- Email: [email protected]
Enhanced temporal pain processing in multiple system atrophy
Neuroscience Letters 555 (2013) 203–208
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Enhanced temporal pain processing in multiple system atrophy Armando Perrotta a,∗ , Monica Bolla b , Mariano Serrao c , Marco Paparatti c , Cristina Tassorelli b,d , Francesco Pierelli a , Giorgio Sandrini b,d a
IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy Department of Medical and Surgical Science and Biotechnology, Sapienza University of Rome, Rome, Italy d Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy b
c
h i g h l i g h t s • Multiple system atrophy subjects showed a facilitated temporal processing of pain. • MSA and PD showed a comparable level of facilitation in temporal pain processing. • Striatonigral neurodegeneration could favor a facilitated temporal pain processing.
a r t i c l e
i n f o
Article history: Received 8 July 2013 Received in revised form 26 August 2013 Accepted 14 September 2013 Keywords: Multiple system atrophy Pain Temporal summation Nociceptive withdrawal reflex
a b s t r a c t Pain processing has been poorly studied in multiple system atrophy (MSA), notwithstanding these subjects complaint pain very frequently. We hypothesized that, as observed in other basal ganglia neurodegenerative disorders involving the striatonigral projections, also in MSA with predominant parkinsonian signs could be detected an abnormal pain processing. We used the temporal summation threshold (TST) of the nociceptive withdrawal reflex (NWR) and the related pain sensation to evaluate the temporal pain processing at spinal level in eleven MSA subjects and compared them with fifteen Parkinson’s disease (PD) subjects, in both during “on” and “off” treatment with l-Dopa, and fifteen healthy subjects. MSA showed a significant reduction in NWR TST as well as facilitation in other pain responses when compared to healthy subjects; no differences were detected between “on” and “off” condition; no differences were detected between MSA and PD subjects in term of neurophysiological and pharmacological responses. We demonstrated a facilitated temporal processing of pain in MSA subjects paralleling findings from PD. We hypothesize that the abnormal pain processing detected in both MSA and PD, could represent a consequence of the striatonigral neurodegeneration which in turn make these subjects more prone to develop pain conditions. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Multiple system atrophy (MSA) is a progressive neurodegenerative disorder, characterized by variable combination of parkinsonism, autonomic failure, cerebellar ataxia and corticospinal symptoms, as consequence of degeneration of striatonigral, olivoponto-cerebellar and spinal structures [11,12,28]. Very little is known about pain elaboration in MSA, notwithstanding epidemiological studies have revealed that MSA patients complaint pain symptoms very frequently [4,27]. Pain symptoms have been recognized and largely described in basal ganglia disorders, such as
∗ Corresponding author at: INM Neuromed, IRCCS, via Atinense, 18, 86077 Pozzilli, Isernia, Italy. Tel.: +39 0865 929471; fax: +39 0865 929530. E-mail addresses: [email protected], [email protected] (A. Perrotta). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.09.035
Parkinson’s disease (PD) [2,5] and it has been hypothesized that the neurodegeneration of the basal ganglia could act in favor of this phenomenon [3]. In particular, in animal models have been demonstrated that basal ganglia exert a balancing role on pain processing at spinal level, via descending inhibitory and facilitatory projections, confirming that abnormalities in their activity could have a direct or indirect consequence on pain perception [21,22]. It is conceivable that in MSA with predominant parkinsonian signs, the basal ganglia neurodegeneration, leading to a dysfunction of the striatal dopaminergic projection, could give rise, per se, to an abnormal pain processing which, in turn, could predispose these subjects to a clinical pain syndromes. A useful tool to evaluate the pain processing and the related influence of the supraspinal descending control pathways, is the study of the wind-up phenomenon in animals and of the temporal summation of pain in humans, consisting both in a temporary frequency-dependent facilitation of the responses of sensory
204
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
neurons after constant-intensity stimulation of C-fibers. Temporal summation of pain may be regarded as a neural mechanism physiologically devoted to encoding and detecting nociceptive inputs at spinal as well as at trigeminal level and, in this sense, its enhancement could reflect the presence of abnormal pain processing [7]. Temporal summation of pain develops in parallel with the temporal summation of the nociceptive withdrawal reflex (NWR) of the lower limb, represented by an progressive increase in magnitude of the NWR size after a series of constant-intensity electrical stimuli activating A delta and C fibers and can be objectively tested in men through the recording of the temporal summation threshold (TST) of the NWR of the lower limb [1,24]. TST of NWR results in an objective representation of TS of pain, and it has been demonstrated to be a very sensitive tool for exploring physiological and pathophysiological nociception in several conditions, including basal ganglia disorders [18,19]. Indeed, in PD subjects without clinical pain conditions have been demonstrated a facilitated temporal processing of pain stimuli at spinal level, revealed through a reduction in TST of the NWR detectable from a very early stage of the disease, restricted to initially or more affected side and not influenced by l-Dopa administration [18]. Therefore, we evaluated the TST of the NWR and the related pain sensation in subjects with MSA with predominant parkinsonian signs and without clinical pain symptoms and compared the obtained results with those from PD, in both groups evaluating the effect of the treatment with l-Dopa. 2. Materials and methods The study was approved by the local Ethics Committee (No. 07/2011) and was carried out following the guidelines for proper human research conduct in accordance with the Helsinki Declaration of 1975 as revised in 2000 and all the participants gave their written consent. 2.1. Study population Eleven subjects with probable MSA with predominant parkinsonian features [12] and fifteen patients with idiopathic PD, diagnosed according to the second consensus criteria for MSA and the United Kingdom Parkinson’ Disease Society Brain Bank criteria, respectively [12,14], were recruited at the Movement Disorders Unit of the IRCCS “C. Mondino Institute of Neurology” Foundation, University of Pavia, Italy. The clinical stage of the disease was determined using the Hoehn and Yahr (HY) scale (1967) [13]; global motor disability was evaluated by means of the Unified Multiple System Atrophy Rating Scale, part II [28] and Unified Parkinson’s Disease Rating Scale, part III (UPDRS-III) [8]. In order to compare the motor impairment between MSA and PD groups the UPDRS-III score has been calculated also in MSA subjects. Exclusion criteria were: a HY score ≥ 2.5 in the “off” condition; limb tremor; serious systemic, neurological or psychiatric diseases, including cognitive impairment (Mini-Mental State Examination score < 25), bipolar disorders, obsessive–compulsive disorders, and depression (Beck Depression Inventory, BDI, >18); current use of anti-depressive medications or analgesics; clinical or instrumental evidence of any central or peripheral disease potentially causing sensory impairment; fibromyalgia, neuropathic pain, complex regional pain syndrome, according to the current guidelines, and other pain conditions [15]. We also excluded subjects with pain attributable to musculoskeletal or radicular-neuropathic disorders, dystonia, akathisic discomfort or central pain, all diagnosed according to established criteria for PD [9,26]. This in the attempt to avoid any confounding
Table 1 Demographic and clinical data of the study population. Healthy subjects
MSA
PD
F/M Disease duration, y
58.6 ± 8.1 (48–61) 5/10 –
UMASRS-II total score OFF
–
65.6 ± 6.8 (56–74) 4/11 8.1 ± 3.6a (7–12) –
UPDRS-III total score OFF
–
UPDRS-III items 22 + 26 OFF
–
67.5 ± 6.8 (54–76) 3/8 3.3 ± 1.3 (2–6) 30.6 ± 7.6 (19–43) 28.5 ± 4.9 (23–38) 3.9 ± 1.6 (3–5)
Age, y
27.9 ± 4.8 (22–38) 4.3 ± 1.5 (3–6)
a p < .05 vs. MSA. MSA, multiple systemic atrophy; PD, Parkinson’s disease; UPDRS, Unified Parkinson’s Disease Rating Scale part III scores; UMASRS, Unified Multiple Systemic Atrophy Rating Scale part II scores (range).
factor that could interfere with the study of the pain processing related to neurodegenerative disorder per se. On entering the study, all the patients were receiving pharmacological treatment with l-Dopa (mean dose, 348 ± 64.5 mg in MSA and 367.4 ± 81.2 mg in PD), in 18 (7 MSA and 11 PD) cases in combination with no long-lasting dopaminergic medication. In order to have a comparable level of clinical severity between MSA and PD group, we decided to recruit PD subjects with bilateral involvement but predominantly unilateral signs (HY stages 2 and 2.5). The level of clinical disability was further determined by using the UPDRS-III subscores for rigidity and agility of the lower limb in the “off” state; item 22 and 26, subscores from 0 to 8 for both MSA and PD group. Fifteen healthy individuals, without neurological disorders or a clinical history (including family history) of neurological disorders, were recruited as the control group. Table 1 shows the demographic and clinical data collected in the study population.
