Evidence for cortical hyperexcitability of the affected limb representation area in CRPS: a psychophysical and transcranial magnetic stimulation study

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1 Pain 113 (2005) Evidence for cortical hyperexcitability of the affected limb representation area in CRPS: a psychophysical and transcranial magnetic stimulation study Elon Eisenberg a,d,e, *, Andrei V. Chistyakov b,e, Marina Yudashkin c, Boris Kaplan b,e, Hava Hafner b,e, Moshe Feinsod b,e a Pain Relief Uniti, Rambam (Maimonides) Medical Center, P.O. Box 9602, Haifa 31096, Israel b Laboratory of Clinical Neurosciences, Department of Neurosurgery, Rambam (Maimonides) Medical Center, Haifa, Israel c Department of Anesthesiology, Bnai-Zion Medical Center, Haifa, Israel d Haifa Pain Research Group, Haifa, Israel e B. Rappaport Faculty of Medicine, the Technion, Israel Institute of Technology, Haifa, Israel Received 23 June 2004; received in revised form 9 September 2004; accepted 28 September 2004 Abstract Functional alterations in noxious, sensory and motor circuits within the central nervous system may play an important role in the pathophysiology of complex regional pain syndrome (CRPS). The aim of the present study was to search for further evidence of hyperexcitability in the hemisphere contralateral to the affected limb in patients with CRPS by employing both psychophysical and transcranial magnetic stimulation (TMS) methods. Twelve patients with CRPS type I, confined to the distal part of a limb (six in an upperlimb and six in a lower-limb), were enrolled in the study. The quantitative thermal, mechanical and wind-up like pain testing was performed at the most painful site in the affected limb and in the ipsilateral limb. Results were then compared to those found at mirror sites in the contralateral limbs. TMS was used to assess the inter-hemispheric difference in parameters of corticospinal excitability, intracortical inhibition, and intracortical facilitation. The quantitative thermal and mechanical testing showed significant differences in cold, heat and mechanical pain thresholds, as well as in the first and last wind-up stimuli between the affected and the contralateral limbs of the CRPS patients. No significant differences between the ipsilateral unaffected limbs and their contralateral pair limbs were found. A significant reduction in the short intracortical inhibition associated with a significant increase of the I-wave facilitation was found in the hemisphere contralateral to the affected side in the upper-limb CRPS group. No significant inter-hemispheric asymmetry between the affected and the non-affected sides was revealed in the lower-limb CRPS group. Taken together, these results suggest that in patients with well-localized CRPS, there is evidence for sensory and motor CNS hyperexcitability, though it seems to involve only corresponding regions within the CNS rather than the entire hemisphere. q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Complex regional pain syndrome; Transcranial magnetic stimulation; Cortical excitability; Quantitative sensory testing 1. Introduction * Corresponding author. Address: Pain Relief Uniti, Rambam (Maimonides) Medical Center, P.O. Box 9602, Haifa 31096, Israel. Tel.: C ; fax: C address: e_eisenberg@rambam.health.gov.il (E. Eisenberg). Complex regional pain syndrome (CRPS), either with identifiable nerve injury (type II) or without (type I), is characterized by spontaneous and stimulus-evoked pain, edema, vasomotor and sudomotor abnormalities, motor dysfunction, and trophic changes (Stanton-Hicks et al., 1995). The symptoms typically occur in the distal part of the affected limb, usually following a relatively benign trauma /$20.00 q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi: /j.pain

2 100 E. Eisenberg et al. / Pain 113 (2005) However, many reports indicate that the signs and symptoms of CRPS may gradually spread to more proximal sites and even involve the entire limb. Furthermore, sensory impairments in some patients with CRPS may extend to a quadrant or to half of the body, usually ipsilateral to the affected limb (Rommel and Thimineur, 2001). These findings, as well as the motor changes (weakness, tremor, dystonia, and neglect) found in affected CRPS limbs, suggest that functional alterations in noxious, sensory and motor circuits within the central nervous system may occur in patients with CRPS. Also suggestive of functional disturbances in multiple CNS locations are the results of functional MRI, PET and SPECT tests conducted on these patients, revealing significant