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Quantitative and fiber-selective evaluation of pain and sensory dysfunction in patients with Parkinson's disease
Parkinsonism and Related Disorders 21 (2015) 361e365
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Quantitative and fiber-selective evaluation of pain and sensory dysfunction in patients with Parkinson's disease Yi Chen a, 1, Cheng-Jie Mao a, 1, Si-Jiao Li a, Fen Wang a, b, Jing Chen a, Hui-Jun Zhang a, Ling Li a, Sha-Sha Guo a, Ya-Ping Yang a, b, c, Chun-Feng Liu a, b, c, * a Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China b Institute of Neuroscience, Soochow University, Suzhou 215123, China c Beijing Key Laboratory for Parkinson's Disease, Beijing 100053, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 August 2014 Received in revised form 20 December 2014 Accepted 11 January 2015
Introduction: Pain and sensory disturbances affect many patients with Parkinson's disease (PD). The present study aimed to evaluate the pain and sensory sensitivity of each class of afferent fibers in PD patients and determine the effects of dopaminergic therapy on pain and sensory sensitivity. Methods: Current perception threshold (CPT) and pain tolerance thresholds (PTT) at three frequencies, 2000 Hz, 250 Hz, and 5 Hz, to stimulate Ab fibers, Ad fibers, and small C-polymodal fibers, respectively, were measured in 72 PD patients and 35 healthy controls. Results: CPT was higher at all three frequencies and PTT was lower at 2000 Hz and 250 Hz in PD patients with pain versus healthy controls (P < 0.05). CPT was higher at 2000 Hz and 250 Hz and PTT was lower at 2000 Hz and 250 Hz in PD patients without pain versus healthy controls (P < 0.05). PD patients with pain exhibited higher CPT at 5 Hz and 250 Hz than PD patients without pain (P < 0.05). Dopaminergic therapy did not affect CPT or PPT in PD patients (P > 0.05). Conclusions: Abnormal Ad fiber- and Ab fiber-dependent sensory inputs may exist in PD. Abnormal sensory inputs via C fibers and Ad fibers might be associated with the presence of pain in PD. Because dopaminergic therapy failed to mitigate these sensory and pain dysfunctions, mechanisms not involving the dopaminergic pathway are likely to be implicated. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Pain Thresholds
1. Introduction Pain and sensory disturbances are common non-motor symptoms of Parkinson's disease (PD) and occur in many patients; these symptoms often have a dramatic negative impact on the patient's quality of life. However, the pathogenesis of pain and sensory disturbances in PD patients is not fully understood. Information from several psychophysical, neurophysiological, and imaging studies has provided useful information on pain-processing mechanisms in PD that presents with and without pain. These studies, however, have yielded heterogenous results, probably because of methodological
* Corresponding author. Department of Neurology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215004, China. Tel.: þ86 512 67783307; fax: þ86 512 68284303. E-mail address: [email protected] (C.-F. Liu). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.parkreldis.2015.01.008 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
factors [1,2]. Quantitative sensory testing, the nociceptive withdrawal reflex to electrical stimuli, and scalp CO2 laser-evoked potentials are commonly used to assess sensory and pain perception in PD patients. Augmented sensitivity to experimental pain and low sensitivity to somatic sensation in PD patients was demonstrated by reduced pain thresholds and increased sensory thresholds [3e6]. However, none of these assessments seem suitable to evaluate a change in the thresholds of any class of afferent fibers, despite the fact that quantitative analysis of each afferent class is essential to understand the underlying mechanisms of the pathological state and to evaluate the effect of analgesics. The Neurometer®CPT (Neurotron, Baltimore, MD, USA) [7] is an apparatus that selectively measures the thresholds of three classes of afferent fibers by applying three different sinusoidal frequencies (2000 Hz, 250 Hz, and 5 Hz) at various intensities. The Neurometer®CPT is now widely used to evaluate peripheral nerve sensitization and dysfunction in various painful states, including neuropathic pain, or to evaluate the efficacy of analgesic drugs
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[8e10]. No neurodiagnostic measure besides the Neurometer®CPT can evaluate the full spectrum of sensory nerve function. The use of the Neurometer®CPT in the present study makes it the first to evaluate pain and sensory sensitivity of each class of afferent fibers in PD patients. We also investigated the relationship of these thresholds with the presence or absence of pain, patients' use of L-dopa, and the severity of motor dysfunction. The therapeutic effects of dopaminergic medication were also evaluated to further understand pathological mechanisms underlying the pain and sensory dysfunction in PD.
differences in CPT or PTT obtained at each frequency, with side (the more- and lessaffected sides) as the within-subjects factor and status group (like PDP, PDNP, or controls) as the between-subjects factor. Various ANCOVAs were used for each independent variable and post-hoc comparisons were made with the Bonferroni test. The statistical analysis was performed at a 95% confidence level and a P-value less than 0.05 was typically considered statistically significant. However, because three groups were included, the P-values were corrected post-hoc with the Bonferroni test and P-values less than 0.015 were considered to meet the threshold for significance.
