areas that facilitate, and cerebral areas that inhibit, nociceptive inputs.27,42,43,56 The present study cannot help to resolve the question of whether greater cerebral activation in response to noxious inputs may be imputed to a general phenomenon of hypervigilance to multimodal stimuli,25,31 as has been suggested in recent studies,9 since it did not investigate other sensory modalities. In regard to the second point (2), the results of the present study provide the first evidence in support of the hypothesis of reduced habituation, and even facilitation, of cerebral potentials in response to repetitive noxious stimuli in FM patients, as demonstrated by their increased amplitude. These results correspond with previous findings of reduced habituation to painful heat stimuli (as measured by Quantitative Sensory Testing), a phenomenon that may contribute to the pathophysiology of chronic pain in FM patients.45 In FM patients in the present study, the reduced habituation of vertex LEP was accompanied by reduced habituation of laser-pain perception. This confirms that the lack of a reduction in cortical recruitment across repetitive stimuli corresponds to a lack of decline of pain perception. The reduced habituation of laser-pain perception and cortical processing was not confined to the tender point, but seemed instead to be a generalized phenomenon. Studies have found a similar pattern in migraine patients, in both critical and intercritical phases.13,53 It would be interesting to establish whether FM patients, in common with migraine patients, show reduced habituation to multimodal stimuli in accordance with the generalized hypervigilance hypothesis. At present, there are no objective measures with which to characterize the
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sensory style of FM patients. Reduced habituation to noxious inputs, which facilitates an increase in pain perception and (possibly) central sensitization, may be implicated in some nonorganic chronic pain syndromes.53,55 This may explain the observed overlap between pain syndromes such as migraine and FM.15 LEPs therefore assist in distinguishing between ‘‘neuropathic’’ and ‘‘sine material’’ models of pain.20 However, the origin of reduced habituation remains contentious. Increased neuronal excitability and reduced inhibition have both been proposed as the cause of reduced habituation in syndromes as migraine.1,10 The results of the present study suggest that the pathophysiology of FM may involve a biobehavioral model of reactivity to painful, and probably multimodal, stimuli as a result of altered central neuronal excitability, as with other chronic pain syndromes.16 This may explain the positive effect of Antiepileptic Drugs (AEDs) in the management of FM.34 This class of drugs has been shown to be effective in reducing the phenomenon of dishabituation of event-related potentials.12 In the present study, a tendency toward a progressive increase in the amplitude of N2 and P2 was observed when the tender point was stimulated. However, no significant difference in the habituation pattern was observed across the 3 stimulation sites. Further analysis, involving the performance of an increased number of repetition series, would probably emphasize the progressive facilitation of cortical recruitment that is induced by repetitive painful stimulation of tender points. This would provide an explanation of the localization of pain in FM in terms of a generalized phenomenon of reduced habituation and a local increase in central sensitization processes. Another interesting finding (3) of the present study was that FM patients with self-reported symptoms of depression showed a more pronounced reduction of N2 wave habituation. No correlation was found between LEP findings and measures of fibromyalgia severity such as pain at tender points, quality of life, and impact of the disease on daily living. This confirms that FM is a complex syndrome and that abnormal central pain processing is not the only factor that determines the severity of symptoms. In accordance with previous studies of chronic pain syndromes,14 patients with clinically evident
psychiatric disorders were excluded from the present study since these disorders may confound evaluation of the features of the investigated disease.59 The Zung scales60,61 are used to rate anxiety and depression in the general population and provide an estimate of their subclinical manifestations. In FM patients in the present study, reduced habituation of the N2 vertex component was facilitated by the presence of symptoms that may be attributable to depression. In the present study, the habituation index of the P2 approached, and that of the N2–P2 complex actually achieved, a significant correlation with depression. These results were not reported since correlations with P < .01 were discarded in order to avoid spurious results. Reduced habituation and increased amplitude of long latency somatosensory potentials have been reported in patients with major depression.18 The phenomenon of reduced habituation has been imputed to a thalamo-cortical dysrhythmia, in which a deficit in serotoninergic and monoaminergic neurotransmission is the main chemical abnormality.10 This deficit has been well established for major depression.40 Furthermore, deficient habituation of the limbic cortex, which is involved in the control of affective status, has been shown to be inversely correlated with serotoninergic receptor density.19 In animal models, treatment with reserpine has been shown to result in a significant decrease in the muscle pressure threshold, tactile allodynia, and increased immobility time in the forced swim test, which are features that may indicate depression.35 Reserpine causes a decrease in the levels of biogenic amines (dopamine, norepinephrine, and 5-hydroxytryptamine) in the spinal cord, thalamus, and prefrontal cortex areas, which are closely involved in pain signal processing. In summary, the results of the present study suggest that the pathophysiology of FM may involve a generalized increase in the perception of painful stimuli and reduced habituation of the sensory cortex, as has been proposed for other chronic pain syndromes. This may be caused by altered excitability of the sensory cortex and facilitated by the presence of depressive symptoms and abnormalities in central neurotransmission. These findings provide further support for the use of medications with effects on the CNS in the management of FM.
