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Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial
Journal of Clinical Neuroscience xxx (xxxx) xxx
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Clinical study
Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial Nisa Vorasoot a, Pichet Termsarasab a, Kunlawat Thadanipon b, Teeratorn Pulkes a,⇑ a b
Division of Neurology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
a r t i c l e
i n f o
Article history: Received 24 July 2019 Accepted 25 August 2019 Available online xxxx Keywords: Parkinson disease Micrographia Handwriting Handwriting exercise Fine motor function Visual cue Neuroplasticity
a b s t r a c t Parkinson disease (PD) patients frequently experience micrographia and difficulty writing, which could potentially impact their quality of life. This study aimed to determine whether handwriting exercise could improve fine manual motor function in PD. The study was a randomized controlled trial assessing the efficacy of a 4-week handwriting exercise using a newly developed handwriting practice book. The primary endpoint was an improvement in the time used to complete the handwriting test. Secondary endpoints were accuracy of the writing performance, patient’s subjective rating scale of their handwriting and a UPDRS part III motor examination. Of a total of 46 subjects, 23 were randomly assigned to the handwriting exercise group. After 4 weeks, the mean time used to complete the test was significantly lower in the exercise group, compared to the control group (143.43 ± 34.02 vs. 175 ± 48.88 s, p = 0.015). Mean time used to complete the handwriting test decreased from the baseline by 16.16% in the exercise group, but increased by 3.63% in the control group (p < 0.001). Significant improvements were also observed by assessing the subjective rating scale and the UPDRS part III scores. The 4-week handwriting exercise using the studied handwriting practice book appears to promote an improvement in writing speed and motor function of hands. The optimal duration and frequency of the exercise, the quantity and characteristic of the letters in the handwriting practice book, and the benefits of the exercise in other languages merit further studies. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Handwriting abnormality is a common feature in PD. In addition to small handwriting, micrographia in PD is also characterized by a progressive reduction in amplitude during a writing task [1]. The exact prevalence of micrographia in PD has not been clearly established in the literature, varying widely from 9% to 75% [2– 4]. Micrographia, as well as difficulty writing and signing, can potentially have negative impacts on quality of life. While levodopa remains a mainstay of pharmacological therapy for PD, motor rehabilitation can serve as an adjunctive nonpharmacological therapy [5]. Several studies have shown that motor learning in PD can be improved by means of cueing and feedback strategies [6,7]. Cues are a reference or trigger for movement generation which, in the case of PD, can be either visual or auditory [8], and feedback refers to the provision of external information which supplements the internal sensory pathways to guide learning [9]. Several studies have shown benefits of short-term ⇑ Corresponding author at: 270 Rama 6 Road, Ratchathewi, Bangkok, Thailand. E-mail address: [email protected] (T. Pulkes).
training with visual cues and feedback, especially for gait in PD [10–13]. Examples include treadmill walking and cycling exercises with visual cues [14–19]. One recent study demonstrated improvement in the upper limb task from technology-assisted rehabilitation with visual cues [20]. Our study aimed to determine whether handwriting exercise could improve writing skills and motor function in PD patients. We developed a handwriting practice book which consisted of the 44 letters in the Thai alphabet. It was hypothesized that the book would improve patients’ writing by visual cues. The results of the 4-week handwriting exercise were then compared to the results of the control group.
2. Methods 2.1. Study design The study was a single center, evaluator-blinded, randomized controlled trial conducted in the neurology clinic at Ramathibodi Hospital, Mahidol University. It was carried out from June 2018
https://doi.org/10.1016/j.jocn.2019.08.119 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
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to December 2018. The study was registered on Thai Clinical Trials Registry (http://www.clinicaltrials.in.th).
size of four. The handwriting exercise group performed handwriting exercises using the handwriting practice book for 4 weeks.
2.2. Ethics and consent
2.5. Intervention
This study was undertaken according to the principles of the Declaration of Helsinki. The research protocol was approved by the Ethical Committee of Ramathibodi Hospital (ID04-61–19). All participants were informed and gave written and verbal consents.
The handwriting practice book consisted of 44 Thai alphabets. Each letter, approximately 1.5x1.5 cm in size, was in the form of dotted framework: each dot was 1 mm in diameter and the diameter-to-diameter distance between each dot was 0.5 mm. Each page contained 30 copies of the identical letter of the alphabet. Patients in the exercise group were informed to do 5 pages in the handwriting practice book every day for 4 weeks. After the 4 weeks, patients returned the handwriting practice book for compliance evaluation.