3. Results 3.1. Subject characteristics
2. Patients and methods Patients with a clinical diagnosis of PD according to the criteria of the United Kingdom PD Society Brain Bank were recruited from the Department of Neurology of the Second Affiliated Hospital of Soochow University, China. Age- and sex-matched pain-free healthy controls were also recruited at our institution. Patients with dementia, depression, or concomitant disorders that might hamper sensory function were excluded. All patients were evaluated using the Unified PD Rating Scale (UPDRS) and the Hoehn and Yahr (H&Y) scale. Each patient was evaluated to confirm which side was most affected according to the UPDRS score. This study was approved by the ethics committee of the Second Affiliated Hospital of Soochow University. Each patient signed written consent before participation. PD patients were asked to describe any pain or sensory disturbances they were experiencing at the time of the study and that had already persisted for at least two months. The location of any pain was noted using the Brief Pain Inventory (BPI), and pain severity was recorded using the Visual Analog Scale (VAS). Pain and sensory disturbances were classified according to Ford's scheme [1]. The group of PD patients was divided into PD patients with pain (PDP) and PD patients without pain (PDNP). Medical conditions associated with or predisposing to painful symptoms, including diabetes, osteoporosis, rheumatic disease, arthritis, and disk herniation, were checked by examination and evaluation of patient clinical records. Medication histories were noted with respect to L-dopa exposure and patients were subdivided into those with exposure to L-dopa (ELD) and those with no exposure to L-dopa (NLD). An approximation of the cumulative life-time amount of L-dopa was made based on the following equation: (daily amount of L-dopa (in mg) at 1 year after commencement) 365 þ [1/2] [maximum daily amount of Ldopa þ daily amount of L-dopa at 1 year after commencement] [interval (in years) from 1 year after commencement to reaching maximum dose 365] þ [1/2] [maximum daily amount of L-dopa þ daily amount of L-dopa at death or discontinuation of L-dopa] [interval (in years) from reaching maximum dose to death or L-dopa discontinuation 365]. 2.1. Apparatus and procedure The Neurometer®CPT [7] was used to measure both current perception threshold (CPT) and pain tolerance thresholds (PTT). To selectively stimulate nerve fiber populations, the device applies transcutaneous sine-wave stimulation at 2000 Hz, 250 Hz, and 5 Hz at a current intensity of 0.01e9.9 mA via surface electrodes applied to the skin. The 2000 Hz frequency stimulates large Ab fibers, the 250 Hz frequency activates Ad fibers, and the 5 Hz frequency stimulates small Cpolymodal fibers. Both CPT and PTT were measured on both the patients' middle fingers. The left and right fingers were tested separately in a random order across patients. During the first round of testing, PD patients were instructed to refrain from taking any dopaminergic medications the night before testing (referred to as “without medications” or “PDNM”). Patients were asked to take dopaminergic medications (equivalent to the first morning dose plus 100 mg of L-dopa) 1 h before the second round of testing (referred to as the “with medications” state or “PDM”). PTT was always tested last to minimize skin sensitization. Part III of the UPDRS, the clinician-scored monitored motor evaluation, was also assessed before and after dopaminergic medication. To measure CPT, participants were asked to identify the presence or absence of the stimulus through a forced choice protocol. After an initial tentative threshold was determined, we administered stimuli that varied near the presumed threshold to confirm the consistency and reproducibility of the threshold measurement. The threshold of perception was the measured response. To measure PTT, participants self-administered the electrical stimuli, which increased in intensity through a series of predetermined levels. The test started when participants held down the test button. When the stimulus became “intolerable pain”, the participant released the test button to stop the test; the intensity at this point was recorded as the PTT. 2.2. Statistical analysis The data were analyzed with the SPSS package version 17 (SPSS Inc., Chicago, IL, USA) and the results were expressed as means and standard deviations. Differences in age and gender distributions between the two groups were assessed using independent Student's t-tests and c2 tests. A two-way ANOVA was used to assess the
Demographic and clinical characteristics of the study population are presented in Table 1. This study was performed using 72 PD patients and 35 age- and sex-matched controls. Thirty patients (41.7%) reported having experienced significant pain or sensory disturbances that had lasted two months or more. Complaints consisted mostly of musculoskeletal pain (seven in the neck and shoulder, 10 in the lower back, and eight in the lower extremities) and also included three instances of peripheral neuropathic pain (ischioneuralgia) and two of central neuropathic pain (a burning sensation present all over the body). The PD subgroups did not differ significantly with respect to age, gender, disease duration, or L-dopa equivalent dose (P > 0.05), but differences in the UPDRS motor score and H&Y stage were observed (P < 0.05). PD patients with pain exhibited more severe UPDRS motor scores and more advanced H&Y stages than did PD patients without pain. 3.2. Pain and sensory sensitivity in PD patients and controls Significant differences in CPT were evident between groups but not between sides at 2000 Hz, 250 Hz, and 5 Hz, and in PTT at 2000 Hz and 250 Hz. PTT at 5 Hz did not differ between groups or between sides (Table 2). Post-hoc analyses revealed CPT to be significantly higher at all frequencies and PTT to be significantly lower at 2000 Hz and 250 Hz in PD patients with pain than in healthy controls. CPT was significantly higher at 2000 Hz and 250 Hz and PTT was significantly lower at 2000 Hz and 250 Hz in PD patients without pain than in healthy controls. PD patients with pain had higher CPT at 5 Hz and 250 Hz than PD patients without pain (Table 2). 3.3. The relationship of PD severity to pain and sensory thresholds The H&Y stage did not correlate with CPT or PTT, while the UPDRS motor score exhibited a significant positive correlation with Table 1 Demographic and clinical characteristics of the study population. CTRL (n ¼ 35)
PD (n ¼ 72)
PDNP (n ¼ 42) PDP (n ¼ 30) P
44/28
28/14
16/14
Age (yrs)
65.9 ± 8.9 64.8 ± 8.8
65.9 ± 8.9
63.2 ± 8.4
Disease duration (yrs) H&Y stage (1e5) UPDRS III LEDD, mg
e
4.9 ± 3.1
4.4 ± 2.9
5.6 ± 3.2
0.076a 0.259b 0.518a 0.203b 0.119b
e
2.0 ± 0.7
1.9 ± 0.7
2.3 ± 0.6
0.007b
e e
29.5 ± 13.4 25.6 ± 12.9 362.7 ± 273.2 330.3 ± 285.4
Gender (M/F) 19/16
35.1 ± 12.3 0.002b 402.3 ± 258.2 0.279b
CTRL, healthy controls; PD, patients with Parkinson's disease; PDP, PD patients with clinical pain; PDNP, PD patients without clinical pain; UPDRS III, Unified Parkinson's Disease Rating Scale, part III (motor assessment); H&Y, Hoehn and Yahr; LEDD, Ldopa equivalent daily dose. a CTRL - PD comparison. b PDNP - PDP comparison.