2.2. Nociceptive withdrawal reflex measurements 2.2.1. Nociceptive withdrawal reflex The NWR from the lower limb was investigated according to a validated method, between 09.00 and 11.00 to minimize the effect of diurnal variation [22]. The subjects were seated comfortably in a quiet room at constant temperature (23 ± 2 ◦ C). Their lower limbs were positioned to ensure complete muscle relaxation (knee flexed at 130◦ and ankle at 90◦ ). Before formal measurements were started, the subjects underwent training to familiarize them with the pain threshold assessment procedure. The sural nerve was stimulated percutaneously via a pair of standard surface electrodes (Ag/AgCl) applied to degreased skin behind the lateral malleolus. The transcutaneous electrical stimulus consisted of a constant current pulse train of five individual 1-ms pulses delivered at 200 Hz (equal to an inter-stimulus interval of 4 ms), randomly applied every 25–40 s. Electromyographic reflex responses were recorded from the capitis brevis of the biceps femoris via surface electrodes (Ag/AgCl). The filter bandpass setting was between 3 Hz and 3 kHz. The analysis time was 300 ms, with the sensitivity set at 100 mV. Each response was full-wave rectified and integrated in the 80–130 ms post-stimulus interval [24] (Medelec, Synergy, UK). The staircase method was used to evaluate the NWR threshold (Th), defined as the stimulation intensity generating stable reflex responses with an amplitude exceeding 20 V for more than 10 ms in the time interval 80–130 ms over five stimuli. The stimulation intensity was fixed at 1.2 × Th; five reflex responses were recorded
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
and the mean NWR Area under the curve (Area) was computed using a computerized method. The subjects rated the psychophysical pain sensation for each stimulus on an 11-point numerical rating scale (NRS), graded from 0 = no pain to 10 = unbearable pain. The first recording of each session was discarded in an attempt to reduce the influence of the startle reaction. 2.2.2. Temporal summation of the NWR The sural nerve was stimulated using a constant current pulse train of five individual 1-ms pulses delivered at 200 Hz repeated five times at a frequency of 2 Hz, as previously described [1]. The current intensity was increased (in 1 mA steps) from 2 mA until detection of temporal summation. A TST of the NWR was considered when a clear facilitation of the reflex response size (greater than 20 V for 10 ms or more) in the 4th and 5th trace, compared to the 1st one, was detectable during the course of the five individual pulses train in the time interval 80–130 ms, and accepted when three consecutive recordings gave the same threshold. The subjects rated the psychophysical pain sensation for the first and fifth stimulus at TST on an 11-point NRS, graded from 0 = no pain to 10 = unbearable pain. 2.3. Study design The first clinical and neurophysiological evaluation was performed during an 18-hour overnight withdrawal of l-Dopa and dopaminergic agonist medications, the “off” condition. A second evaluation was undertaken, at least 40 min after administration of an appropriate oral dose of dispersible l-Dopa, the “on” condition. An appropriate dose of l-Dopa was calculated to be equal to 150% of the usual morning dose of l-Dopa, plus the morning dopaminergic agonist dose in the subjects also receiving dopaminergic medication. Clinical assessments and neurophysiological tests were performed by various independent expert investigators who were unaware of the study design. In all subjects both the left and right side were evaluated in random order and were considered according to condition (“on” and “off”). 2.4. Statistical analysis The groups were matched for gender, age and weight, in order to minimize the effect of any physiological or pathological conditions liable to influence the various parameters of the NWR or TST of the NWR [24]. Student’s t-tests or 2 tests were performed as needed. Differences between groups (MSA, PD and healthy subjects) were analyzed using a series of independent one-way analysis of variance (ANOVA), with groups (MSA “off”, PD “off” and healthy subjects or MSA “on”, PD “on” and healthy subjects) as factors and neurophysiological and psychophysical data as dependent variables. Student’s t-test with Bonferroni’s correction was used for post hoc analysis of group mean differences. The Mann–Whitney test was used to compare the mean clinical data values (disease duration, UPDRS-III total score, UPDRS-III subscores for lower limbs) recorded in MSA and PD subjects and to compare neurophysiological and psychophysical data on the left and right side in all subjects. The Wilcoxon signed rank test for paired data was used to compare MSA and PD values recorded in the “on” and “off” conditions. To detect a psychophysical temporal summation of pain, the Wilcoxon signed rank test for paired data was used to compare NRS scores for the fifth stimulus versus the first stimulus recorded at the TST both in all subjects. In a further evaluation, a series of one-way ANOVAs were used to compare the degree of temporal summation of pain (difference between the NRS score for the fifth stimulus
205
and for the first stimulus at the TST in each group) between groups (factor: MSA “off”, PD “off” and healthy subjects or MSA “on”, PD “on” and healthy subjects), in order determine whether temporal summation of pain was enhanced in the patient groups compared to the control group. Spearman’s correlation test was used to look for statistically significant correlations between clinical and neurophysiological parameters. The results were expressed as mean values ± SD. p values <.05 were considered statistically significant. All statistics were calculated using the SPSS (17.0) program for Windows (SPSS, Chicago, IL). 3. Results The patients’ clinical characteristics and motor scales scores are shown in Table 1. No significant differences in gender, age, weight or MMSE and BDI scores were found between patients and healthy subjects (all p > .05). No differences were found in mean UPDRS-III total score and mean UPDRS-III subscores for lower limbs (items 22–26) between MSA and PD group during the “off” condition (Table 1). The UPDRSIII total score was found to be significantly improved in the “on” versus the “off” condition in PD group while no change has been detected in MSA group. No significant correlations were found between neurophysiological and psychophysical data and clinical variables (disease duration and UPDRS scores and subscores). 3.1. Neurophysiological parameters Given that no side differences emerged in the neurophysiological and psychophysical parameters in all studied groups, we used the right side values in the statistical analysis. One-way ANOVA revealed significant between-group differences in mean NWR Th in both “off” (F(2,39) = 9.648, p = .0001) and “on” (F(2,39) = 8.423, p = .001) condition with a significant NWR Th reduction in both MSA and PD when compared to the healthy subjects (Table 2); in mean NWR Area in “off” (F(2,39) = 4.171, p = .023) condition with a significant NWR Area increase in MSA group when compared to the healthy subjects (Table 2); in mean NWR TST in both “off” (F(2,39) = 7.388, p = .002) and “on” (F(2,39) = 4.780, p = .014) condition with a significant NWR TST reduction in both MSA and PD when compared to the healthy subjects (Fig. 1; Table 2). 3.2. Psychophysical measurements One-way ANOVA revealed significant between-group differences in mean NRS scores at the fifth stimulus of the TST in both “off” (F(2,39) = 6.286, p = .004) and “on” (F(2,39) = 5.343, p = .009) with a significant NRS score increase in PD group when compared to the healthy subjects (Table 3). Table 2 Mean values ± S.D. of the NWR parameters (Th, Area, TST) following single and repeated stimulation in MSA, PD and healthy subjects. Th (mA)
Area (ms/V)
TST (mA)
Healthy subjects
14.9 ± 4.0
782.2 ± 375.1
MSA “off” MSA “on”
9.8 ± 7.0 10.1 ± 6.8a
1665.9 ± 1451.0 1703.0 ± 1859.3
7.7 ± 4.8a 7.5 ± 6.4a
1318.2 ± 356.2 1270.1 ± 552.0
7.6 ± 1.7a 8.0 ± 1.7a
PD “off” PD “on”
a
8.0 ± 2.4a 8.3 ± 3.0a
11.7 ± 3.3 a
a p < .05 vs. healthy subjects. NWR, nociceptive withdrawal reflex; Th, NWR threshold; Area, area under the curve of the NWR at 1.2 × Th; TST, temporal summation threshold of the NWR; MSA, multiple system atrophy; PD, Parkinson’s disease.