References
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6. Burckhardt CS, Clark SR, Bennett RM: The Fibromyalgia Impact Questionnaire (FIQ): Development and validation. J Rheumatol 18:728-733, 1991 7. Burgmer M, Gaubitz M, Konrad C, Wrenger M, Hilgart S, Heuft G, Pfleiderer B: Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia. Psychosom Med 71: 566-573, 2009 8. Carmon A, Mor J, Goldberg J: Evoked cerebral responses to noxious thermal stimuli in humans. Exp Brain Res 25: 103-107, 1976
de Tommaso et al 9. Carrillo-de-la-Pen˜a MT, Vallet M, Pe´rez MI, Go´mezPerretta C: Intensity dependence of auditory-evoked cortical potentials in fibromyalgia patients: A test of the generalized hypervigilance hypothesis. J Pain 7:480-487, 2006 10. Coppola G, Pierelli F, Schoenen J: Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia 27:1429-1439, 2007 11. Cruccu G, Anand P, Attal N, Garcia-Larrea L, Haanpa¨a¨ M, Jørum E, Serra J, Jensen TS: EFNS guidelines on neuropathic pain assessment. Eur J Neurol 11:153-162, 2004 12. de Tommaso M, Guido M, Sardaro M, Serpino C, Vecchio E, De Stefano G, Di Claudio T, Specchio LM, Livrea P: Effects of topiramate and levetiracetam vs placebo on habituation of contingent negative variation in migraine patients. Neurosci Lett 442:81-85, 2008 13. de Tommaso M, Lo Sito L, Di Fruscolo O, Sardaro M, Pia Prudenzano M, Lamberti P, Livrea P: Lack of habituation of nociceptive evoked responses and pain sensitivity during migraine attack. Clin Neurophysiol 116:1254-1264, 2005 14. de Tommaso M, Losito L, Difruscolo O, Libro G, Guido M, Livrea P: Changes in cortical processing of pain in chronic migraine. Headache 45:1208-1218, 2005 15. de Tommaso M, Sardaro M, Serpino C, Costantini F, Vecchio E, Prudenzano M, Lamberti P, Livrea P: Fibromyalgia comorbidity in primary headaches. Cephalalgia 29:453-464, 2009 16. de Tommaso M: Central nervous system excitability in migraine: Who is right? Pain 118(1-2):137-144, 2005 17. de Tommaso M: Laser-evoked potentials in primary headaches and cranial neuralgias. Expert Rev Neurother 8: 1339-1345, 2008 18. Dietl T, Dirlich G, Vogl L, Nickel T, Sonntag A, Strian F, Lechner C: Enhanced long-latency somatosensory potentials in major depressive disorder. J Psychiatr Res 35:43-48, 2001 19. Fisher PM, Meltzer CC, Price JC, Coleman RL, Ziolko SK, Becker C, Moses-Kolko EL, Berga SL, Hariri AR: Medial prefrontal cortex 5-ht2a density is correlated with amygdala reactivity, response habituation, and functional coupling. Cereb Cortex 19:2499-2507, 2009 20. Garcia-Larrea L, Convers P, Magnin M, Andre-Obadia N, Peyron R, Laurent B, Mauguiere F: Laser-evoked potential abnormalities in central pain patients: The influence of spontaneous and provoked pain. Brain 125:2766-2781, 2002 21. Garcia-Larrea L, Frot M, Valeriani M: Brain generators of laser-evoked potentials: From dipoles to functional significance. Neurophysiol Clin 33:279-292, 2003 22. Gibson SJ, Littlejohn GO, Gorman MM, Helme RD, Granges G: Altered heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in subjects with fibromyalgia syndrome. Pain 58: 185-193, 1994 23. Gibson SJ, LeVasseur SA, Helme RD: Cerebral eventrelated responses induced by CO2 laser stimulation in subjects suffering from cervico-brachial syndrome. Pain 47: 173-182, 1991 24. Headache Classification Committee: The International Classification of Headache Disorders II. Cephalalgia 24: 24-136, 2004 25. Hollins M, Harper D, Gallagher S, Owings EW, Lim PF, Miller V, Siddiqi MQ, Maixner W: Perceived intensity and unpleasantness of cutaneous and auditory stimuli: An evalua-
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processing in the human parasylvian cortex. Neuroimage 20: 441-454, 2003 42. Schmidt-Wilcke T, Luerding R, Weigand T, Ju¨rgens T, Schuierer G, Leinisch E, Bogdahn U: Striatal grey matter increase in patients suffering from fibromyalgia–a voxelbased morphometry study. Pain 132:S109-S116, 2007 43. Schmidt-Wilcke T: Variations in brain volume and regional morphology associated with chronic pain. Curr Rheumatol Rep 10:467-474, 2008 44. Simms RW, Roy SH, Hrovat M, Anderson JJ, Skrinar G, LePoole SR, Zerbini CA, de Luca C, Jolesz F: Lack of association between fibromyalgia syndrome and abnormalities in muscle energy metabolism. Arthritis Rheum 37:794-800, 1994 45. Smith BW, Tooley EM, Montague EQ, Robinson AE, Cosper CJ, Mullins PG: Habituation and sensitization to heat and cold pain in women with fibromyalgia and healthy controls. Pain 140:420-428, 2008 46. Starz TW, Sinclair JD, Okifuji A: Putting the finger on fibromyalgia: The manual tender point survey. J Musculoskel Med 17:61-67, 1997 47. Staud R: Biology and therapy of fibromyalgia: Pain in fibromyalgia sindrome. Arthritis Res Ther 8:208, 2006 48. Staud R, Rodriguez ME: Mechanisms of disease: Pain in fibromyalgia syndrome. Nat Clin Pract Rheumatol 2:90-98, 2006 49. Stisi S, Cazzola M, Buskila D, Spath M, Giamberardino MA, Sarzi-Puttini, Arioli G, Alciati A, Leardini G, Gorla R, Marsico A, Ceccherelli F, Bazzichi L, Carignola RL, Gracely RH, Salaffi F, Marinangeli F, Torta R, Di Franco M, Biasi G, Cassisi G, Casale R, Altomonte L, Atzeni F (Italian Fibromyalgia Network): Etiopathogenetic mechanisms of fibromyalgia syndrome. Reumatismo 60:25-35, 2008