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Table 2 CPT and PTT data from PD patients and healthy controls. Current perception threshold (CPT)
PDNP (n ¼ 42) MAS LAS PDP (n ¼ 30) MAS LAS CTRL (n ¼ 35) Left side Right side P value Between groups Between sides P valuea PDNP vs. PDP PDNP vs. CTRL PDP vs. CTRL
Pain tolerance thresholds (PTT)
2000 Hz
250 Hz
5 Hz
2000 Hz
250 Hz
5 Hz
307.8 ± 63.5 318.8 ± 70.5
112.4 ± 36.7 119.4 ± 35.1
70.3 ± 27.9 71.8 ± 32.9
651.1 ± 214.9 691.1 ± 208.4
273.6 ± 158.7 249.7 ± 131.3
246.6 ± 212.9 222.8 ± 222.5
311.1 ± 68.1 332.3 ± 95.4
122.9 ± 47.7 140.8 ± 43.9
86.2 ± 48.5 98.2 ± 49.7
665.7 ± 188.7 674.8 ± 199.3
267.0 ± 102.6 310.0 ± 125.6
266.3 ± 241.8 339.9 ± 300.7
284.3 ± 41.4 288.7 ± 39.5
102.4 ± 21.4 101.2 ± 15.6
68.7 ± 14.6 69.6 ± 15.2
737.6 ± 189.2 749.8 ± 154.2
338.6 ± 90.5 336.0 ± 80.3
207.0 ± 54.4 215.0 ± 112.8
0.005* 0.28
<0.001* 0.072
<0.001* 0.362
0.039* 0.266
0.001* 0.682
0.506 0.302
0.452 0.011** 0.002**
0.008** 0.012** <0.001**
<0.001** 0.724 <0.001**
0.968 0.023* 0.033*
0.168 <0.001** 0.022*
0.348 0.828 0.271
Values are in CPT unit (1 unit ¼ 0.01 mA), and are expressed as mean ± standard deviation (95% confidence interval). PDP, PD patients with clinical pain, PDNP, PD patients without clinical pain, CTRL, healthy controls. MAS, more affected side, LAS, less affected side. *: significance at 0.05 level, **: significance at 0.015 level for Bonferroni correction for multiple comparisons. a Post-hoc analyses (2-two way ANOVA test).
CPT at 5 Hz from the more affected side of patients (r ¼ 0.325, P ¼ 0.005), as did the rigid score (r ¼ 0.239, P ¼ 0.043) and the more-affected side motor score (r ¼ 0.253, P ¼ 0.043). The cumulative dose of L-dopa exhibited a significant negative correlation with PTT at 5 Hz from the more-affected side of patients (r ¼ 0.280, P ¼ 0.017). The daily dose of L-dopa exhibited a significant positive correlation with CPT at 5 Hz from the moreaffected side of patients (r ¼ 0.255, P ¼ 0.031) and a significant negative correlation with PTT at 2000 Hz and 5 Hz from the moreaffected side of patients (2000 Hz: r ¼ 0.251, P ¼ 0.033; 5 Hz: r ¼ 0.258, P ¼ 0.029). 3.4. The influence of L-dopa exposure on CPT or PTT Of the patients with PD, 17 patients (6 women) had no exposure to L-dopa (NLD; mean age, 60.8 years; mean illness duration, 2.5 years; mean UPDRS III score,19.4) while 55 patients (22 women) had L-dopa exposure (ELD; mean age, 65.9 years; mean illness duration, 5.7 years; mean UPDRS III score, 32.7). PD patients with
and without exposure to L-dopa did not differ significantly with respect to age or gender (P > 0.05), but differences in disease duration, the UPDRS motor score, and H&Y stage were observed (P < 0.05). Significant differences were evident between groups but not between sides in CPT and PTT at all frequencies (Table 3). Post-hoc analyses revealed CPT to be significantly higher at all frequencies and PTT to be significantly lower at 2000 Hz and 250 Hz in PD patients with L-dopa exposure than in healthy controls. PTT at 5 Hz was significantly higher in PD patients without L-dopa exposure than in healthy controls. CPT was significantly higher at all frequencies and PTT was significantly lower at all frequencies in PD patients with exposure to L-dopa than those without (Table 3). 3.5. The inefficacy of acute dopaminergic medication in affecting CPT or PTT Thirty-six PD patients completed the protocol of a second round of testing. Mean L-dopa equivalent dose for this challenge was
Table 3 CPT and PTT data from PD patients with and without exposure to L-dopa. Current perception threshold (CPT)
NLD (n ¼ 17) MAS LAS ELD (n ¼ 55) MAS LAS CTRL (n ¼ 35) Left side Right side P value between groups between sides P valuea NLD vs. ELD NLD vs. CTRL ELD vs. CTRL
Pain tolerance thresholds (PTT)
2000 Hz
250 Hz
5 Hz
2000 Hz
250 Hz
5 Hz
301.1 ± 41.3 289.4 ± 61.9
101.9 ± 37.9 106.1 ± 38.1
61.6 ± 24.1 63.4 ± 32.9
765.8 ± 209.8 811.3 ± 201.8
330.6 ± 176.7 303.5 ± 130.1
307.3 ± 193.1 280.0 ± 180.2
311.2 ± 70.4 335.9 ± 84.4
121.1 ± 41.7 135.2 ± 38.8
81.7 ± 40.6 88.8 ± 43.8
622.1 ± 188.5 647.1 ± 190.9
252.9 ± 116.7 264.6 ± 133.9
182.5 ± 123.9 209.2 ± 171.4
284.3 ± 41.4 288.7 ± 39.5
102.4 ± 21.4 101.2 ± 15.6
68.7 ± 14.6 69.6 ± 15.2
737.6 ± 189.2 749.8 ± 154.2
338.6 ± 90.5 336.0 ± 80.3
207.0 ± 54.4 215.0 ± 112.8
0.049* 0.65
0.002* 0.254
0.004* 0.569
<0.001* 0.355
0.027* 0.769
0.002* 0.991
0.025* 0.515 <0.001**
<0.001** 0.757 <0.001**
0.001** 0.345 0.002**
<0.001** 0.252 <0.001**
0.014** <0.419 <0.001**
<0.001** <0.001** 0.595
Values are in CPT unit (1 unit ¼ 0.01 mA), and are expressed as mean ± standard deviation (95% confidence interval). NLD, PD patients without exposure to L-dopa, ELD, PD patients with exposure to L-dopa, CTRL, healthy controls. MAS, more affected side, LAS, less affected side. *: significance at 0.05 level, **: significance at 0.015 level for Bonferroni correction for multiple comparisons. a Post-hoc analyses (2-two way ANOVA test).