206
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
Fig. 1. Temporal summation threshold of the nociceptive withdrawal reflex at baseline in a representative subject. Note during the course of the train of 5 individual pulses the facilitation of the reflex response size in the fourth and fifth trace compared to the first one.
Table 3 Mean values ± S.D. of the sensory threshold, NRS measurements following single and repeated stimulation and degree of the temporal summation of pain in MSA, PD and healthy subjects. ST (mA)
NRS values at NWR 1.2 × Th
NRS values at 1st s TST
NRS values at 5th s TST
NRS values at 5th s minus 1st s TST
Healthy subjects
0.8 ± 0.3
5.6 ± 1.5
3.8 ± 1.5
5.5 ± 1.4b
1.6 ± 1.1
MSA “off” MSA “on”
1.1 ± 0.5 1.4 ± 1.0
5.3 ± 2.1 4.8 ± 2.0
4.8 ± 2.8 4.2 ± 1.8
6.1 ± 2.6b 5.5 ± 1.3b
1.3 ± 1.8 0.7 ± 0.6
PD “off” PD “on”
0.8 ± 0.3 1.0 ± 0.3
5.8 ± 1.2 5.4 ± 1.3
4.9 ± 1.4 5.1 ± 1.4
7.6 ± 1.2a , b 7.0 ± 1.5a , b
2.7 ± 1.8 1.9 ± 2.1
a
p < .05 vs. healthy subjects. p < .05 vs. 1st s of the NRS TST. ST, sensory threshold; NRS, numerical rating scale; Th, nociceptive withdrawal reflex threshold; TST, nociceptive withdrawal reflex temporal summation threshold; 5th s, fifth stimulus of the TST; MSA, multiple system atrophy; PD, Parkinson’s disease. b
For patients and controls, significant temporal summation of pain sensation was observed in the NRS scores at the fifth versus the first stimulus of the TST (all p < .05) (Table 3).
4. Discussion The main results of this study are summarized as follows: subjects with MSA with predominant parkinsonian signs showed a significant reduction in TST and in Th of the NWR as well as a significant increase in Area values when compared to healthy subjects; no differences in neurophysiological and psychophysical findings were detected in MSA group between “on” and “off” condition; no differences were detected between MSA and PD subjects in term
of neurophysiological and psychophysical responses, as well as in term of response to l-Dopa administration. In subjects with MSA we demonstrated a facilitated temporal processing of pain stimuli (reduced TST) and a generalized facilitation in pain responses (NWR Th and Area) in absence of clinical pain conditions. Neurophysiological findings in MSA group are in line with PD group, indeed both groups showed a significant reduction in both TST and NWR Th when compared to healthy subjects, as well as no differences were detected in neurophysiological parameters (TST, NWR Th and Area) between the two groups of patients. PD group neurophysiological findings are consistent with previous reports of facilitated temporal pain processing [18] as well as of reduction in NWR Th [10,17,18] in PD. On the contrary, psychophysical findings (NRS values) in MSA failed to show significant
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
differences when compared to healthy subjects. This discrepancy between objective (TST and NWR Th) and subjective parameters (NRS values) could be explained by the higher intersubject variability of the psychophysical parameters coupled with a small sample size in MSA group with respect to both healthy and PD subjects. A further explanation could come from the recent observation of an impaired temporal processing of the somatosensory perception in MSA-P subjects when compared to both PD and healthy subjects [23]. It could be hypothesized that an abnormal temporal processing of the somatosensory perception could represent an interfering factor to the temporal processing of psychophysical pain sensation. In humans, the TST of the NWR develops in parallel with temporal summation of pain and is considered the clinical counterpart of the wind-up phenomenon observed in animals. Wind-up and temporal summation of pain represent a form of short term neuronal plasticity which subserves the integration of sensory stimuli in central nervous system through a temporary change in sensory neurons excitability, shifting the sensory information from tactile to nociceptive, before transmitting the nociceptive inputs to the higher centers of the brain that, in turn, regulate pain processing by descending brainstem pathways [6,16]. One of the most typical abnormalities resulting from pain processing dysfunction is represented by the activity-dependent changes in the excitability of central neurons resulting in an abnormal temporal summation of pain stimuli [7]. As observed in PD patients [18], also in MSA could be hypothesized that the neurodegeneration, in prevalence of the striato-nigral projection, could play a role in facilitating the temporal processing of pain stimuli, and this could predispose them to the development of pain syndromes. Indeed, in animals, the striatum exerts a balancing effect on pain hypersensitivity at spinal level, via both ipsilateral adrenal dopaminergic descending inhibitory projections and GABA-ergic descending facilitatory projections [21]. Interestingly, no differences were detected in neurophysiological and psychophysical parameters between MSA and PD group, both showing a comparable level of facilitation in temporal processing of pain and lack of response to l-Dopa administration. In this sense, similarities between MSA and PD have been also demonstrated in a common abnormal reaction to facial nociceptive stimuli [20,25]. Furthermore, the detected bilateral facilitation in pain processing in both MSA and PD subjects probably reflects, when compared to the PD subjects at early stage of the disease in which the abnormal temporal pain processing is strictly unilateral [18], a symmetrical diffuse neurodegeneration which parallels the distribution of the clinical motor signs. These data permit to speculate about a common pathophysiological mechanism at the basis of facilitation in temporal processing of pain in both MSA and PD subjects that seems not strictly linked to a direct dopaminergic deafferentation due to a lack of effect on both neurophysiological and psychophysical parameters of l-Dopa administration. The lack of influence of the l-Dopa on pain responses in PD group parallels a previous observation [18] but it is in contrast with other report [10] in which a clear effect of the l-Dopa has been demonstrated on NWR Th. A possible explanation for the lack of l-Dopa effect could be that the dopaminergic deafferentation process following the striato-nigral neural degeneration, is a long lasting phenomenon which give rise to a series of plastic neural rearrangements in the central nervous system, including the spinal projections, which cannot be easily reverted after a single l-Dopa administration. However, the small sample size, which represents a limitation of the present study, could have influenced, at least in part, the results of the l-Dopa administration as well as of the psychophysical pain perception of temporal summation of pain in MSA group. In conclusion, our work demonstrated an abnormal pain elaboration in subjects with MSA without clinical pain syndromes. MSA subjects showed a facilitation in temporal pain processing
207
overlapping the abnormalities detected in PD subjects with a comparable clinical severity. Our data support the hypothesis that common patophysiological mechanisms could be at the basis of this abnormal pain processing which could make both MSA and PD patients more prone to develop pain symptoms.