Habituation and Fibromyalgia 52. Truini A, Galeotti F, Romaniello A, Virtuoso M, Iannetti GD, Cruccu G: Laser-evoked potentials: Normative values. Clin Neurophysiol 116:821-826, 2005 53. Valeriani M, de Tommaso M, Restuccia D, Le Pera D, Guido M, Iannetti GD, Libro G, Truini A, Di Trapani G, Puca F, Tonali P, Cruccu G: Reduced habituation to experimental pain in migraine patients: A CO2 laser evoked potentials study. Pain 105:57-64, 2003 54. Valeriani M, Rambaud L, Mauguiere F: Scalp topography and dipolar source modelling of potentials evoked by CO2 laserstimulation of the hand. Electroencephalogr Clin Neurophysiol 100:343-353, 1996 55. Valeriani M, Sestito A, Le Pera D, De Armas L, Infusino F, Malese T, Sgueglia GA, Tonali PA, Crea F, Restuccia D, Lanza GA: Abnormal cortical pain processing in patients with cardiac syndrome X. Eur Heart J 26:975-982, 2005 56. Valet M, Gu¨ndel H, Sprenger T, Sorg C, Mu¨hlau M, Zimmer C, Henningsen P, To¨lle TR: Patients with pain disorder show gray-matter loss in pain-processing structures: A voxel-based morphometric study. Psychosom Med 71: 49-56, 2009 57. Ware JE, Kosinski M, Dewey JE: How to score version 2 of the SF-36 (r) health survey. Lincoln, RI, Quality Metric Incorporated, 2000 58. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL and the American College of Rheumatology: The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum 33: 160-172, 1990 59. Wood PB, Glabus MF, Simpson R, Patterson JC 2nd: Changes in gray matter density in fibromyalgia: Correlation with dopamine metabolism. J Pain 10:609-618, 2009
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61. Zung WWK: SAS, Self-Rating Anxiety Scale, in Guy W (ed): ECDEU Assessment Manual For Psychopharmacology, revised ed. Rockville, MD, National Institute of Health, Psycho-pharmacology Research Branch, 1976, pp 337-340
Laser-Evoked Potentials Habituation in Fibromyalgia Marina de Tommaso,* Antonio Federici,y Roberto Santostasi,* Rita Calabrese,* Eleonora Vecchio,* Giovanni Lapadula,z Fiorenzo Iannone,z Paolo Lamberti,* and Paolo Livrea* * Department of Neurological and Psychiatric Sciences, Bari University, Bari, Italy. y Department of Physiology and Pharmacology, Bari University, Bari, Italy. z Department of Internal and Public Medicine, Bari University, Bari, Italy.
Abstract: Abnormalities of central pain processing play an important role in the pathophysiology of fibromyalgia (FM). The aims of the present study were to: 1) evaluate habituation of laser-evoked potentials (LEP) to repeated painful stimulation of 1 tender and 2 nontender points; and 2) determine correlations between LEP abnormalities and major clinical features of FM. Fourteen consecutive FM outpatients and 13 normal controls were included. LEP were recorded from scalp designations Fz, Cz, Pz, T3, and T4. The dorsum of the right hand, the right supra-orbital zone, and the right knee (a tender point in all patients) were subjected to repeated CO2 laser stimuli. For each stimulation site, recordings were obtained for 3 consecutive series of 20 stimuli. The 3 main findings in FM patients were: 1) an increased amplitude of vertex LEP and subjective laser pain; 2) decreased habituation of vertex LEP and subjective laser pain; and 3) a correlation between reduced N2 wave habituation and the severity of self-reported depressive symptoms. As with other chronic pain syndromes, the pathophysiology of FM may involve a generalized increase in the perception of painful stimuli and reduced habituation of the sensory cortex. Perspective: Reduced habituation of cortical responses to laser stimuli in FM patients suggests alterations in the pattern of cortical excitability. This is facilitated by depressive symptoms and abnormalities in central neurotransmission. These findings provide further support for the use of medications with effects on the central nervous system in the management of FM. ª 2011 by the American Pain Society Key words: Fibromyalgia, laser-evoked potentials, habituation.