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197.05 ± 90.6 mg, with a range from 100 mg to 300 mg. Mean disease duration was 5.1 ± 3.3 years, and the mean H&Y stage was 2.2 ± 0.7. The UPDRS motor score of 32.6 ± 13.3 without medication was significantly different from the UPDRS motor score of 23.1 ± 9.3 after medications (P ¼ 0.001). CPT and PTT were not affected by medication state (P > 0.05) (Table 4), even when comparing the PD patients subgrouped according to pain status. In the subgroup with pain, the VAS score before medications of 4.9 ± 1.0 was significantly different than that after medication of 4.1 ± 1.4 (P ¼ 0.021). 4. Discussion The present study is the first to evaluate pain and sensory sensitivity of each class of afferent fibers in PD patients. It is difficult to compare our results with previous studies due to the significant differences in design and methodology. However, the most conclusive result from our study that sensory thresholds are higher and pain thresholds are lower in PD patients than in controls agrees with previous studies [3e6,11e14]. This study demonstrates that PD patients, with or without pain, exhibit higher CPT and lower PTT at 2000 Hz and 250 Hz than healthy controls. We suspect that both nocuous and innocuous abnormalities exist in Ad fiber- and Ab fiber-dependent sensory inputs in PD patients. Because significant differences were observed in CPT at 5 Hz and 250 Hz between PD patients with and without pain, abnormal sensory inputs through C fibers and Ad fibers might be associated with the presence of pain in PD; Ad fibers and C fibers are the main fibers responsible for pain processing. Peripheral nerve fiber abnormalities may play a relevant role in the pathogenesis of the pain and sensory dysfunction of PD. This hypothesis is supported by the finding of Nolano et al. [15] that PD patients have significant losses at the level of free nerve endings and encapsulated nerve endings. The correlation between sensory or pain perception and motor deficit is controversial. Zambito Marsala et al. [13] demonstrated correlation between the pain threshold and UPDRS score. Another recent study found somatosensory temporal discrimination threshold affected the UPDRS subscores for axial motor deficits [16]. In our study, the UPDRS motor score, including the UPDRS motor subscore on the more-affected side, was positively associated with CPT at 5 Hz from the more-affected side of patients. The findings that sensory thresholds tend to increase as PD motor symptoms worsen suggest these pathologies share the same mechanism. Recent studies [17,18] have provided evidence of peripheral neuropathy due to hypovitaminosis (Vitamin B12) as a result of Ldopa therapy. Here we observed that the cumulative dose of L-dopa exhibited a significant negative correlation with PTT at 5 Hz from the more-affected side of patients. PD patients with L-dopa exposure exhibit higher CPT at all frequencies compared to healthy
controls. However, no differences in CPT were found at any frequency in PD patients without L-dopa exposure compared to healthy controls. CPT was significantly higher at all frequencies and PTT was significantly lower at all frequencies in PD patients with exposure to L-dopa than in those without. Thus we hypothesized that L-dopa use may directly or indirectly leads to nerve fiber dysfunction. Since differences in disease duration, the UPDRS motor score, and H&Y stage were observed in PD patients with and without exposure, we could not exclude the possibility that other factors, including PD alone, might cause peripheral impairment. The effects of dopaminergic therapy on pain thresholds remain controversial. Some investigators have reported that dopaminergic therapy leaves the pain threshold unchanged [12,19,20],whereas others have found that it increases this threshold [11,21]. In our study, we found no differences in CPT or PTT between PD patients with and without medication, independent of any improvement in parkinsonian motor symptoms or the presence of clinical pain. Overall, these findings suggest that acute dopaminergic medications exert little, if any, effect on pain and sensory thresholds, indicating that mechanisms not involving the dopaminergic system are likely to be implicated. In agreement with neurophysiological investigations, the effects of dopaminergic therapy on spontaneous pain are also controversial. In our study, the VAS score significantly decreased after dopaminergic medication. Because pain thresholds were unchanged, the amelioration of pain in PD could only result from the alleviation of motor symptoms by dopaminergic medications. As for the other findings of this study, we found no differences between the more- and less-affected sides in CPT and PTT at all frequencies. Thus, although motor symptoms in PD are typically asymmetric in the beginning, we found no asymmetric changes in pain or sensory perception. Finally, we should recognize some limitations of our study. First, our study group was not homogenous, particularly because PD includes different modes of clinical presentation and evolution. As such, the progression and response to treatment differ between patients. Second, several types of pain were experienced by the study group; while musculoskeletal pain was the most frequently reported, it was not the only type. A larger study group would allow the study specifically of a central pain subgroup. Third, because the location patients reported pain and the site at which we tested PTT was inconsistent, we cannot be certain that the PTT we tested was representative. Therefore, it is possible that the failure to detect differences in pain thresholds between PD patients with and without pain resulted from a lack of power in the study. In conclusion, abnormal Ad fiber and Ab fiber-dependent sensory inputs might exist in PD. Abnormal sensory inputs through C fibers and Ad fibers might be associated with the presence of pain in PD. In particular, higher sensory sensitivity correlated with the motor symptom severity. Prolonged L-dopa use may leads to
Table 4 The therapeutic effects of dopaminergic medication. Current perception threshold (CPT)
PDNM (n ¼ 36) MAS LAS PDM (n ¼ 36) MAS LAS P value Between groups Between sides
Pain tolerance thresholds (PTT)
2000 Hz
250 Hz
5 Hz
2000 Hz
250 Hz
5 Hz
305.9 ± 81.7 311.9 ± 75.1
116.2 ± 47.3 125.3 ± 33.2
80.3 ± 46.9 74.9 ± 33.7
677.6 ± 191.4 715.1 ± 208.4
275.3 ± 126.7 291.1 ± 144.9
244.4 ± 151.9 279.6 ± 191.7
304.8 ± 71.3 314.7 ± 67.4
107.4 ± 49.2 123.7 ± 46.6
75.4 ± 57.7 75.1 ± 48.1
659.6 ± 206.4 698.4 ± 196.8
291.6 ± 191.8 303.6 ± 159.9
266.3 ± 221.7 286.4 ± 200.9
0.945 0.519
0.483 0.088
0.766 0.720
0.605 0.256
0.584 0.598
0.658 0.393
PDNM, PD patients without medications; PDM, PD patients with medications; MAS, more affected side; LAS, less affected side.
Y. Chen et al. / Parkinsonism and Related Disorders 21 (2015) 361e365
neuropathy. Dopaminergic therapy failed to mitigate these sensory and pain changes. These data will add to the growing knowledge on the mechanisms of sensory and pain dysfunction in PD.
[5]
Conflicts of interest
[6]
All authors disclosed that there’s no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work.
[7] [8] [9]
Authorship Chun-Feng Liu, Yi Chen and Cheng-Jie Mao conceived and designed the study. Yi Chen, Cheng-Jie Mao and Si-Jiao Li collected the data and performed the test. All authors analyzed the data, discussed the results and co-wrote and commented on the manuscript. All authors have approved the final article.
[10]
[11]
[12]
Funding sources for study [13]
This work was supported by grants from A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions; Jiangsu Provincial Special Program of Medical Science (BL2014042); Suzhou Science and Technology Development Program (SZS201205); Suzhou Clinical Key Disease Diagnosis and Treatment Technology Foundation (LCZX201304).