References [1] L. Arendt-Nielsen, J. Brennum, S. Sindrup, P. Bak, Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system, Eur. J. Appl. Physiol. Occup. Physiol. 68 (1994) 266–273. [2] A.G. Beiske, J.H. Loge, A. Ronningen, E. Svensson, Pain in Parkinson’s disease: prevalence and characteristics, Pain 141 (2009) 173–177. [3] E.H. Chudler, W.K. Dong, The role of the basal ganglia in nociception and pain, Pain 60 (1995) 3–38. [4] C. Colosimo, L. Morgante, A. Antonini, P. Barone, T.P. Avarello, E. Bottacchi, A. Cannas, M.G. Ceravolo, R. Ceravolo, G. Cicarelli, R.M. Gaglio, L. Giglia, F. Iemolo, M. Manfredi, G. Meco, A. Nicoletti, M. Pederzoli, A. Petrone, A. Pisani, F.E. Pontieri, R. Quatrale, S. Ramat, R. Scala, G. Volpe, S. Zappulla, A.R. Bentivoglio, F. Stocchi, G. Trianni, D.P. Del, L. Simoni, R. Marconi, Non-motor symptoms in atypical and secondary parkinsonism: the PRIAMO study, J. Neurol. 257 (2010) 5–14. [5] G. Defazio, A. Berardelli, G. Fabbrini, D. Martino, E. Fincati, A. Fiaschi, G. Moretto, G. Abbruzzese, R. Marchese, U. Bonuccelli, D.P. Del, P. Barone, V.E. De, A. Albanese, A. Antonini, M. Canesi, L. Lopiano, M. Zibetti, G. Nappi, E. Martignoni, P. Lamberti, M. Tinazzi, Pain as a nonmotor symptom of Parkinson disease: evidence from a case-control study, Arch. Neurol. 65 (2008) 1191–1194. [6] R. Dubner, G.J. Bennett, Spinal and trigeminal mechanisms of nociception, Annu. Rev. Neurosci. 6 (1983) 381–418. [7] P.K. Eide, Wind-up and the NMDA receptor complex from a clinical perspective, Eur. J. Pain 4 (2000) 5–15. [8] S. Fahn, R. Elton, Unified Parkinson’s disease rating scale, in: S. Fahn, C. Mardsen, D. Calne (Eds.), Recent Developments in Parkinson’s Disease, Macmillan Healthcare Information, New Jersey, 1987, pp. 153–613. [9] B. Ford, Pain in Parkinson’s disease, Mov. Disord. 25 (Suppl. 1) (2010) S98– S103. [10] A. Gerdelat-Mas, M. Simonetta-Moreau, C. Thalamas, F. Ory-Magne, T. Slaoui, O. Rascol, C. Brefel-Courbon, Levodopa raises objective pain threshold in Parkinson’s disease: a RIII reflex study, J. Neurol. Neurosurg. Psychiatry 78 (2007) 1140–1142. [11] F. Geser, G.K. Wenning, K. Seppi, M. Stampfer-Kountchev, C. Scherfler, M. Sawires, C. Frick, J.P. Ndayisaba, H. Ulmer, M.T. Pellecchia, P. Barone, H.T. Kim, J. Hooker, N.P. Quinn, A. Cardozo, E. Tolosa, M. Abele, T. Klockgether, K. Ostergaard, E. Dupont, N. Schimke, K.M. Eggert, W. Oertel, R. Djaldetti, W. Poewe, Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG), Mov. Disord. 21 (2006) 179–186. [12] S. Gilman, G.K. Wenning, P.A. Low, D.J. Brooks, C.J. Mathias, J.Q. Trojanowski, N.W. Wood, C. Colosimo, A. Durr, C.J. Fowler, H. Kaufmann, T. Klockgether, A. Lees, W. Poewe, N. Quinn, T. Revesz, D. Robertson, P. Sandroni, K. Seppi, M. Vidailhet, Second consensus statement on the diagnosis of multiple system atrophy, Neurology 71 (2008) 670–676. [13] M.M. Hoehn, M.D. Yahr, Parkinsonism: onset, progression and mortality, Neurology 17 (1967) 427–442. [14] A.J. Hughes, S.E. Daniel, L. Kilford, A.J. Lees, Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases, J. Neurol. Neurosurg. Psychiatry 55 (1992) 181–184. [15] H. Merksey, N. Bogduk, Classification of Chronic Pain. Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, IASP Press, Seattle, 1994, pp. 209–212. [16] M.J. Millan, Descending control of pain, Prog. Neurobiol. 66 (2002) 355– 474. [17] V. Mylius, I. Engau, M. Teepker, K. Stiasny-Kolster, K. Schepelmann, W.H. Oertel, S. Lautenbacher, J.C. Möller, Pain sensitivity and descending inhibition of pain in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry 80 (2009) 24–28. [18] A. Perrotta, G. Sandrini, M. Serrao, S. Buscone, C. Tassorelli, M. Tinazzi, R. Zangaglia, C. Pacchetti, M. Bartolo, F. Pierelli, E. Martignoni, Facilitated temporal summation of pain at spinal level in Parkinson’s disease, Mov. Disord. 26 (2011) 442–448. [19] A. Perrotta, C. Serpino, C. Cormio, M. Serrao, G. Sandrini, F. Pierelli, M. de Tommaso, Abnormal spinal cord pain processing in Huntington’s disease. The role of the diffuse noxious inhibitory control, Clin. Neurophysiol. 123 (2012) 1624–1630. [20] A. Perrotta, M. Serrao, M. Bartolo, L. Valletta, N. Locuratolo, F. Pujia, F. Fattapposta, P. Bramanti, G.A. Amabile, F. Pierelli, L. Parisi, Abnormal head nociceptive withdrawal reaction to facial nociceptive stimuli in Parkinson’s disease, Clin. Neurophysiol. 116 (2005) 2091–2098. [21] A. Pertovaara, H. Wei, Dual influence of the striatum on neuropathic hypersensitivity, Pain 137 (2008) 50–59. [22] S. Potvin, S. Grignon, S. Marchand, Human evidence of a supra-spinal modulating role of dopamine on pain perception, Synapse 63 (2009) 390–402. [23] L. Rocchi, A. Conte, A. Nardella, P. Li Voti, F. Di Biasio, G. Leodori, G. Fabbrini, A. Berardelli, Somatosensory temporal discrimination threshold may help to
208
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
differentiate patients with multiple system atrophy from patients with Parkinson’s disease, Eur. J. Neurol. 20 (2013) 714–719. [24] G. Sandrini, M. Serrao, P. Rossi, A. Romaniello, G. Cruccu, J.C. Willer, The lower limb flexion reflex in humans, Prog. Neurobiol. 77 (2005) 353–395. [25] M. Serrao, F.R. Di, M. Bartolo, A. Perrotta, C. Tassorelli, G. Coppola, C. Davassi, L. Padua, G. Sandrini, F. Pierelli, The contribution of trigemino-cervical reflexes in distinguishing progressive supranuclear palsy from multiple system atrophy, Clin. Neurophysiol. 122 (2011) 1812–1815.
[26] M. Tinazzi, V.C. Del, E. Fincati, S. Ottaviani, N. Smania, G. Moretto, A. Fiaschi, D. Martino, G. Defazio, Pain and motor complications in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry 77 (2006) 822–825. [27] F. Tison, G.K. Wenning, M.A. Volonte, W.R. Poewe, P. Henry, N.P. Quinn, Pain in multiple system atrophy, J. Neurol. 243 (1996) 153–156. [28] G.K. Wenning, F. Tison, S.Y. Ben, S.E. Daniel, N.P. Quinn, Multiple system atrophy: a review of 203 pathologically proven cases, Mov. Disord. 12 (1997) 133–147.