F
ibromyalgia (FM) is a chronic disorder characterized by widespread pain and tenderness on palpation. Associated symptoms include nonrestorative sleep, fatigue, and cognitive dysfunction.49 Studies have failed to reliably identify any abnormality in the muscle tissue of FM patients.39,44 Abnormalities in pain processing appear to play an important role in the pathophysiology of FM, in particular for deep-tissue impulse input, central sensitization, and disorders of mood.47,48 The abnormal central pain mechanisms implicated in FM include temporal summation of pain (or windup) and central sensitization.48 Received November 15, 2009; Revised April 29, 2010; Accepted June 3, 2010. Supported by the P.R.I.N. project (protocol 20089CZ48N_003) of the Italian Ministry for Universities and Research. Address reprint requests to Prof. Marina de Tommaso, Department of Neurological and Psychiatric Sciences, Neurophysiopathology of Pain Unit, Bari University (Italy), Policlinico, Piazza Giulio Cesare 11, 70124 Bari. E-mail: [email protected] 1526-5900/$36.00 ª 2011 by the American Pain Society doi:10.1016/j.jpain.2010.06.004
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Laser-evoked potentials (LEP) are a useful tool for the selective evaluation of nociceptive pathways in experimental pain models and diseases of the central and peripheral nervous systems.51 These can be recorded from the vertex (‘‘late components,’’ termed N2 and P2) and the temporal region (‘‘early components,’’ termed N1) of the skull using selective activation of Ad (laserevoked potentials [LEP] and C [ultra-late LEP]) mechanothermal nociceptors in the superficial layers of the skin.10 The LEP waveform may also be influenced by nonnociceptive factors such as levels of attention, arousal,4 and anxiety.23 LEP patterns have been used to elucidate mechanisms underlying the generation and modulation of neuropathic and non-neuropathic central pain.20 Research in FM patients has demonstrated a correlation between a decrease in heat pain threshold and enhanced vertex LEP amplitude.22 Enhancement of N1 and P2 amplitudes may indicate peripheral and central sensitization, abnormalities that involve stronger sensory and attentional processing of nociceptive stimuli.31,32 The LEP pattern observed in these studies resembled that
de Tommaso et al observed in patients presenting with severe nonorganic (‘‘sine materia’’) pain and hyperalgesia.20 Studies have reported that FM patients display a generalized hypervigilance to multimodal stimuli that was associated with specific hyperattention to painful stimuli and which was particularly manifest during stimulation of tender points.25,31 A study investigating the intensitydependence of auditory-evoked cortical potentials showed that FM patients were hypervigilant to acoustic stimuli and showed reduced inhibition of the response to noxious and intense auditory stimuli, a phenomenon that the authors attributed to serotonergic deficit.9 A recent study found that FM patients showed reduced habituation to painful heat and cold stimuli, and that this was correlated with anxiety, depression, fatigue, and pain.45 Enhanced LEP may, therefore, be a consequence of reduced habituation to painful stimuli. The amplitude of an evoked potential is a quantitative index of the neuronal population that is activated by particular sensory inputs. It tends to decrease during repetitive sensory stimulation as a consequence of a progressive reduction in the neuronal response. The physiological phenomenon of a progressive reduction in the activation of the sensory cortex in response to repetitive stimuli is termed habituation. Thompson and Spencer50 have defined habituation as a decrement in the amplitude of the response of the sensory cortex to repeated presentations of similar stimuli (in the absence of receptor or effector fatigue) to avoid brain over-stimulation. In pain syndromes characterized by a normal or increased amplitude of basal LEP, such asmigraine and cardiac X syndrome,53,55 reduced habituation to repetitive, painful laser stimulation may suggest an abnormal level of activation and excitability in cortical areas, which exacerbates the perceived intensity of painful stimuli.16,53,55 The aims of the present study were to: 1) evaluate LEP habituation to repeated painful stimulation of 1 tender and 2 nontender points in FM patients and corresponding anatomical regions in normal controls; and 2) determine correlations between LEP abnormalities and the major clinical features of FM.
Methods Subjects Fourteen consecutive outpatients (11 females and 3 males; age range 32 to 55; mean age 45.5 6 4.5) presenting for the first time to the Neurophysiopathology of Pain Unit (Neurological and Psychiatric Sciences Department, Bari University) were included in the present study. The inclusion criterion was a diagnosis of FM according to the criteria of the American College of Rheumatology (ACR).58 Thirteen normal controls (10 females and 3 males; age range 31 to 56; mean age 44.9 6 5.5) were also included. Patients and controls were similar in age (ANOVA with age as a factor F = .9 ns). Subjects with a general medical, neurological, or psychiatric disease were excluded from the study. Psychiatric disorders were defined according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed
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Results of One-Way ANOVA With LEP Amplitudes and Subjective Laser Pain Rating, Measured by VAS, as Variables. The Bonferroni Test Was Computed as Post Hoc Test. The Significant Results Are Reported
Table 1.