changes in perfusion of the thalamus, medulla, and prefrontal cortex (Apkarian et al., 2001; Rommel and Thimineur, 2001). Transcranial magnetic stimulation (TMS) is a safe, noninvasive neurophysiological technique used for investigating the function of the human central motor system in health and disease. Single-pulse and paired-pulse TMS have been widely used for the assessment of central motor conduction and of global corticospinal and intrinsic intracortical excitability (Chen, 2000). In a conditioningtest TMS paradigm, the motor evoked potential (MEP) elicited by a suprathreshold stimulus can either be inhibited by a sub-threshold conditioning stimulus at inter-stimulus intervals (ISIs) of 1 5 ms or facilitated at ISIs of ms. These phenomena are termed the short intracortical inhibition (SICI) and the intracortical facilitation (ICF), respectively. An additional phenomenon is that of the long intracortical inhibition (LICI), which can be assessed at ISIs of ms with both conditioning and test stimuli applied at suprathreshold intensity. The SICI, LICI and ICF appear to be mediated by separate inhibitory and excitatory interneuronal circuits (Chen, 2004; Kujirai et al., 1993; Ziemann et al., 1996). Another technique of paired-pulse TMS employs a suprathreshold conditioning stimulus followed by a subthreshold test stimulus at ISIs of approximately 1.4 and 2.5 ms. This technique can be used to evaluate the interaction of indirect waves (I-waves) generated by TMS in the corticospinal tract (Ziemann et al., 1998). To the best of our knowledge, there is only one previously reported TMS study on cortical excitability in patients with CRPS (Schwenkreis et al., 2003a), which demonstrated bilateral reduction of the short intracortical inhibition but no interhemispheric asymmetry. The aim of the present study was to seek further evidence of hyperexcitability in the hemisphere contralateral to the affected limb in patients with CRPS confined to the distal part of a limb by employing two methods: (1) comparisons of various psychophysical parameters in the limbs of the affected and the unaffected sides of the body; and (2) evaluation of inter-hemispheric differences in the parameters of cortical excitability, as assessed by TMS. 2. Methods 2.1. Subjects The study population consisted of patients who were referred to the Pain Relief Unit at Rambam Medical Center in Haifa, Israel between November 2002 and February 2003 with a possible diagnosis of CRPS. Of the 18 consecutive patients who were considered for the study, 12 met the CRPS criteria established by Bruehl et al. (1999). Patients who had any other unrelated medical problems were excluded from the study. The upper limits of the normal range for the parameters of cortical excitability were obtained from 14 healthy subjects matched for handedness, sex and age (10 right-handers and four left-handers; four women and 10 men with a mean age of 30.9G 12.7). The study protocol was approved by the hospital s Ethics Committee, and a written informed consent was obtained from all patients and control subjects Psychophysical evaluation The evaluation included three parts: (a) a questionnaire covering demographic data as well as the circumstances and date of pain onset; (b) evaluation of changes in skin temperature or color, sudomotor abnormalities, swelling, motor dysfunction, or trophic changes in the skin, hair or nails of the affected limb; and (c) measurement of pain intensity on a 10-cm blank visual analogue scale (VAS; Price et al., 1983), together with the Short Form of the McGill Pain Questionnaire (SF-MPQ; Melzack, 1975). The examination consisted of the following methods: (a) Three paintbrush strokes were applied to the painful site on the affected limb and the contralateral limb in order to test for hypoesthesia or mechanical allodynia. (b) A single pinprick (X3) was administered for the assessment of mechanical hyperalgesia. (c) Quantitative thermal testing (QTT) was conducted on a Medoc TSA-2001 device (Medoc, Israel), using the method of limits (Yarnitsky and Fowler, 1995), to determine the thresholds for warm and cold sensations and for heat and cold pain. A Peltier thermode, size 30!30 mm, was attached to the skin. Stimulator temperature range was C, and skin adaptation temperature was a constant 32 8C. Increasing stimuli were applied, directed from the adaptation temperature toward the sensation range at a temperature change rate of 1 8C/s. Subjects were asked to depress a switch at the instant when they perceived a specific sensation (e.g. a cold sensation). At each site, three readings