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Acknowledgments [17]
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Quantitative and fiber-selective evaluation of pain and sensory dysfunction in patients with Parkinson's disease Yi Chen a, 1, Cheng-Jie Mao a, 1, Si-Jiao Li a, Fen Wang a, b, Jing Chen a, Hui-Jun Zhang a, Ling Li a, Sha-Sha Guo a, Ya-Ping Yang a, b, c, Chun-Feng Liu a, b, c, * a Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China b Institute of Neuroscience, Soochow University, Suzhou 215123, China c Beijing Key Laboratory for Parkinson's Disease, Beijing 100053, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 August 2014 Received in revised form 20 December 2014 Accepted 11 January 2015
Introduction: Pain and sensory disturbances affect many patients with Parkinson's disease (PD). The present study aimed to evaluate the pain and sensory sensitivity of each class of afferent fibers in PD patients and determine the effects of dopaminergic therapy on pain and sensory sensitivity. Methods: Current perception threshold (CPT) and pain tolerance thresholds (PTT) at three frequencies, 2000 Hz, 250 Hz, and 5 Hz, to stimulate Ab fibers, Ad fibers, and small C-polymodal fibers, respectively, were measured in 72 PD patients and 35 healthy controls. Results: CPT was higher at all three frequencies and PTT was lower at 2000 Hz and 250 Hz in PD patients with pain versus healthy controls (P < 0.05). CPT was higher at 2000 Hz and 250 Hz and PTT was lower at 2000 Hz and 250 Hz in PD patients without pain versus healthy controls (P < 0.05). PD patients with pain exhibited higher CPT at 5 Hz and 250 Hz than PD patients without pain (P < 0.05). Dopaminergic therapy did not affect CPT or PPT in PD patients (P > 0.05). Conclusions: Abnormal Ad fiber- and Ab fiber-dependent sensory inputs may exist in PD. Abnormal sensory inputs via C fibers and Ad fibers might be associated with the presence of pain in PD. Because dopaminergic therapy failed to mitigate these sensory and pain dysfunctions, mechanisms not involving the dopaminergic pathway are likely to be implicated. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Pain Thresholds
1. Introduction Pain and sensory disturbances are common non-motor symptoms of Parkinson's disease (PD) and occur in many patients; these symptoms often have a dramatic negative impact on the patient's quality of life. However, the pathogenesis of pain and sensory disturbances in PD patients is not fully understood. Information from several psychophysical, neurophysiological, and imaging studies has provided useful information on pain-processing mechanisms in PD that presents with and without pain. These studies, however, have yielded heterogenous results, probably because of methodological
* Corresponding author. Department of Neurology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215004, China. Tel.: þ86 512 67783307; fax: þ86 512 68284303. E-mail address: [email protected] (C.-F. Liu). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.parkreldis.2015.01.008 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
factors [1,2]. Quantitative sensory testing, the nociceptive withdrawal reflex to electrical stimuli, and scalp CO2 laser-evoked potentials are commonly used to assess sensory and pain perception in PD patients. Augmented sensitivity to experimental pain and low sensitivity to somatic sensation in PD patients was demonstrated by reduced pain thresholds and increased sensory thresholds [3e6]. However, none of these assessments seem suitable to evaluate a change in the thresholds of any class of afferent fibers, despite the fact that quantitative analysis of each afferent class is essential to understand the underlying mechanisms of the pathological state and to evaluate the effect of analgesics. The Neurometer®CPT (Neurotron, Baltimore, MD, USA) [7] is an apparatus that selectively measures the thresholds of three classes of afferent fibers by applying three different sinusoidal frequencies (2000 Hz, 250 Hz, and 5 Hz) at various intensities. The Neurometer®CPT is now widely used to evaluate peripheral nerve sensitization and dysfunction in various painful states, including neuropathic pain, or to evaluate the efficacy of analgesic drugs
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[8e10]. No neurodiagnostic measure besides the Neurometer®CPT can evaluate the full spectrum of sensory nerve function. The use of the Neurometer®CPT in the present study makes it the first to evaluate pain and sensory sensitivity of each class of afferent fibers in PD patients. We also investigated the relationship of these thresholds with the presence or absence of pain, patients' use of L-dopa, and the severity of motor dysfunction. The therapeutic effects of dopaminergic medication were also evaluated to further understand pathological mechanisms underlying the pain and sensory dysfunction in PD.
differences in CPT or PTT obtained at each frequency, with side (the more- and lessaffected sides) as the within-subjects factor and status group (like PDP, PDNP, or controls) as the between-subjects factor. Various ANCOVAs were used for each independent variable and post-hoc comparisons were made with the Bonferroni test. The statistical analysis was performed at a 95% confidence level and a P-value less than 0.05 was typically considered statistically significant. However, because three groups were included, the P-values were corrected post-hoc with the Bonferroni test and P-values less than 0.015 were considered to meet the threshold for significance.