MAIN FACTORS Diagnosis (FM versus controls) F= DF = P= Sites (Hand versus face versus knee) F= DF = P= Diagnosis sites F= DF = P= Post hoc test (Bonferroni P value) Face versus knee Hand versus knee Hand versus face
N1
N2
P2
N2–P2
VAS
.85 1 ns
14.23 1 .0001
8.81 1 .003
15.15 1 .0001
6.87 1 .009
1.41 2 ns
1.14 2 ns
4.78 2 .009
3.38 2 .036
.72 2 ns
.1 2 ns Sites
.5 2 ns Sites
.35 2 ns Sites
.3 2 ns Sites
.53 2 ns Sites
ns ns ns
.045 ns ns
.003 ns .034
.007 ns .045
ns ns ns
(DSM-IV).2 Patients receiving medications with effects on the central nervous system were also excluded to rule out any medication effects on subjective pain and evoked responses. The ICHD-II criteria24 were applied to identify and exclude patients with migraine, a very frequent comorbid disorder in FM patients,15 since this is characterized by reduced LEP habituation.17 Patients with chronic tension-type headache were also excluded, although a history of episodic tension-type headache was not an exclusion criterion. Headaches were defined according to ICHD-II criteria.24 All subjects provided written informed consent. The study was approved by the Ethics Committee of The Bari Policlinic General Hospital. All patients completed The Fibromyalgia Impact Questionnaire.6 They also completed the Zung Self-Rating Depression (SDS)60 and Anxiety (SAS)61 Scales since these are considered reliable tools for the detection of anxiety and depressive symptoms in the general nonpsychiatricpatient population and have been applied to evaluate headache patients with comorbid FMS.4 The Manual Tender Point Survey (MTPS) was used to rate the severity of pain experienced upon palpation of the 18 tender points defined by the ACR.36,46 In addition, all patients were asked to complete the Short-Form 36 Health Survey (SF36).57 The Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were also evaluated,57as well as the Multidimensional Assessment of Fatigue.3
Laser-Evoked Potentials Recording The relaxed and awake subject was seated in a comfortable chair in a quiet room with a temperature of 21
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Laser evoked potentials amplitudes
face hand knee
14
uV
12 10 8 6 4 2 0 controls
FM patients
controls
N1
FM patients
controls
N2
FM patients P2
Figure 1. Mean values and standard deviations of LEP amplitudes in patients (n 14) and controls (n 13).
to 23 C. The subjects and the experimenters wore protective goggles throughout data acquisition and the subjects were asked to keep their eyes closed. Five scalp electrodes were placed along the midline (Fz, Cz, and Pz positions of the 10–20 International System, referring to the nasion) and at T3 and T4, referring to Fz (impedance below 5000 ohms), with the ground at Fpz. A further electrode was placed above the right eye to record the EOG. Signals were amplified, filtered (.5–100 Hz), and stored on a biopotential analyzer (MICROMED System Plus; MICROMED, Mogliano Veneto, Italy).
Stimulation The stimulation site was visualized with an He–Ne laser beam. Following each stimulus, the laser beam was shifted slightly to avoid nociceptor sensitization and skin damage. The pain stimulus was a laser pulse (wavelength 10.6 mm) generated by a CO2 laser (Neurolas, Electronic Engineering, Florence, Italy). The beam diameter was 2.5 mm and the duration of the stimulus pulse was 25 ms. In all subjects, the laser power and duration were set at a suprathreshold level5 using a 10-point ver-
60
controls FM patients
LEP Analysis
LASER PAIN PERCEPTION
50
VAS
40
30
20
10
0 f ace
hand
bal analogue scale in which 0 corresponded to no sensation, 4 to the Pain Threshold, and 10 to intolerable pain. All subjects perceived the 25-ms duration and 7.5-watt intensity laser stimuli as a painful pinprick, and gave ratings of $6 for more than 50% of 20 stimuli.5 The dorsum of the right hand and the right supraorbital zone were selected as the 2 nontender points. All patients had reported that the right knee was a tender point and so this was selected as the tender point for the present study. Three consecutive series of 20-laser stimuli were delivered to each stimulation site with an interstimulus interval (ISI) of 10 seconds. A 1-minute interval was interposed between each series. The site of stimulation was changed after a 10-minute interval. The order of the stimulation sites was varied at random between subjects. All subjects had been informed about the modality and rating of the stimulation prior to the procedure. At the end of each series of stimulation, all subjects were requested to rate the average pain perceived for the 20-laser stimuli using a 0 to 100 visual analogue pain scale (Laser-pain VAS), in which 0 indicated no pain (white) and 100 indicated the most severe pain imaginable (red).
knee
Figure 2. Mean values and standard deviations of subjective pain induced by laser stimuli, as measured by visual 0 to 100 VAS in patients (n 14) and controls (n 13).