were obtained for each thermal sensation, and their average was determined as the threshold score. (d) Mechanical touch and pain thresholds were measured by applying graded punctate stimuli to the skin, using a series of 20 nylon filaments of varying bending pressure (von Frey filaments) that represent stimuli from 10 mg to 300 g. The weakest stimulus that the patient identified upon two out of three stimulus applications was recorded as the perception threshold. (e) A series of 10 pinpricks were administered at the rate of 1/s for the assessment of mechanical induced wind-up like pain. Patients were instructed to report the intensity of the pain induced by the first and the last pinprick on a VAS. Tests were performed at the most painful site on the affected limb, followed by a threshold measurement at the mirror site on the contralateral limb. Thresholds were then tested on the other two limbs, either at the thenar eminence or at the dorsum of the feet. All tests were carried

3 E. Eisenberg et al. / Pain 113 (2005) out by one examiner (M.Y.) during the morning hours (between 8 and 11 a.m.) under controlled room temperature Neurophysiological measurements For the assessment of cortical excitability, patients were seated in a comfortable chair with arms resting on pillows and elbows semi-flexed. They wore a tightly fitting cap to mark the sites for transcranial magnetic stimulation and to ensure an accurate repositioning of the coil throughout the study. Using a Nicolet Viking 4 system (Nicolet Biomedical Ins., Wisconsin, USA), motor evoked potentials (MEPs) were recorded separately from each side by placing surface disc electrodes on the abductor pollicis brevis (APB) muscle with a tendon belly montage. Audiovisual EMG feedback was given in order to ensure complete muscle relaxation. Trials in which EMG activity occurred were discarded from analysis. In all single-pulse and paired-pulse TMS studies, the interval between trials was at least 6 s. The TMS of the motor cortex was achieved by using a Magstim 200 magnetic stimulator (Magstim, UK). The magnetic pulses were delivered through a figure-of-eight coil (external diameter of each loop: 90 mm; peak magnetic field: 2.2 T). The coil was placed tangentially to the scalp over the optimal scalp position for producing MEPs of maximal amplitude in the contralateral APB muscle, and the handle was pointed backwards and about 458 away from the midline. In this coil position, the current induced in the brain flows in a posterior to anterior direction and preferentially activates the corticospinal neurons trans-synaptically. The combination of manual handling and mechanical fixation of the coil and head was used to avoid uncontrolled coil displacements during the TMS session. The parameters of cortical excitability that were assessed included the resting (rmt) and the active (amt) motor thresholds, the MEP/M-wave amplitude ratio, the central motor conduction time (CMCT), the intracortical facilitation (ICF), the short intracortical inhibition (SICI), the long intracortical inhibition (LICI), and the I-wave interaction. The rmt was defined as the lowest stimulus intensity capable of eliciting in the relaxed APB at least five MEPs with an amplitude of at least 50 mv in a series of 10 consecutive trials of single-pulse TMS. The amt was measured during a voluntary isometric contraction of the contralateral APB, with a force level of about 20% of maximal EMG. It was defined as the minimum stimulus intensity required to produce an average MEPO100 mv over five consecutive single-pulse TMS trials. The MEP amplitude was measured peak-to-peak at a TMS intensity of 20% above the rmt during muscle relaxation. The MEP/M-wave amplitude ratio was then calculated by dividing the MEP amplitude by the maximal M-wave amplitude obtained after supramaximal peripheral electrical stimulation of the median nerve at the wrist. The MEP/M-wave amplitude ratio was the result of averaging 10 single-pulse TMS trials. The CMCT was defined as the difference between the shortest latency of the motor response elicited by single-pulse TMS at an intensity of 30% above the rmt and the peripheral latency assessed by the F-wave method. The SICI, the LICI and the ICF were assessed by using the standard conditioning-test paradigms (Chen, 2000; Kujirai et al., 1993; Ziemann et al., 1998). For this purpose, two Magstim 200 (Magstim, UK) magnetic stimulators were connected through a BiStim module to a figure-of-eight coil. The intensity of suprathreshold stimuli was kept the same in all paired-pulse TMS trials and was adjusted to produce an