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Enhanced temporal pain processing in multiple system atrophy Armando Perrotta a,∗ , Monica Bolla b , Mariano Serrao c , Marco Paparatti c , Cristina Tassorelli b,d , Francesco Pierelli a , Giorgio Sandrini b,d a
IRCCS Mediterranean Neurological Institute Neuromed, Pozzilli, Italy IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy Department of Medical and Surgical Science and Biotechnology, Sapienza University of Rome, Rome, Italy d Department of Public Health and Neuroscience, University of Pavia, Pavia, Italy b
c
h i g h l i g h t s • Multiple system atrophy subjects showed a facilitated temporal processing of pain. • MSA and PD showed a comparable level of facilitation in temporal pain processing. • Striatonigral neurodegeneration could favor a facilitated temporal pain processing.
a r t i c l e
i n f o
Article history: Received 8 July 2013 Received in revised form 26 August 2013 Accepted 14 September 2013 Keywords: Multiple system atrophy Pain Temporal summation Nociceptive withdrawal reflex
a b s t r a c t Pain processing has been poorly studied in multiple system atrophy (MSA), notwithstanding these subjects complaint pain very frequently. We hypothesized that, as observed in other basal ganglia neurodegenerative disorders involving the striatonigral projections, also in MSA with predominant parkinsonian signs could be detected an abnormal pain processing. We used the temporal summation threshold (TST) of the nociceptive withdrawal reflex (NWR) and the related pain sensation to evaluate the temporal pain processing at spinal level in eleven MSA subjects and compared them with fifteen Parkinson’s disease (PD) subjects, in both during “on” and “off” treatment with l-Dopa, and fifteen healthy subjects. MSA showed a significant reduction in NWR TST as well as facilitation in other pain responses when compared to healthy subjects; no differences were detected between “on” and “off” condition; no differences were detected between MSA and PD subjects in term of neurophysiological and pharmacological responses. We demonstrated a facilitated temporal processing of pain in MSA subjects paralleling findings from PD. We hypothesize that the abnormal pain processing detected in both MSA and PD, could represent a consequence of the striatonigral neurodegeneration which in turn make these subjects more prone to develop pain conditions. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Multiple system atrophy (MSA) is a progressive neurodegenerative disorder, characterized by variable combination of parkinsonism, autonomic failure, cerebellar ataxia and corticospinal symptoms, as consequence of degeneration of striatonigral, olivoponto-cerebellar and spinal structures [11,12,28]. Very little is known about pain elaboration in MSA, notwithstanding epidemiological studies have revealed that MSA patients complaint pain symptoms very frequently [4,27]. Pain symptoms have been recognized and largely described in basal ganglia disorders, such as
∗ Corresponding author at: INM Neuromed, IRCCS, via Atinense, 18, 86077 Pozzilli, Isernia, Italy. Tel.: +39 0865 929471; fax: +39 0865 929530. E-mail addresses: [email protected], [email protected] (A. Perrotta). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.09.035
Parkinson’s disease (PD) [2,5] and it has been hypothesized that the neurodegeneration of the basal ganglia could act in favor of this phenomenon [3]. In particular, in animal models have been demonstrated that basal ganglia exert a balancing role on pain processing at spinal level, via descending inhibitory and facilitatory projections, confirming that abnormalities in their activity could have a direct or indirect consequence on pain perception [21,22]. It is conceivable that in MSA with predominant parkinsonian signs, the basal ganglia neurodegeneration, leading to a dysfunction of the striatal dopaminergic projection, could give rise, per se, to an abnormal pain processing which, in turn, could predispose these subjects to a clinical pain syndromes. A useful tool to evaluate the pain processing and the related influence of the supraspinal descending control pathways, is the study of the wind-up phenomenon in animals and of the temporal summation of pain in humans, consisting both in a temporary frequency-dependent facilitation of the responses of sensory
204
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
neurons after constant-intensity stimulation of C-fibers. Temporal summation of pain may be regarded as a neural mechanism physiologically devoted to encoding and detecting nociceptive inputs at spinal as well as at trigeminal level and, in this sense, its enhancement could reflect the presence of abnormal pain processing [7]. Temporal summation of pain develops in parallel with the temporal summation of the nociceptive withdrawal reflex (NWR) of the lower limb, represented by an progressive increase in magnitude of the NWR size after a series of constant-intensity electrical stimuli activating A delta and C fibers and can be objectively tested in men through the recording of the temporal summation threshold (TST) of the NWR of the lower limb [1,24]. TST of NWR results in an objective representation of TS of pain, and it has been demonstrated to be a very sensitive tool for exploring physiological and pathophysiological nociception in several conditions, including basal ganglia disorders [18,19]. Indeed, in PD subjects without clinical pain conditions have been demonstrated a facilitated temporal processing of pain stimuli at spinal level, revealed through a reduction in TST of the NWR detectable from a very early stage of the disease, restricted to initially or more affected side and not influenced by l-Dopa administration [18]. Therefore, we evaluated the TST of the NWR and the related pain sensation in subjects with MSA with predominant parkinsonian signs and without clinical pain symptoms and compared the obtained results with those from PD, in both groups evaluating the effect of the treatment with l-Dopa. 2. Materials and methods The study was approved by the local Ethics Committee (No. 07/2011) and was carried out following the guidelines for proper human research conduct in accordance with the Helsinki Declaration of 1975 as revised in 2000 and all the participants gave their written consent. 2.1. Study population Eleven subjects with probable MSA with predominant parkinsonian features [12] and fifteen patients with idiopathic PD, diagnosed according to the second consensus criteria for MSA and the United Kingdom Parkinson’ Disease Society Brain Bank criteria, respectively [12,14], were recruited at the Movement Disorders Unit of the IRCCS “C. Mondino Institute of Neurology” Foundation, University of Pavia, Italy. The clinical stage of the disease was determined using the Hoehn and Yahr (HY) scale (1967) [13]; global motor disability was evaluated by means of the Unified Multiple System Atrophy Rating Scale, part II [28] and Unified Parkinson’s Disease Rating Scale, part III (UPDRS-III) [8]. In order to compare the motor impairment between MSA and PD groups the UPDRS-III score has been calculated also in MSA subjects. Exclusion criteria were: a HY score ≥ 2.5 in the “off” condition; limb tremor; serious systemic, neurological or psychiatric diseases, including cognitive impairment (Mini-Mental State Examination score < 25), bipolar disorders, obsessive–compulsive disorders, and depression (Beck Depression Inventory, BDI, >18); current use of anti-depressive medications or analgesics; clinical or instrumental evidence of any central or peripheral disease potentially causing sensory impairment; fibromyalgia, neuropathic pain, complex regional pain syndrome, according to the current guidelines, and other pain conditions [15]. We also excluded subjects with pain attributable to musculoskeletal or radicular-neuropathic disorders, dystonia, akathisic discomfort or central pain, all diagnosed according to established criteria for PD [9,26]. This in the attempt to avoid any confounding
Table 1 Demographic and clinical data of the study population. Healthy subjects
MSA
PD
F/M Disease duration, y
58.6 ± 8.1 (48–61) 5/10 –
UMASRS-II total score OFF
–
65.6 ± 6.8 (56–74) 4/11 8.1 ± 3.6a (7–12) –
UPDRS-III total score OFF
–
UPDRS-III items 22 + 26 OFF
–
67.5 ± 6.8 (54–76) 3/8 3.3 ± 1.3 (2–6) 30.6 ± 7.6 (19–43) 28.5 ± 4.9 (23–38) 3.9 ± 1.6 (3–5)
Age, y
27.9 ± 4.8 (22–38) 4.3 ± 1.5 (3–6)
a p < .05 vs. MSA. MSA, multiple systemic atrophy; PD, Parkinson’s disease; UPDRS, Unified Parkinson’s Disease Rating Scale part III scores; UMASRS, Unified Multiple Systemic Atrophy Rating Scale part II scores (range).
factor that could interfere with the study of the pain processing related to neurodegenerative disorder per se. On entering the study, all the patients were receiving pharmacological treatment with l-Dopa (mean dose, 348 ± 64.5 mg in MSA and 367.4 ± 81.2 mg in PD), in 18 (7 MSA and 11 PD) cases in combination with no long-lasting dopaminergic medication. In order to have a comparable level of clinical severity between MSA and PD group, we decided to recruit PD subjects with bilateral involvement but predominantly unilateral signs (HY stages 2 and 2.5). The level of clinical disability was further determined by using the UPDRS-III subscores for rigidity and agility of the lower limb in the “off” state; item 22 and 26, subscores from 0 to 8 for both MSA and PD group. Fifteen healthy individuals, without neurological disorders or a clinical history (including family history) of neurological disorders, were recruited as the control group. Table 1 shows the demographic and clinical data collected in the study population.