An investigator who was blind to the clinical condition analyzed the LEP recordings for 1 second, with a 100-ms prestimulus time, at a sampling rate of 512 Hz. All runs containing transient signals that exceeded 65 mV on any recording channel were excluded from the average by an automatic artifact rejection algorithm. Other artifacts were inspected visually. An average of at least 15 artifact-free responses was obtained off-line for each stimulation series. For each stimulation site (right hand, right supra-orbital zone, and right knee), an average was obtained across each series of stimuli. LEP were identified on the basis of their latency and distribution, and 3 responses (N1, N2, and P2) were labelled according to Valeriani et al.54 The N2a (termed N2) and P2 components were analyzed at the vertex (Cz) and the N1 component was analyzed at T3-Fz.
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the LEP amplitudes and the VAS values obtained in the third and the first block of evoked responses was computed. This was termed the habituation index (HI). To optimize assessment of habituation, these quotients were also computed between the second and the first, and the third and the second blocks of evoked responses.
N1 habituation controls FM patients
16 14 12 10
uV
119
8
Statistical Analysis
6 4 2 0 I°
II°
III°
I°
II°
f ace
III°
I°
h an d
II°
III°
k n ee
N2 habituation 14 12 10
uV
8 6 4 controls FM patients
2
Results
0 I°
II°
III°
I°
f ace
II°
III°
I°
h an d
II°
III°
k n ee
P2 habituation
25 controls n° 13 FMS patients n° 14
20
uV
15
10
5
0 I°
II°
III°
f ace
The Kolmogorov-Smirnov statistic, with a Lilliefors significance level, was applied to test for normality. The mean VAS values, the N1, N2, and P2 amplitudes and latencies, (computed across the 3 repetitions), and the Habituation Index were used as the variables for a 2-way ANOVA analysis. Diagnosis and the site of stimulation were the main factors. The Bonferroni was applied as a post hoc test for differences across the 3 sites of stimulation. The Spearman correlation test was used to correlate the main LEP abnormalities with clinical features. In view of the large number of correlations and the possibility of spuriously significant results, only correlations with P values of <.01 were considered. To determine correlations, mean LEP and VAS values across the 3 sites of stimulation and the 3 repetitions, and the mean habituation index across the 3 sites of stimulation, were considered.
I°
II°
III°
k n eee
I°
II°
III°
h an d
Figure 3. Amplitudes of laser-evoked potentials in the 3 consecutive series of stimulation, showing the course of habituation in patients (n 14) and controls (n 13).
Trace Absolute latencies of the scalp potentials were measured at the highest peak of each response component. The amplitude of each wave was measured from the baseline. Baseline was measured automatically by calculating the average signal on the whole sweep and subtracting it from the trace (ASA- v.4.6 by ANT software; Advanced Neuro Technology, Enschede, The Netherlands). The peak-to-peak amplitude was taken into consideration for the vertex biphasic LEP component (N2–P2). To assess LEP and laser pain habituation, the quotient between
The N1, N2, and P2 latencies were similar for FM patients and controls for all 3 stimulation sites. The N1 amplitude was also similar in patients and controls for all 3 stimulation sites. (Table 1; Fig 1). The amplitudes of N2 and P2 (and consequently of the N2–P2 complex) were increased in FM patients compared to controls (Table 1; Fig 1). The N2 and P2 amplitudes were not significantly different between the patients and controls with respect to the site of stimulation: The N2 amplitude was larger at the face level, in respect to the knee levels, the P2 at the face in respect to both the hand and knee. (Table 1; Fig 1). FM patients reported greater subjective laser pain than controls for all stimulation sites (Table1; Fig 2). In FM patients, no significant difference in subjective laser pain was found across the 3 sites of stimulation. In controls, the N2 and P2 amplitudes were reduced in the second and third blocks of averaged responses for all stimulation sites (Figs 3 and 4). This reduction was particularly pronounced for the N2 wave (Fig 3). In FM patients, the progressive reduction in N2 and P2 amplitudes was less evident at the face and hand levels (Fig 3), whereas a progressive increase in vertex LEP amplitudes emerged across the 3 consecutive series of stimulations at the tender (knee) point (Figs 3 and 4). FM patients showed a significant increase in the habituation index of N2, P2, and the N2–P2 complex, which indicates reduced habituation across the 3 series of stimulation, for all 3 stimulation sites (Table 2; Figs 3 and 4). The VAS scores, which indicate subjective perception of laser pain, also showed reduced habituation across the 3 series of stimulation in FM patients (Table 2). In controls, the N1 wave amplitude showed a tendency toward a progressive reduction in
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Figure 4. Laser-evoked potentials obtained by the right knee in a representative fibromyalgia patient and a normal control. Each trace is the average of 15 responses.
the second and third repetitions (Fig 3). FM patients showed a nonsignificant trend toward an increased N1 habituation index (Table 2; Fig 3). No significant differences in LEP and VAS scores were found across the II versus I and III versus II repetitions, either between groups or across the sites of stimulation. In FM patients, the N2–P2 complex amplitude was positively correlated with VAS scores (Spearman correlation test: .625: P = .009). The N2 amplitude was positively correlated with the duration of FM (Spearman correlation test: .645: P = .008). Higher N2 habituation index values (which indicate reduced habituation) were positively correlated with the severity of self-reported depressive symptoms, as measured by SDS (Spearman correlation test: .701: P = .005; Fig 5). Other correlations between P2 and N2–P2 amplitude habituation indices and main clinical features did not achieve statistical significance.