3. Results 3.1. Subject characteristics
2. Patients and methods Patients with a clinical diagnosis of PD according to the criteria of the United Kingdom PD Society Brain Bank were recruited from the Department of Neurology of the Second Affiliated Hospital of Soochow University, China. Age- and sex-matched pain-free healthy controls were also recruited at our institution. Patients with dementia, depression, or concomitant disorders that might hamper sensory function were excluded. All patients were evaluated using the Unified PD Rating Scale (UPDRS) and the Hoehn and Yahr (H&Y) scale. Each patient was evaluated to confirm which side was most affected according to the UPDRS score. This study was approved by the ethics committee of the Second Affiliated Hospital of Soochow University. Each patient signed written consent before participation. PD patients were asked to describe any pain or sensory disturbances they were experiencing at the time of the study and that had already persisted for at least two months. The location of any pain was noted using the Brief Pain Inventory (BPI), and pain severity was recorded using the Visual Analog Scale (VAS). Pain and sensory disturbances were classified according to Ford's scheme [1]. The group of PD patients was divided into PD patients with pain (PDP) and PD patients without pain (PDNP). Medical conditions associated with or predisposing to painful symptoms, including diabetes, osteoporosis, rheumatic disease, arthritis, and disk herniation, were checked by examination and evaluation of patient clinical records. Medication histories were noted with respect to L-dopa exposure and patients were subdivided into those with exposure to L-dopa (ELD) and those with no exposure to L-dopa (NLD). An approximation of the cumulative life-time amount of L-dopa was made based on the following equation: (daily amount of L-dopa (in mg) at 1 year after commencement) 365 þ [1/2] [maximum daily amount of Ldopa þ daily amount of L-dopa at 1 year after commencement] [interval (in years) from 1 year after commencement to reaching maximum dose 365] þ [1/2] [maximum daily amount of L-dopa þ daily amount of L-dopa at death or discontinuation of L-dopa] [interval (in years) from reaching maximum dose to death or L-dopa discontinuation 365]. 2.1. Apparatus and procedure The Neurometer®CPT [7] was used to measure both current perception threshold (CPT) and pain tolerance thresholds (PTT). To selectively stimulate nerve fiber populations, the device applies transcutaneous sine-wave stimulation at 2000 Hz, 250 Hz, and 5 Hz at a current intensity of 0.01e9.9 mA via surface electrodes applied to the skin. The 2000 Hz frequency stimulates large Ab fibers, the 250 Hz frequency activates Ad fibers, and the 5 Hz frequency stimulates small Cpolymodal fibers. Both CPT and PTT were measured on both the patients' middle fingers. The left and right fingers were tested separately in a random order across patients. During the first round of testing, PD patients were instructed to refrain from taking any dopaminergic medications the night before testing (referred to as “without medications” or “PDNM”). Patients were asked to take dopaminergic medications (equivalent to the first morning dose plus 100 mg of L-dopa) 1 h before the second round of testing (referred to as the “with medications” state or “PDM”). PTT was always tested last to minimize skin sensitization. Part III of the UPDRS, the clinician-scored monitored motor evaluation, was also assessed before and after dopaminergic medication. To measure CPT, participants were asked to identify the presence or absence of the stimulus through a forced choice protocol. After an initial tentative threshold was determined, we administered stimuli that varied near the presumed threshold to confirm the consistency and reproducibility of the threshold measurement. The threshold of perception was the measured response. To measure PTT, participants self-administered the electrical stimuli, which increased in intensity through a series of predetermined levels. The test started when participants held down the test button. When the stimulus became “intolerable pain”, the participant released the test button to stop the test; the intensity at this point was recorded as the PTT. 2.2. Statistical analysis The data were analyzed with the SPSS package version 17 (SPSS Inc., Chicago, IL, USA) and the results were expressed as means and standard deviations. Differences in age and gender distributions between the two groups were assessed using independent Student's t-tests and c2 tests. A two-way ANOVA was used to assess the
Demographic and clinical characteristics of the study population are presented in Table 1. This study was performed using 72 PD patients and 35 age- and sex-matched controls. Thirty patients (41.7%) reported having experienced significant pain or sensory disturbances that had lasted two months or more. Complaints consisted mostly of musculoskeletal pain (seven in the neck and shoulder, 10 in the lower back, and eight in the lower extremities) and also included three instances of peripheral neuropathic pain (ischioneuralgia) and two of central neuropathic pain (a burning sensation present all over the body). The PD subgroups did not differ significantly with respect to age, gender, disease duration, or L-dopa equivalent dose (P > 0.05), but differences in the UPDRS motor score and H&Y stage were observed (P < 0.05). PD patients with pain exhibited more severe UPDRS motor scores and more advanced H&Y stages than did PD patients without pain. 3.2. Pain and sensory sensitivity in PD patients and controls Significant differences in CPT were evident between groups but not between sides at 2000 Hz, 250 Hz, and 5 Hz, and in PTT at 2000 Hz and 250 Hz. PTT at 5 Hz did not differ between groups or between sides (Table 2). Post-hoc analyses revealed CPT to be significantly higher at all frequencies and PTT to be significantly lower at 2000 Hz and 250 Hz in PD patients with pain than in healthy controls. CPT was significantly higher at 2000 Hz and 250 Hz and PTT was significantly lower at 2000 Hz and 250 Hz in PD patients without pain than in healthy controls. PD patients with pain had higher CPT at 5 Hz and 250 Hz than PD patients without pain (Table 2). 3.3. The relationship of PD severity to pain and sensory thresholds The H&Y stage did not correlate with CPT or PTT, while the UPDRS motor score exhibited a significant positive correlation with Table 1 Demographic and clinical characteristics of the study population. CTRL (n ¼ 35)
PD (n ¼ 72)
PDNP (n ¼ 42) PDP (n ¼ 30) P
44/28
28/14
16/14
Age (yrs)
65.9 ± 8.9 64.8 ± 8.8
65.9 ± 8.9
63.2 ± 8.4
Disease duration (yrs) H&Y stage (1e5) UPDRS III LEDD, mg
e
4.9 ± 3.1
4.4 ± 2.9
5.6 ± 3.2
0.076a 0.259b 0.518a 0.203b 0.119b
e
2.0 ± 0.7
1.9 ± 0.7
2.3 ± 0.6
0.007b
e e
29.5 ± 13.4 25.6 ± 12.9 362.7 ± 273.2 330.3 ± 285.4
Gender (M/F) 19/16
35.1 ± 12.3 0.002b 402.3 ± 258.2 0.279b
CTRL, healthy controls; PD, patients with Parkinson's disease; PDP, PD patients with clinical pain; PDNP, PD patients without clinical pain; UPDRS III, Unified Parkinson's Disease Rating Scale, part III (motor assessment); H&Y, Hoehn and Yahr; LEDD, Ldopa equivalent daily dose. a CTRL - PD comparison. b PDNP - PDP comparison.