MEP with a peak-topeak amplitude of mv. The SICI and the ICF were measured at inter-stimulus intervals (ISIs) of 2 and 10 ms, respectively. The conditioning (subthreshold) stimulus was applied at an intensity of 95% of the amt. The intensity of the test stimulus was at a suprathreshold level. The LICI was elicited at an ISI of 100 ms, with both conditioning and test stimuli applied at the same suprathreshold intensity. The I-wave interaction was assessed at ISIs of 1.4 and 2.5 ms. The intensity of the first stimulus was at a suprathreshold level. The intensity of the second stimulus was set at 80% of the rmt. For each ISI, eight trials were performed. These were randomly mixed with 16 trials of the test stimulus alone. The size (area under the rectified MEP curve) of the mean conditioned MEP at a given ISI was expressed as a percentage of the size of the mean unconditioned MEP elicited by single-test TMSs. For each measure of cortical excitability, the difference between the affected and the unaffected hemispheres was calculated in the CRPS groups. In the control group, the difference between the dominant and the non-dominant sides was assessed Statistical analysis Results of psychophysical and neurophysiological tests were analyzed separately, using the repeated measures ANOVA with GROUP (upper-limb CRPS, lower-limb CRPS, or control) as the between-subject factor and SIDE (affected/non-affected or dominant/non-dominant) as the within-subject factor. Significant F- tests were followed by post-hoc student s t-tests performed with a Bonferroni adjustment for multiple comparisons. Within-group comparisons between the affected and the contralateral limbs, as well as between the non-affected ipsilateral limbs and their contralateral limbs, were calculated by using the paired sample two-tailed t-test. The between-group differences were estimated by the independent sample two-tailed t-test. Results were considered significant at the 0.05 level (P-value), and the data are presented as meansgsd. 3. Results 3.1. Subjects All 12 CRPS subjects were classified as CRPS type I, with the affected extremity equally divided between upper and lower extremities. None of the patients had any signs or symptoms of CRPS in the contralateral limb. The affected limb was on the dominant side in seven patients, and on the non-dominant side in five patients. The demographic data are summarized in Table Psychophysical evaluation The average pain intensity of the two CRPS groups (upper and lower extremities), as indicated by the VAS, was in the moderate range (Table 1). The average SF-MPQ score was above 20 in both groups. Pain duration was slightly

4 102 E. Eisenberg et al. / Pain 113 (2005) Table 1 Demographic and pain characteristics CRPS Hand Foot n 6 6 Age (years) 33G10 32G9 M/F 4/2 5/1 Handedness before CRPS right/left 4/2 5/1 Affected side dominant/non-dominant 4/2 3/3 Immobility of the affected limb 5 6 Pain duration (months) 31G41 20G21 VAS (0 10) 7.3G G2.3 SF-MPQ score 21G10 22G9 shorter in the lower-limb CRPS group, though statistically insignificant. Spontaneous and evoked pain, as well as typical CRPS changes in temperature, color and swelling of the affected limb, were reported by all CRPS patients. Likewise, examination revealed hyperalgesia/allodynia, temperature/color and motor/trophic changes in all CRPS subjects (Table 2). Notably, immobility of the affected limb was found in 11 of the 12 patients. No abnormalities were detected upon examination of the healthy limbs of all 12 subjects. Quantitative thermal and mechanical testing showed significant differences in cold, heat and mechanical pain thresholds, as well as in the first and last wind-up stimuli, between the affected and the contralateral limbs of the CRPS patients (Table 3). No significant differences between the unaffected ipsilateral limbs and their contralateral limbs were found in the CRPS patients Evaluation of cortical excitability Of the 12 patients who participated in the study, one patient with upper-limb CRPS was not able to cooperate sufficiently for the neurophysiological assessment because of severe pain evoked by wrist muscle contraction following the magnetic stimulation. Results presented below refer to the remaining 11 patients Control group In healthy subjects, the rmt, the amt, the MEP/M-wave amplitude ratio, and the CMCT, as well as the SICI, the LICI and the ICF, showed no correlation with handedness or any inter-hemispheric asymmetry (Fig. 1). In contrast, the I-wave facilitation at ISIs of 1.4 and 2.5 ms was significantly less prominent in the dominant hemisphere than