Results of One-Way ANOVA With LEPs Habituation Index (HI) as Variables. The Significant Results Are Reported
Table 2.
MAIN FACTORS Diagnosis (FM versus controls) F= DF = P= Sites (Hand versus face versus knee) F= DF = P= Diagnosis sites F= DF = P= Post hoc test (Bonferroni) Hand versus knee Face versus knee Hand versus face
N1 HI
N2 HI
P2 HI
N2 P2 HI
VAS HI
2 1 ns
7.45 1 .009
4.45 1 .043
4.48 1 .042
4.7 1 .034
.59 2 ns
1.29 2 ns
.38 2 ns
1.16 2 ns
2.73 2 ns
.54 2 ns Sites
1.28 2 ns Sites
.46 2 ns Sites
.13 2 ns Sites
2 2 ns Sites
ns ns ns
ns ns ns
ns ns ns
ns ns ns
ns ns ns
Discussion The present study yielded 3 main results: 1) patients with FM showed increased amplitude of vertex LEP and increased laser pain for all stimulation sites; 2) they showed decreased habituation of both the vertex LEP and subjective laser pain; and 3) the reduction in N2 habituation was more pronounced in patients with higher self-reported levels of depression. The first finding (1) partly replicates the results of previous studies. Gibson et al22 found an increase in the amplitude of vertex LEP in response to stimulation of tender and nontender points, suggesting a greater activation of central nervous system (CNS) pathways in response to noxious input. In contrast to the findings of the present study, Lorenz et al32 observed an increase in the amplitude of the N170, which corresponds to the N1 wave, in response to painful laser stimulation. Research has demonstrated that this occipito-temporal negative component is involved in focussed attention and spatial discrimination,41 and it is thought to originate in the opercular cortex.21 One study found that the N1 amplitude was normal or even reduced in patients with migraine, who, in common with FM patients, display greater activation of the central nociceptive system and an increase in the amplitude of the vertex waves, particularly during an attack.17 In the present study, the amplitude of the vertex complex was increased in FM patients. This complex appears to express the attentive orientation toward noxious stimuli (specifically stimulus-driven orienting processes) and the salience of the evoking stimulus.28-30,32 It is thought to originate in the posterior insula and anterior cingulate cortex,21 which are areas that elaborate the attentive and emotional components of pain.37 Noxious stimuli may, therefore, induce greater activation of specific cortical areas in FM patients. Nevertheless, virtually identical factors modulate the negative (N1, N2) and positive (P2) components of LEP.33 However, the small amplitude of the N1 may result in high variability between subjects51 and thus conflicting results across studies. In one study of FM patients, increased N2–P2 amplitude was found to correspond to an increase in pain sensitivity to laser stimuli.8 This corresponds with the finding of abnormalities of pain perception in FM
de Tommaso et al
The Journal of Pain
Correlation between N2 habituation index and depression levels 60 55
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Figure 5. Relationship between (A) N2 habituation index, computed as the ratio between the N2 wave amplitude obtained in the third series and that obtained in the first series of stimulation in the FM patients: The mean habituation index across the 3 different sites of stimulation is considered. (B) N2 mean amplitude across the 3 sites of stimulation and illness duration. (C) N2–P2 mean amplitude across the 3 sites of stimulation and laser VAS.
patients reported from studies that have applied various methods of sensory testing.47 Abnormalities of LEP and pain perception appeared to be widespread rather than restricted to the tender point. This confirms that there is a general increase in the activation of cortical areas devoted to the processing of pain stimuli in FM patients, irrespective of the site of stimulation.22,29 In accordance with other studies of LEP in normal subjects,52 controls in the present study were found to have increased amplitudes of vertex LEP at the face level compared with the amplitude of LEP obtained from stimulation of other sites. No significant differences in LEP
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amplitudes were observed between the hand and knee levels, as has been described in previous studies for stimulation of the foot.52 The more proximal location of the knee stimulation point used in the present study would have reduced the difference in amplitude between LEP obtained at the hand and the leg in both patients and normal controls. The observation of increased LEP amplitudes in response to stimulation of hyperalgesic sites may provide support for the hypothesis that FM pain is functional in nature, since reduced LEP amplitudes have been reported in pain of neuropathic origin.20 These findings confirm that LEPs are a useful tool for elucidating the mechanisms that underlie chronic pain syndromes.11 The results of the present study correspond with fMRI findings of significantly greater activation in the anterior insula and the cingulate cortex in response to painful stimuli.38 This enhanced activation of cortical areas that are devoted to the processing of nociceptive stimuli appears to contradict the findings of some voxel-based morphometry studies, which have reported a decrease in grey matter volume in the prefrontal cortex, the amygdala, and the anterior cingulate cortex (ACC) in FM patients.7,59 However, studies that have controlled for clinical features such as the presence of an affective disorder have not replicated these morphological findings.26 It is plausible that in FM and other forms of chronic pain, structural changes may differentially affect brain regions involved in pain modulation, resulting in an altered balance between cerebral areas that facilitate, and cerebral areas that inhibit, nociceptive inputs.27,42,43,56 The present study cannot help to resolve the question of whether greater cerebral activation in response to noxious inputs may be imputed to a general phenomenon of hypervigilance to multimodal stimuli,25,31 as has been suggested in recent studies,9 since it did not investigate other sensory modalities. In regard