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Table 2 CPT and PTT data from PD patients and healthy controls. Current perception threshold (CPT)
PDNP (n ¼ 42) MAS LAS PDP (n ¼ 30) MAS LAS CTRL (n ¼ 35) Left side Right side P value Between groups Between sides P valuea PDNP vs. PDP PDNP vs. CTRL PDP vs. CTRL
Pain tolerance thresholds (PTT)
2000 Hz
250 Hz
5 Hz
2000 Hz
250 Hz
5 Hz
307.8 ± 63.5 318.8 ± 70.5
112.4 ± 36.7 119.4 ± 35.1
70.3 ± 27.9 71.8 ± 32.9
651.1 ± 214.9 691.1 ± 208.4
273.6 ± 158.7 249.7 ± 131.3
246.6 ± 212.9 222.8 ± 222.5
311.1 ± 68.1 332.3 ± 95.4
122.9 ± 47.7 140.8 ± 43.9
86.2 ± 48.5 98.2 ± 49.7
665.7 ± 188.7 674.8 ± 199.3
267.0 ± 102.6 310.0 ± 125.6
266.3 ± 241.8 339.9 ± 300.7
284.3 ± 41.4 288.7 ± 39.5
102.4 ± 21.4 101.2 ± 15.6
68.7 ± 14.6 69.6 ± 15.2
737.6 ± 189.2 749.8 ± 154.2
338.6 ± 90.5 336.0 ± 80.3
207.0 ± 54.4 215.0 ± 112.8
0.005* 0.28
<0.001* 0.072
<0.001* 0.362
0.039* 0.266
0.001* 0.682
0.506 0.302
0.452 0.011** 0.002**
0.008** 0.012** <0.001**
<0.001** 0.724 <0.001**
0.968 0.023* 0.033*
0.168 <0.001** 0.022*
0.348 0.828 0.271
Values are in CPT unit (1 unit ¼ 0.01 mA), and are expressed as mean ± standard deviation (95% confidence interval). PDP, PD patients with clinical pain, PDNP, PD patients without clinical pain, CTRL, healthy controls. MAS, more affected side, LAS, less affected side. *: significance at 0.05 level, **: significance at 0.015 level for Bonferroni correction for multiple comparisons. a Post-hoc analyses (2-two way ANOVA test).
CPT at 5 Hz from the more affected side of patients (r ¼ 0.325, P ¼ 0.005), as did the rigid score (r ¼ 0.239, P ¼ 0.043) and the more-affected side motor score (r ¼ 0.253, P ¼ 0.043). The cumulative dose of L-dopa exhibited a significant negative correlation with PTT at 5 Hz from the more-affected side of patients (r ¼ 0.280, P ¼ 0.017). The daily dose of L-dopa exhibited a significant positive correlation with CPT at 5 Hz from the moreaffected side of patients (r ¼ 0.255, P ¼ 0.031) and a significant negative correlation with PTT at 2000 Hz and 5 Hz from the moreaffected side of patients (2000 Hz: r ¼ 0.251, P ¼ 0.033; 5 Hz: r ¼ 0.258, P ¼ 0.029). 3.4. The influence of L-dopa exposure on CPT or PTT Of the patients with PD, 17 patients (6 women) had no exposure to L-dopa (NLD; mean age, 60.8 years; mean illness duration, 2.5 years; mean UPDRS III score,19.4) while 55 patients (22 women) had L-dopa exposure (ELD; mean age, 65.9 years; mean illness duration, 5.7 years; mean UPDRS III score, 32.7). PD patients with
and without exposure to L-dopa did not differ significantly with respect to age or gender (P > 0.05), but differences in disease duration, the UPDRS motor score, and H&Y stage were observed (P < 0.05). Significant differences were evident between groups but not between sides in CPT and PTT at all frequencies (Table 3). Post-hoc analyses revealed CPT to be significantly higher at all frequencies and PTT to be significantly lower at 2000 Hz and 250 Hz in PD patients with L-dopa exposure than in healthy controls. PTT at 5 Hz was significantly higher in PD patients without L-dopa exposure than in healthy controls. CPT was significantly higher at all frequencies and PTT was significantly lower at all frequencies in PD patients with exposure to L-dopa than those without (Table 3). 3.5. The inefficacy of acute dopaminergic medication in affecting CPT or PTT Thirty-six PD patients completed the protocol of a second round of testing. Mean L-dopa equivalent dose for this challenge was
Table 3 CPT and PTT data from PD patients with and without exposure to L-dopa. Current perception threshold (CPT)
NLD (n ¼ 17) MAS LAS ELD (n ¼ 55) MAS LAS CTRL (n ¼ 35) Left side Right side P value between groups between sides P valuea NLD vs. ELD NLD vs. CTRL ELD vs. CTRL
Pain tolerance thresholds (PTT)
2000 Hz
250 Hz
5 Hz
2000 Hz
250 Hz
5 Hz
301.1 ± 41.3 289.4 ± 61.9
101.9 ± 37.9 106.1 ± 38.1
61.6 ± 24.1 63.4 ± 32.9
765.8 ± 209.8 811.3 ± 201.8
330.6 ± 176.7 303.5 ± 130.1
307.3 ± 193.1 280.0 ± 180.2
311.2 ± 70.4 335.9 ± 84.4
121.1 ± 41.7 135.2 ± 38.8
81.7 ± 40.6 88.8 ± 43.8
622.1 ± 188.5 647.1 ± 190.9
252.9 ± 116.7 264.6 ± 133.9
182.5 ± 123.9 209.2 ± 171.4
284.3 ± 41.4 288.7 ± 39.5
102.4 ± 21.4 101.2 ± 15.6
68.7 ± 14.6 69.6 ± 15.2
737.6 ± 189.2 749.8 ± 154.2
338.6 ± 90.5 336.0 ± 80.3
207.0 ± 54.4 215.0 ± 112.8
0.049* 0.65
0.002* 0.254
0.004* 0.569
<0.001* 0.355
0.027* 0.769
0.002* 0.991
0.025* 0.515 <0.001**
<0.001** 0.757 <0.001**
0.001** 0.345 0.002**
<0.001** 0.252 <0.001**
0.014** <0.419 <0.001**
<0.001** <0.001** 0.595
Values are in CPT unit (1 unit ¼ 0.01 mA), and are expressed as mean ± standard deviation (95% confidence interval). NLD, PD patients without exposure to L-dopa, ELD, PD patients with exposure to L-dopa, CTRL, healthy controls. MAS, more affected side, LAS, less affected side. *: significance at 0.05 level, **: significance at 0.015 level for Bonferroni correction for multiple comparisons. a Post-hoc analyses (2-two way ANOVA test).