in the non-dominant hemisphere (Fig. 2; ANOVA, paired t-test, P!0.01), indicating stronger inhibitory control of motor output in the dominant hemisphere CRPS group Among the parameters of cortical excitability, a significant inter-hemispheric difference was found for the SICI and for the I-wave facilitation in patients with upperlimb CRPS. The SICI at 2 ms ISI was significantly reduced on the affected side, as compared to the unaffected side (Fig. 1; ANOVA, paired t-test, P!0.05) and as compared to the dominant and the non-dominant sides in the control group (ANOVA, t-test, P!0.01). For this parameter, a significant interaction of GROUP!SIDE (ANOVA, P!0.05) was found between the upper- and lower-limb CRPS groups. The reduction of the SICI was associated with a significant increase of the I-wave facilitation at 1.4 ms ISI in the hemisphere contralateral to the affected side, regardless of whether this side was dominant or non-dominant prior to the development of CRPS (Fig. 2; ANOVA, paired t-test, P!0.05). In those patients in whom the dominant hand was affected (nz3), an inverse inter-hemispheric asymmetry in the I-wave facilitation between the dominant and the non-dominant sides was revealed. In patients with CRPS in the nondominant hand (nz2), the inter-hemispheric asymmetry in Table 2 Detailed subjective and objective characteristics of the 12 CRPS patients Patient Pain location History Objective findings Temp/color Swelling/ sweating Motor/ trophic Allodynia/ hyperalgesia Temp/color Hyperesthesia Edema/sudomotor 1 UE C C C C C C C C 2 UE C C C C C C C C 3 UE C C K C C C C C 4 UE K C C C C C C C 5 UE C C C K C C C K 6 UE C C C C C C C C 7 LE C C C C C C C C 8 LE C C C C C C C C 9 LE C C C C C C C C 10 LE C C C C K C C C 11 LE C C C C C C C C 12 LE K C C C C C C C UE, upper extremity; LE, lower extremity; temp/color, temperature/color changes; motor/trophic, motor/trophic changes; C, present; K, absent. Motor/ trophic

5 E. Eisenberg et al. / Pain 113 (2005) Table 3 Psychophysical findings Parameter Affected site** Non-affected site*** Affected limb Contralateral limb P Ipsilateral healthy limb Contralateral healthy limb Touch sensation* (gr) 0.15G G G G Touch pain* (gr) 1.0G G G G Warm sensation* (8C) 37.1G G G G Heat pain* (8C) 39.3G G G G Cold sensation* (8C) 27.7G G G G Cold pain* (8C) 21.7G G G G Wind-up first (VAS) 3.7G G G G Wind-up last (VAS) 6.5G G G G * Threshold; ** affected site refers to the part of the body (upper or lower) with the CRPS limb; *** non-affected site refers to the part of the body (upper or lower) in which both limbs were unaffected by CRPS. P the I-wave facilitation remained unchanged. No significant difference in the parameters of cortical excitability between the affected and the non-affected sides was observed in the lower-limb CRPS group. 4. Discussion The results of this study clearly show signs of psychophysical hyperexcitability in the affected limb, as compared to the contralateral limb. No such signs could be identified in the unaffected ipsilateral limb when compared to its contralateral side. These findings indicate that in this group of patients, among whom the CRPS was localized to the distal part of one limb, there was no psychophysical evidence of hemibody hyperexcitability. The results of the paired-pulse TMS trials further demonstrate that CRPS is associated with a significant reduction in intracortical inhibition and enhancement of the I-wave facilitation in the hemisphere contralateral to the affected limb. The intracortical inhibition (ICI) as assessed at the inter-stimulus interval of 2 ms was completely abolished in the affected side in patients with upper-limb CRPS and this difference was significant not only in comparison with the ICI in the unaffected side but also in comparison with the ICI in either side in control subjects. Such an abnormal inter-hemispheric asymmetry of the ICI was found only in the upper-limb CRPS group. No significant difference in the level of the intracortical Fig. 1. Inter-hemispheric differences in the short intracortical inhibition (SICI), as assessed by paired-pulse TMS at 2 ms ISI between the affected and the non-affected sides in patients with upper- and lower-limb CRPS and the dominant and non-dominant hemispheres in controls (MeanGSD, *P! 0.01, paired t-test). Fig. 2. Inter-hemispheric differences in the I-wave facilitation, as assessed by paired-pulse TMS at 1.4 ms ISI between the affected and the nonaffected sides in patients with upper- and lower-limb CRPS and the dominant and non-dominant hemispheres in controls (MeanGSD, *P! 0.01, paired t-test).