2.2. Nociceptive withdrawal reflex measurements 2.2.1. Nociceptive withdrawal reflex The NWR from the lower limb was investigated according to a validated method, between 09.00 and 11.00 to minimize the effect of diurnal variation [22]. The subjects were seated comfortably in a quiet room at constant temperature (23 ± 2 ◦ C). Their lower limbs were positioned to ensure complete muscle relaxation (knee flexed at 130◦ and ankle at 90◦ ). Before formal measurements were started, the subjects underwent training to familiarize them with the pain threshold assessment procedure. The sural nerve was stimulated percutaneously via a pair of standard surface electrodes (Ag/AgCl) applied to degreased skin behind the lateral malleolus. The transcutaneous electrical stimulus consisted of a constant current pulse train of five individual 1-ms pulses delivered at 200 Hz (equal to an inter-stimulus interval of 4 ms), randomly applied every 25–40 s. Electromyographic reflex responses were recorded from the capitis brevis of the biceps femoris via surface electrodes (Ag/AgCl). The filter bandpass setting was between 3 Hz and 3 kHz. The analysis time was 300 ms, with the sensitivity set at 100 mV. Each response was full-wave rectified and integrated in the 80–130 ms post-stimulus interval [24] (Medelec, Synergy, UK). The staircase method was used to evaluate the NWR threshold (Th), defined as the stimulation intensity generating stable reflex responses with an amplitude exceeding 20 V for more than 10 ms in the time interval 80–130 ms over five stimuli. The stimulation intensity was fixed at 1.2 × Th; five reflex responses were recorded
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
and the mean NWR Area under the curve (Area) was computed using a computerized method. The subjects rated the psychophysical pain sensation for each stimulus on an 11-point numerical rating scale (NRS), graded from 0 = no pain to 10 = unbearable pain. The first recording of each session was discarded in an attempt to reduce the influence of the startle reaction. 2.2.2. Temporal summation of the NWR The sural nerve was stimulated using a constant current pulse train of five individual 1-ms pulses delivered at 200 Hz repeated five times at a frequency of 2 Hz, as previously described [1]. The current intensity was increased (in 1 mA steps) from 2 mA until detection of temporal summation. A TST of the NWR was considered when a clear facilitation of the reflex response size (greater than 20 V for 10 ms or more) in the 4th and 5th trace, compared to the 1st one, was detectable during the course of the five individual pulses train in the time interval 80–130 ms, and accepted when three consecutive recordings gave the same threshold. The subjects rated the psychophysical pain sensation for the first and fifth stimulus at TST on an 11-point NRS, graded from 0 = no pain to 10 = unbearable pain. 2.3. Study design The first clinical and neurophysiological evaluation was performed during an 18-hour overnight withdrawal of l-Dopa and dopaminergic agonist medications, the “off” condition. A second evaluation was undertaken, at least 40 min after administration of an appropriate oral dose of dispersible l-Dopa, the “on” condition. An appropriate dose of l-Dopa was calculated to be equal to 150% of the usual morning dose of l-Dopa, plus the morning dopaminergic agonist dose in the subjects also receiving dopaminergic medication. Clinical assessments and neurophysiological tests were performed by various independent expert investigators who were unaware of the study design. In all subjects both the left and right side were evaluated in random order and were considered according to condition (“on” and “off”). 2.4. Statistical analysis The groups were matched for gender, age and weight, in order to minimize the effect of any physiological or pathological conditions liable to influence the various parameters of the NWR or TST of the NWR [24]. Student’s t-tests or 2 tests were performed as needed. Differences between groups (MSA, PD and healthy subjects) were analyzed using a series of independent one-way analysis of variance (ANOVA), with groups (MSA “off”, PD “off” and healthy subjects or MSA “on”, PD “on” and healthy subjects) as factors and neurophysiological and psychophysical data as dependent variables. Student’s t-test with Bonferroni’s correction was used for post hoc analysis of group mean differences. The Mann–Whitney test was used to compare the mean clinical data values (disease duration, UPDRS-III total score, UPDRS-III subscores for lower limbs) recorded in MSA and PD subjects and to compare neurophysiological and psychophysical data on the left and right side in all subjects. The Wilcoxon signed rank test for paired data was used to compare MSA and PD values recorded in the “on” and “off” conditions. To detect a psychophysical temporal summation of pain, the Wilcoxon signed rank test for paired data was used to compare NRS scores for the fifth stimulus versus the first stimulus recorded at the TST both in all subjects. In a further evaluation, a series of one-way ANOVAs were used to compare the degree of temporal summation of pain (difference between the NRS score for the fifth stimulus
205
and for the first stimulus at the TST in each group) between groups (factor: MSA “off”, PD “off” and healthy subjects or MSA “on”, PD “on” and healthy subjects), in order determine whether temporal summation of pain was enhanced in the patient groups compared to the control group. Spearman’s correlation test was used to look for statistically significant correlations between clinical and neurophysiological parameters. The results were expressed as mean values ± SD. p values <.05 were considered statistically significant. All statistics were calculated using the SPSS (17.0) program for Windows (SPSS, Chicago, IL). 3. Results The patients’ clinical characteristics and motor scales scores are shown in Table 1. No significant differences in gender, age, weight or MMSE and BDI scores were found between patients and healthy subjects (all p > .05). No differences were found in mean UPDRS-III total score and mean UPDRS-III subscores for lower limbs (items 22–26) between MSA and PD group during the “off” condition (Table 1). The UPDRSIII total score was found to be significantly improved in the “on” versus the “off” condition in PD group while no change has been detected in MSA group. No significant correlations were found between neurophysiological and psychophysical data and clinical variables (disease duration and UPDRS scores and subscores). 3.1. Neurophysiological parameters Given that no side differences emerged in the neurophysiological and psychophysical parameters in all studied groups, we used the right side values in the statistical analysis. One-way ANOVA revealed significant between-group differences in mean NWR Th in both “off” (F(2,39) = 9.648, p = .0001) and “on” (F(2,39) = 8.423, p = .001) condition with a significant NWR Th reduction in both MSA and PD when compared to the healthy subjects (Table 2); in mean NWR Area in “off” (F(2,39) = 4.171, p = .023) condition with a significant NWR Area increase in MSA group when compared to the healthy subjects (Table 2); in mean NWR TST in both “off” (F(2,39) = 7.388, p = .002) and “on” (F(2,39) = 4.780, p = .014) condition with a significant NWR TST reduction in both MSA and PD when compared to the healthy subjects (Fig. 1; Table 2). 3.2. Psychophysical measurements One-way ANOVA revealed significant between-group differences in mean NRS scores at the fifth stimulus of the TST in both “off” (F(2,39) = 6.286, p = .004) and “on” (F(2,39) = 5.343, p = .009) with a significant NRS score increase in PD group when compared to the healthy subjects (Table 3). Table 2 Mean values ± S.D. of the NWR parameters (Th, Area, TST) following single and repeated stimulation in MSA, PD and healthy subjects. Th (mA)
Area (ms/V)
TST (mA)
Healthy subjects
14.9 ± 4.0
782.2 ± 375.1
MSA “off” MSA “on”
9.8 ± 7.0 10.1 ± 6.8a
1665.9 ± 1451.0 1703.0 ± 1859.3
7.7 ± 4.8a 7.5 ± 6.4a
1318.2 ± 356.2 1270.1 ± 552.0
7.6 ± 1.7a 8.0 ± 1.7a
PD “off” PD “on”
a
8.0 ± 2.4a 8.3 ± 3.0a
11.7 ± 3.3 a
a p < .05 vs. healthy subjects. NWR, nociceptive withdrawal reflex; Th, NWR threshold; Area, area under the curve of the NWR at 1.2 × Th; TST, temporal summation threshold of the NWR; MSA, multiple system atrophy; PD, Parkinson’s disease.