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197.05 ± 90.6 mg, with a range from 100 mg to 300 mg. Mean disease duration was 5.1 ± 3.3 years, and the mean H&Y stage was 2.2 ± 0.7. The UPDRS motor score of 32.6 ± 13.3 without medication was significantly different from the UPDRS motor score of 23.1 ± 9.3 after medications (P ¼ 0.001). CPT and PTT were not affected by medication state (P > 0.05) (Table 4), even when comparing the PD patients subgrouped according to pain status. In the subgroup with pain, the VAS score before medications of 4.9 ± 1.0 was significantly different than that after medication of 4.1 ± 1.4 (P ¼ 0.021). 4. Discussion The present study is the first to evaluate pain and sensory sensitivity of each class of afferent fibers in PD patients. It is difficult to compare our results with previous studies due to the significant differences in design and methodology. However, the most conclusive result from our study that sensory thresholds are higher and pain thresholds are lower in PD patients than in controls agrees with previous studies [3e6,11e14]. This study demonstrates that PD patients, with or without pain, exhibit higher CPT and lower PTT at 2000 Hz and 250 Hz than healthy controls. We suspect that both nocuous and innocuous abnormalities exist in Ad fiber- and Ab fiber-dependent sensory inputs in PD patients. Because significant differences were observed in CPT at 5 Hz and 250 Hz between PD patients with and without pain, abnormal sensory inputs through C fibers and Ad fibers might be associated with the presence of pain in PD; Ad fibers and C fibers are the main fibers responsible for pain processing. Peripheral nerve fiber abnormalities may play a relevant role in the pathogenesis of the pain and sensory dysfunction of PD. This hypothesis is supported by the finding of Nolano et al. [15] that PD patients have significant losses at the level of free nerve endings and encapsulated nerve endings. The correlation between sensory or pain perception and motor deficit is controversial. Zambito Marsala et al. [13] demonstrated correlation between the pain threshold and UPDRS score. Another recent study found somatosensory temporal discrimination threshold affected the UPDRS subscores for axial motor deficits [16]. In our study, the UPDRS motor score, including the UPDRS motor subscore on the more-affected side, was positively associated with CPT at 5 Hz from the more-affected side of patients. The findings that sensory thresholds tend to increase as PD motor symptoms worsen suggest these pathologies share the same mechanism. Recent studies [17,18] have provided evidence of peripheral neuropathy due to hypovitaminosis (Vitamin B12) as a result of Ldopa therapy. Here we observed that the cumulative dose of L-dopa exhibited a significant negative correlation with PTT at 5 Hz from the more-affected side of patients. PD patients with L-dopa exposure exhibit higher CPT at all frequencies compared to healthy
controls. However, no differences in CPT were found at any frequency in PD patients without L-dopa exposure compared to healthy controls. CPT was significantly higher at all frequencies and PTT was significantly lower at all frequencies in PD patients with exposure to L-dopa than in those without. Thus we hypothesized that L-dopa use may directly or indirectly leads to nerve fiber dysfunction. Since differences in disease duration, the UPDRS motor score, and H&Y stage were observed in PD patients with and without exposure, we could not exclude the possibility that other factors, including PD alone, might cause peripheral impairment. The effects of dopaminergic therapy on pain thresholds remain controversial. Some investigators have reported that dopaminergic therapy leaves the pain threshold unchanged [12,19,20],whereas others have found that it increases this threshold [11,21]. In our study, we found no differences in CPT or PTT between PD patients with and without medication, independent of any improvement in parkinsonian motor symptoms or the presence of clinical pain. Overall, these findings suggest that acute dopaminergic medications exert little, if any, effect on pain and sensory thresholds, indicating that mechanisms not involving the dopaminergic system are likely to be implicated. In agreement with neurophysiological investigations, the effects of dopaminergic therapy on spontaneous pain are also controversial. In our study, the VAS score significantly decreased after dopaminergic medication. Because pain thresholds were unchanged, the amelioration of pain in PD could only result from the alleviation of motor symptoms by dopaminergic medications. As for the other findings of this study, we found no differences between the more- and less-affected sides in CPT and PTT at all frequencies. Thus, although motor symptoms in PD are typically asymmetric in the beginning, we found no asymmetric changes in pain or sensory perception. Finally, we should recognize some limitations of our study. First, our study group was not homogenous, particularly because PD includes different modes of clinical presentation and evolution. As such, the progression and response to treatment differ between patients. Second, several types of pain were experienced by the study group; while musculoskeletal pain was the most frequently reported, it was not the only type. A larger study group would allow the study specifically of a central pain subgroup. Third, because the location patients reported pain and the site at which we tested PTT was inconsistent, we cannot be certain that the PTT we tested was representative. Therefore, it is possible that the failure to detect differences in pain thresholds between PD patients with and without pain resulted from a lack of power in the study. In conclusion, abnormal Ad fiber and Ab fiber-dependent sensory inputs might exist in PD. Abnormal sensory inputs through C fibers and Ad fibers might be associated with the presence of pain in PD. In particular, higher sensory sensitivity correlated with the motor symptom severity. Prolonged L-dopa use may leads to
Table 4 The therapeutic effects of dopaminergic medication. Current perception threshold (CPT)
PDNM (n ¼ 36) MAS LAS PDM (n ¼ 36) MAS LAS P value Between groups Between sides
Pain tolerance thresholds (PTT)
2000 Hz
250 Hz
5 Hz
2000 Hz
250 Hz
5 Hz
305.9 ± 81.7 311.9 ± 75.1
116.2 ± 47.3 125.3 ± 33.2
80.3 ± 46.9 74.9 ± 33.7
677.6 ± 191.4 715.1 ± 208.4
275.3 ± 126.7 291.1 ± 144.9
244.4 ± 151.9 279.6 ± 191.7
304.8 ± 71.3 314.7 ± 67.4
107.4 ± 49.2 123.7 ± 46.6
75.4 ± 57.7 75.1 ± 48.1
659.6 ± 206.4 698.4 ± 196.8
291.6 ± 191.8 303.6 ± 159.9
266.3 ± 221.7 286.4 ± 200.9
0.945 0.519
0.483 0.088
0.766 0.720
0.605 0.256
0.584 0.598
0.658 0.393
PDNM, PD patients without medications; PDM, PD patients with medications; MAS, more affected side; LAS, less affected side.
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neuropathy. Dopaminergic therapy failed to mitigate these sensory and pain changes. These data will add to the growing knowledge on the mechanisms of sensory and pain dysfunction in PD.
[5]
Conflicts of interest
[6]
All authors disclosed that there’s no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work.
[7] [8] [9]
Authorship Chun-Feng Liu, Yi Chen and Cheng-Jie Mao conceived and designed the study. Yi Chen, Cheng-Jie Mao and Si-Jiao Li collected the data and performed the test. All authors analyzed the data, discussed the results and co-wrote and commented on the manuscript. All authors have approved the final article.
[10]
[11]
[12]
Funding sources for study [13]
This work was supported by grants from A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions; Jiangsu Provincial Special Program of Medical Science (BL2014042); Suzhou Science and Technology Development Program (SZS201205); Suzhou Clinical Key Disease Diagnosis and Treatment Technology Foundation (LCZX201304).
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Acknowledgments [17]
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