to the second point (2), the results of the present study provide the first evidence in support of the hypothesis of reduced habituation, and even facilitation, of cerebral potentials in response to repetitive noxious stimuli in FM patients, as demonstrated by their increased amplitude. These results correspond with previous findings of reduced habituation to painful heat stimuli (as measured by Quantitative Sensory Testing), a phenomenon that may contribute to the pathophysiology of chronic pain in FM patients.45 In FM patients in the present study, the reduced habituation of vertex LEP was accompanied by reduced habituation of laser-pain perception. This confirms that the lack of a reduction in cortical recruitment across repetitive stimuli corresponds to a lack of decline of pain perception. The reduced habituation of laser-pain perception and cortical processing was not confined to the tender point, but seemed instead to be a generalized phenomenon. Studies have found a similar pattern in migraine patients, in both critical and intercritical phases.13,53 It would be interesting to establish whether FM patients, in common with migraine patients, show reduced habituation to multimodal stimuli in accordance with the generalized hypervigilance hypothesis. At present, there are no objective measures with which to characterize the
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The Journal of Pain 9
sensory style of FM patients. Reduced habituation to noxious inputs, which facilitates an increase in pain perception and (possibly) central sensitization, may be implicated in some nonorganic chronic pain syndromes.53,55 This may explain the observed overlap between pain syndromes such as migraine and FM.15 LEPs therefore assist in distinguishing between ‘‘neuropathic’’ and ‘‘sine material’’ models of pain.20 However, the origin of reduced habituation remains contentious. Increased neuronal excitability and reduced inhibition have both been proposed as the cause of reduced habituation in syndromes as migraine.1,10 The results of the present study suggest that the pathophysiology of FM may involve a biobehavioral model of reactivity to painful, and probably multimodal, stimuli as a result of altered central neuronal excitability, as with other chronic pain syndromes.16 This may explain the positive effect of Antiepileptic Drugs (AEDs) in the management of FM.34 This class of drugs has been shown to be effective in reducing the phenomenon of dishabituation of event-related potentials.12 In the present study, a tendency toward a progressive increase in the amplitude of N2 and P2 was observed when the tender point was stimulated. However, no significant difference in the habituation pattern was observed across the 3 stimulation sites. Further analysis, involving the performance of an increased number of repetition series, would probably emphasize the progressive facilitation of cortical recruitment that is induced by repetitive painful stimulation of tender points. This would provide an explanation of the localization of pain in FM in terms of a generalized phenomenon of reduced habituation and a local increase in central sensitization processes. Another interesting finding (3) of the present study was that FM patients with self-reported symptoms of depression showed a more pronounced reduction of N2 wave habituation. No correlation was found between LEP findings and measures of fibromyalgia severity such as pain at tender points, quality of life, and impact of the disease on daily living. This confirms that FM is a complex syndrome and that abnormal central pain processing is not the only factor that determines the severity of symptoms. In accordance with previous studies of chronic pain syndromes,14 patients with clinically evident
psychiatric disorders were excluded from the present study since these disorders may confound evaluation of the features of the investigated disease.59 The Zung scales60,61 are used to rate anxiety and depression in the general population and provide an estimate of their subclinical manifestations. In FM patients in the present study, reduced habituation of the N2 vertex component was facilitated by the presence of symptoms that may be attributable to depression. In the present study, the habituation index of the P2 approached, and that of the N2–P2 complex actually achieved, a significant correlation with depression. These results were not reported since correlations with P < .01 were discarded in order to avoid spurious results. Reduced habituation and increased amplitude of long latency somatosensory potentials have been reported in patients with major depression.18 The phenomenon of reduced habituation has been imputed to a thalamo-cortical dysrhythmia, in which a deficit in serotoninergic and monoaminergic neurotransmission is the main chemical abnormality.10 This deficit has been well established for major depression.40 Furthermore, deficient habituation of the limbic cortex, which is involved in the control of affective status, has been shown to be inversely correlated with serotoninergic receptor density.19 In animal models, treatment with reserpine has been shown to result in a significant decrease in the muscle pressure threshold, tactile allodynia, and increased immobility time in the forced swim test, which are features that may indicate depression.35 Reserpine causes a decrease in the levels of biogenic amines (dopamine, norepinephrine, and 5-hydroxytryptamine) in the spinal cord, thalamus, and prefrontal cortex areas, which are closely involved in pain signal processing. In summary, the results of the present study suggest that the pathophysiology of FM may involve a generalized increase in the perception of painful stimuli and reduced habituation of the sensory cortex, as has been proposed for other chronic pain syndromes. This may be caused by altered excitability of the sensory cortex and facilitated by the presence of depressive symptoms and abnormalities in central neurotransmission. These findings provide further support for the use of medications with effects on the CNS in the management of FM.
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