206
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
Fig. 1. Temporal summation threshold of the nociceptive withdrawal reflex at baseline in a representative subject. Note during the course of the train of 5 individual pulses the facilitation of the reflex response size in the fourth and fifth trace compared to the first one.
Table 3 Mean values ± S.D. of the sensory threshold, NRS measurements following single and repeated stimulation and degree of the temporal summation of pain in MSA, PD and healthy subjects. ST (mA)
NRS values at NWR 1.2 × Th
NRS values at 1st s TST
NRS values at 5th s TST
NRS values at 5th s minus 1st s TST
Healthy subjects
0.8 ± 0.3
5.6 ± 1.5
3.8 ± 1.5
5.5 ± 1.4b
1.6 ± 1.1
MSA “off” MSA “on”
1.1 ± 0.5 1.4 ± 1.0
5.3 ± 2.1 4.8 ± 2.0
4.8 ± 2.8 4.2 ± 1.8
6.1 ± 2.6b 5.5 ± 1.3b
1.3 ± 1.8 0.7 ± 0.6
PD “off” PD “on”
0.8 ± 0.3 1.0 ± 0.3
5.8 ± 1.2 5.4 ± 1.3
4.9 ± 1.4 5.1 ± 1.4
7.6 ± 1.2a , b 7.0 ± 1.5a , b
2.7 ± 1.8 1.9 ± 2.1
a
p < .05 vs. healthy subjects. p < .05 vs. 1st s of the NRS TST. ST, sensory threshold; NRS, numerical rating scale; Th, nociceptive withdrawal reflex threshold; TST, nociceptive withdrawal reflex temporal summation threshold; 5th s, fifth stimulus of the TST; MSA, multiple system atrophy; PD, Parkinson’s disease. b
For patients and controls, significant temporal summation of pain sensation was observed in the NRS scores at the fifth versus the first stimulus of the TST (all p < .05) (Table 3).
4. Discussion The main results of this study are summarized as follows: subjects with MSA with predominant parkinsonian signs showed a significant reduction in TST and in Th of the NWR as well as a significant increase in Area values when compared to healthy subjects; no differences in neurophysiological and psychophysical findings were detected in MSA group between “on” and “off” condition; no differences were detected between MSA and PD subjects in term
of neurophysiological and psychophysical responses, as well as in term of response to l-Dopa administration. In subjects with MSA we demonstrated a facilitated temporal processing of pain stimuli (reduced TST) and a generalized facilitation in pain responses (NWR Th and Area) in absence of clinical pain conditions. Neurophysiological findings in MSA group are in line with PD group, indeed both groups showed a significant reduction in both TST and NWR Th when compared to healthy subjects, as well as no differences were detected in neurophysiological parameters (TST, NWR Th and Area) between the two groups of patients. PD group neurophysiological findings are consistent with previous reports of facilitated temporal pain processing [18] as well as of reduction in NWR Th [10,17,18] in PD. On the contrary, psychophysical findings (NRS values) in MSA failed to show significant
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
differences when compared to healthy subjects. This discrepancy between objective (TST and NWR Th) and subjective parameters (NRS values) could be explained by the higher intersubject variability of the psychophysical parameters coupled with a small sample size in MSA group with respect to both healthy and PD subjects. A further explanation could come from the recent observation of an impaired temporal processing of the somatosensory perception in MSA-P subjects when compared to both PD and healthy subjects [23]. It could be hypothesized that an abnormal temporal processing of the somatosensory perception could represent an interfering factor to the temporal processing of psychophysical pain sensation. In humans, the TST of the NWR develops in parallel with temporal summation of pain and is considered the clinical counterpart of the wind-up phenomenon observed in animals. Wind-up and temporal summation of pain represent a form of short term neuronal plasticity which subserves the integration of sensory stimuli in central nervous system through a temporary change in sensory neurons excitability, shifting the sensory information from tactile to nociceptive, before transmitting the nociceptive inputs to the higher centers of the brain that, in turn, regulate pain processing by descending brainstem pathways [6,16]. One of the most typical abnormalities resulting from pain processing dysfunction is represented by the activity-dependent changes in the excitability of central neurons resulting in an abnormal temporal summation of pain stimuli [7]. As observed in PD patients [18], also in MSA could be hypothesized that the neurodegeneration, in prevalence of the striato-nigral projection, could play a role in facilitating the temporal processing of pain stimuli, and this could predispose them to the development of pain syndromes. Indeed, in animals, the striatum exerts a balancing effect on pain hypersensitivity at spinal level, via both ipsilateral adrenal dopaminergic descending inhibitory projections and GABA-ergic descending facilitatory projections [21]. Interestingly, no differences were detected in neurophysiological and psychophysical parameters between MSA and PD group, both showing a comparable level of facilitation in temporal processing of pain and lack of response to l-Dopa administration. In this sense, similarities between MSA and PD have been also demonstrated in a common abnormal reaction to facial nociceptive stimuli [20,25]. Furthermore, the detected bilateral facilitation in pain processing in both MSA and PD subjects probably reflects, when compared to the PD subjects at early stage of the disease in which the abnormal temporal pain processing is strictly unilateral [18], a symmetrical diffuse neurodegeneration which parallels the distribution of the clinical motor signs. These data permit to speculate about a common pathophysiological mechanism at the basis of facilitation in temporal processing of pain in both MSA and PD subjects that seems not strictly linked to a direct dopaminergic deafferentation due to a lack of effect on both neurophysiological and psychophysical parameters of l-Dopa administration. The lack of influence of the l-Dopa on pain responses in PD group parallels a previous observation [18] but it is in contrast with other report [10] in which a clear effect of the l-Dopa has been demonstrated on NWR Th. A possible explanation for the lack of l-Dopa effect could be that the dopaminergic deafferentation process following the striato-nigral neural degeneration, is a long lasting phenomenon which give rise to a series of plastic neural rearrangements in the central nervous system, including the spinal projections, which cannot be easily reverted after a single l-Dopa administration. However, the small sample size, which represents a limitation of the present study, could have influenced, at least in part, the results of the l-Dopa administration as well as of the psychophysical pain perception of temporal summation of pain in MSA group. In conclusion, our work demonstrated an abnormal pain elaboration in subjects with MSA without clinical pain syndromes. MSA subjects showed a facilitation in temporal pain processing
207
overlapping the abnormalities detected in PD subjects with a comparable clinical severity. Our data support the hypothesis that common patophysiological mechanisms could be at the basis of this abnormal pain processing which could make both MSA and PD patients more prone to develop pain symptoms.