6 104 E. Eisenberg et al. / Pain 113 (2005) inhibition of the wrist (APB) motor area was revealed between the dominant and the non-dominant hemispheres in the control group as well as between the affected and the non-affected sides in the lower-limb CRPS group. These finding suggest that impairment of cortical excitability in CRPS occurs within the representation of the affected limb muscles. In contrast to an earlier report (Schwenkreis et al., 2003a), we did not observe a decrease in the short intracortical inhibition in the hemisphere contralateral to the non-affected limb. Moreover, any diminished I-wave facilitation revealed on the unaffected side may reflect increased activity of the inhibitory GABA-ergic circuits, which control I-wave production and play an important role in executing fine voluntary movements (Ziemann et al., 1998). On the other hand, enhancement of I-wave facilitation in the affected hemisphere may result from a reduction or even a loss of inhibitory control due to immobility of the affected limb. Severe active functional immobilization, which presented in all of our patients with upper-limb CRPS, appears to be essential for inducing the bilateral reorganization of the motor cortex excitability that creates a shift in hemispheric dominance to the unaffected side. This suggestion is supported by the inverse interhemispheric asymmetry of I-wave facilitation found in patients with CRPS in the dominant hand. Taken together, the results of both the psychophysical and TMS evaluations used in the present study appear to be aligned in their indication of localized functional CNS disturbances in patients with CRPS. The findings are also in agreement with the results of other CNS imaging modalities, such as functional MRI, PET and SPECT tests, which have revealed significant changes in the perfusion of various CNS locations in CRPS patients (Apkarian et al., 2001; Rommel and Thimineur, 2001). These findings carry particular importance in light of the facts that the pathogenesis of CRPS remains obscure and that no clear effective treatments are currently available. Interestingly enough, these findings are also in agreement with the results of other studies demonstrating unilaterally exaggerated cortical excitability (or disinhibition) in patients following upper-limb immobilization (Zanette et al., 2004) and amputation (Schwenkreis et al., 2000). Immobilization is regarded as a main feature of CRPS. Interestingly enough, signs and symptoms of CRPS (excluding pain) were reported by Butler et al. (1999) in a group of 23 healthy volunteers put in forearm casts for a period of 4 weeks. Thus, there is evidence to suggest that most non-painful signs and symptoms of CRPS can be induced by immobilization per se, even without an inciting painful event (Butler, 2001). Schwenkreis et al. (2003b) showed that NMDA-antagonist memantine-induced changes in the SICI and the ICF in upper-limb amputees are not correlated with a reduction in phantom pain. It has also been established that painful stimuli can exert inhibitory effects (or hypoexcitability) on motor cortex excitability in healthy subjects (Valeriani et al., 1999, 2001). Based on these findings, and the fact that immobilization was indeed present in our patients, we raise the possibility that the cortical hyperexcitability found in CRPS may be related to alterations in the mobility of the affected limb and not necessarily to their painful sensations. In summary, the findings of this study further support the notion that altered CNS excitability is present in patients with CRPS. 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