References [1] L. Arendt-Nielsen, J. Brennum, S. Sindrup, P. Bak, Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system, Eur. J. Appl. Physiol. Occup. Physiol. 68 (1994) 266–273. [2] A.G. Beiske, J.H. Loge, A. Ronningen, E. Svensson, Pain in Parkinson’s disease: prevalence and characteristics, Pain 141 (2009) 173–177. [3] E.H. Chudler, W.K. Dong, The role of the basal ganglia in nociception and pain, Pain 60 (1995) 3–38. [4] C. Colosimo, L. Morgante, A. Antonini, P. Barone, T.P. Avarello, E. Bottacchi, A. Cannas, M.G. Ceravolo, R. Ceravolo, G. Cicarelli, R.M. Gaglio, L. Giglia, F. Iemolo, M. Manfredi, G. Meco, A. Nicoletti, M. Pederzoli, A. Petrone, A. Pisani, F.E. Pontieri, R. Quatrale, S. Ramat, R. Scala, G. Volpe, S. Zappulla, A.R. Bentivoglio, F. Stocchi, G. Trianni, D.P. Del, L. Simoni, R. Marconi, Non-motor symptoms in atypical and secondary parkinsonism: the PRIAMO study, J. Neurol. 257 (2010) 5–14. [5] G. Defazio, A. Berardelli, G. Fabbrini, D. Martino, E. Fincati, A. Fiaschi, G. Moretto, G. Abbruzzese, R. Marchese, U. Bonuccelli, D.P. Del, P. Barone, V.E. De, A. Albanese, A. Antonini, M. Canesi, L. Lopiano, M. Zibetti, G. Nappi, E. Martignoni, P. Lamberti, M. Tinazzi, Pain as a nonmotor symptom of Parkinson disease: evidence from a case-control study, Arch. Neurol. 65 (2008) 1191–1194. [6] R. Dubner, G.J. Bennett, Spinal and trigeminal mechanisms of nociception, Annu. Rev. Neurosci. 6 (1983) 381–418. [7] P.K. Eide, Wind-up and the NMDA receptor complex from a clinical perspective, Eur. J. Pain 4 (2000) 5–15. [8] S. Fahn, R. Elton, Unified Parkinson’s disease rating scale, in: S. Fahn, C. Mardsen, D. Calne (Eds.), Recent Developments in Parkinson’s Disease, Macmillan Healthcare Information, New Jersey, 1987, pp. 153–613. [9] B. Ford, Pain in Parkinson’s disease, Mov. Disord. 25 (Suppl. 1) (2010) S98– S103. [10] A. Gerdelat-Mas, M. Simonetta-Moreau, C. Thalamas, F. Ory-Magne, T. Slaoui, O. Rascol, C. Brefel-Courbon, Levodopa raises objective pain threshold in Parkinson’s disease: a RIII reflex study, J. Neurol. Neurosurg. Psychiatry 78 (2007) 1140–1142. [11] F. Geser, G.K. Wenning, K. Seppi, M. Stampfer-Kountchev, C. Scherfler, M. Sawires, C. Frick, J.P. Ndayisaba, H. Ulmer, M.T. Pellecchia, P. Barone, H.T. Kim, J. Hooker, N.P. Quinn, A. Cardozo, E. Tolosa, M. Abele, T. Klockgether, K. Ostergaard, E. Dupont, N. Schimke, K.M. Eggert, W. Oertel, R. Djaldetti, W. Poewe, Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG), Mov. Disord. 21 (2006) 179–186. [12] S. Gilman, G.K. Wenning, P.A. Low, D.J. Brooks, C.J. Mathias, J.Q. Trojanowski, N.W. Wood, C. Colosimo, A. Durr, C.J. Fowler, H. Kaufmann, T. Klockgether, A. Lees, W. Poewe, N. Quinn, T. Revesz, D. Robertson, P. Sandroni, K. Seppi, M. Vidailhet, Second consensus statement on the diagnosis of multiple system atrophy, Neurology 71 (2008) 670–676. [13] M.M. Hoehn, M.D. Yahr, Parkinsonism: onset, progression and mortality, Neurology 17 (1967) 427–442. [14] A.J. Hughes, S.E. Daniel, L. Kilford, A.J. Lees, Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases, J. Neurol. Neurosurg. Psychiatry 55 (1992) 181–184. [15] H. Merksey, N. Bogduk, Classification of Chronic Pain. Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, IASP Press, Seattle, 1994, pp. 209–212. [16] M.J. Millan, Descending control of pain, Prog. Neurobiol. 66 (2002) 355– 474. [17] V. Mylius, I. Engau, M. Teepker, K. Stiasny-Kolster, K. Schepelmann, W.H. Oertel, S. Lautenbacher, J.C. Möller, Pain sensitivity and descending inhibition of pain in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry 80 (2009) 24–28. [18] A. Perrotta, G. Sandrini, M. Serrao, S. Buscone, C. Tassorelli, M. Tinazzi, R. Zangaglia, C. Pacchetti, M. Bartolo, F. Pierelli, E. Martignoni, Facilitated temporal summation of pain at spinal level in Parkinson’s disease, Mov. Disord. 26 (2011) 442–448. [19] A. Perrotta, C. Serpino, C. Cormio, M. Serrao, G. Sandrini, F. Pierelli, M. de Tommaso, Abnormal spinal cord pain processing in Huntington’s disease. The role of the diffuse noxious inhibitory control, Clin. Neurophysiol. 123 (2012) 1624–1630. [20] A. Perrotta, M. Serrao, M. Bartolo, L. Valletta, N. Locuratolo, F. Pujia, F. Fattapposta, P. Bramanti, G.A. Amabile, F. Pierelli, L. Parisi, Abnormal head nociceptive withdrawal reaction to facial nociceptive stimuli in Parkinson’s disease, Clin. Neurophysiol. 116 (2005) 2091–2098. [21] A. Pertovaara, H. Wei, Dual influence of the striatum on neuropathic hypersensitivity, Pain 137 (2008) 50–59. [22] S. Potvin, S. Grignon, S. Marchand, Human evidence of a supra-spinal modulating role of dopamine on pain perception, Synapse 63 (2009) 390–402. [23] L. Rocchi, A. Conte, A. Nardella, P. Li Voti, F. Di Biasio, G. Leodori, G. Fabbrini, A. Berardelli, Somatosensory temporal discrimination threshold may help to
208
A. Perrotta et al. / Neuroscience Letters 555 (2013) 203–208
differentiate patients with multiple system atrophy from patients with Parkinson’s disease, Eur. J. Neurol. 20 (2013) 714–719. [24] G. Sandrini, M. Serrao, P. Rossi, A. Romaniello, G. Cruccu, J.C. Willer, The lower limb flexion reflex in humans, Prog. Neurobiol. 77 (2005) 353–395. [25] M. Serrao, F.R. Di, M. Bartolo, A. Perrotta, C. Tassorelli, G. Coppola, C. Davassi, L. Padua, G. Sandrini, F. Pierelli, The contribution of trigemino-cervical reflexes in distinguishing progressive supranuclear palsy from multiple system atrophy, Clin. Neurophysiol. 122 (2011) 1812–1815.
[26] M. Tinazzi, V.C. Del, E. Fincati, S. Ottaviani, N. Smania, G. Moretto, A. Fiaschi, D. Martino, G. Defazio, Pain and motor complications in Parkinson’s disease, J. Neurol. Neurosurg. Psychiatry 77 (2006) 822–825. [27] F. Tison, G.K. Wenning, M.A. Volonte, W.R. Poewe, P. Henry, N.P. Quinn, Pain in multiple system atrophy, J. Neurol. 243 (1996) 153–156. [28] G.K. Wenning, F. Tison, S.Y. Ben, S.E. Daniel, N.P. Quinn, Multiple system atrophy: a review of 203 pathologically proven cases, Mov. Disord. 12 (1997) 133–147.