2.3. Participants The diagnosis of Parkinson disease was made according to United Kingdom Parkinson Disease Society Brain Bank criteria, however family history of PD was allowed. Inclusion criteria included that patients must be at least 18 years of age, Hoehn and Yahr (H&Y) stage 1–3 during an on-medication period, on stable pharmacological treatment without motor fluctuations at least for the past 6 weeks, and able to write. Patients with coexisting neurological or musculoskeletal disorders affecting writing movement and patients who underwent deep brain stimulation were excluded. 2.4. Randomization Patients were randomly allocated in a 1:1 ratio into two groups according to a computer-generated random sequence with a block
2.6. Outcomes measurement All measurements were taken at the baseline and at 4 weeks after the intervention. The primary endpoint was an improvement in the time taken to complete the 1-page handwriting test, which consisted of 25 different letters of the Thai alphabet (Supplementary Material). The secondary endpoints included the following parameters and their change from the baseline: time used to complete the test, accuracy of writing, patient’s subjective rating their writing on scale and Unified Parkinson Disease Rating Scale (UPDRS) part III (motor examination). The accuracy of writing
Fig. 1. Flowchart of the experimental procedures.
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
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was assessed by looking at how well the patients’ handwriting matched the dotted framework of each letter: (a) ‘good’ when it passed through the center of the dot; (b) ‘fair’ when it partially passed the dot; (c) ‘poor’ when it did not touch the dot. The blinded author (N.V.) would then count the total numbers of dots categorized into the above conditions. Patients’ subjective rating scale was determined by their perception of their writing ability (categorized into 4 levels: 4 = excellent; 3 = good; 2 = fair; and 1 = poor). 2.7. Statistical analysis To calculate the optimal sample size, a pilot study was conducted to evaluate the writing skills of 20 PD patients in order. Time used to complete the handwriting test was recorded. In the pilot study, the mean ± standard deviation (SD) of the time used to complete the test was 142.3 ± 16.53 s. The sample size was calculated using the formula below.
n¼
z1a2 þ z1b
2
ð2r2 Þ
D2
To detect at least 10% (i.e., 14 s) improvement in the average time used to complete the test with 80% power and a two-tailed significance level of 0.05, the calculated sample size was 21 patients in each group. In order to allow 10% loss-to-follow up rate, we aimed to recruit 23 patients in each group. All information including demographic data, clinical features, H&Y stage, UPDRS part III, levodopa equivalent dose (LED), Montreal Cognitive Assessment (MoCA), time used to complete the handwriting examination, accuracy of the writing and patient’s subjective rating of their handwriting were recorded. Depending on the distribution of data, independent t-test or non-parametric Mann-Whitney U test was employed for comparison of continuous variables, and v2 test or Fisher’s exact test for categorical variables. Statistical significance was defined as p-value < 0.05. The data were analyzed using Stata version 15 (College Station, TX) by K.T. who was blinded to the treatment allocation.
2.08 ± 0.60, p < 0.001) (Table 2, Fig. 2C). UPDRS part III scores after the writing exercise were not different in both groups, (exercise vs. control = 14.39 ± 4.30 vs. 15.87 ± 5.62, p = 0.322) (Table 2, Fig. 2D). However the percentage of reduction of the scores from the baseline was significantly higher in the exercise group (-17.95 ± 14.25%
Table 1 Demographic Characteristics. Characteristics
Exercise N = 23 N (%)
Control N = 23 N (%)
Male Age (yr), mean (SD) Ethnics - Thai - Chinese - Mixed Thai and Chinese Family history of Parkinson disease Smoking Education (yr), mean (SD) Right-handed Right handwriting Right dominant hand tremor or dyskinesia Age onset (yr), mean (SD) Disease duration (yr), mean (SD) Bradykinesia Rigidity Rest tremor Postural instability H&Y (1–3), median (IQR) UPDRS III on medication (0–132), mean (SD) LED (mg/24 hr), mean (SD)
12 (52.17) 66.74 (10.82)
13 (56.52) 69.52 (10.31)
17 (73.91) 0 (0) 6 (26.09) 4 (17.39) 3 (13.04) 10.09 (6.45) 22 (95.65) 22 (95.65) 13 (56.52) 62.30 (12.61) 4.41 (4.23) 23 (100) 22 (95.65) 16 (69.57) 5 (21.74) 2 (2, 2.5) 17.57 (4.52)
17 (73.91) 1 (4.35) 5 (21.74) 3 (13.04) 6 (26.09) 10.04 (4.82) 23 (100) 23 (100) 13 (56.52) 66.22 (11.25) 3.37 (2.36) 23 (100) 23 (100) 20 (86.96) 7 (30.43) 2 (2, 2.5) 16.26 (5.30)
370.79 (252.31) 20.74 (5.08)
512.96 (339.33) 20.39 (3.53)
MoCA (30), mean (SD)
H&Y, Hoehn and Yahr stage; UPDRS III, Unified Parkinson Disease Rating Scale part III; LED, Levodopa equivalent dose; MoCA, Montreal Cognitive Assessment.
Table 2 Comparison between exercise group versus control groups at baseline and after 4 weeks.
3. Results Forty-six patients were enrolled and randomly assigned into either the exercise or control group (Fig. 1). There were 23 patients in each group. The baseline demographic information was similar in both groups, as summarized in Table 1. Overall, the average age was 68.13 ± 10.54 years. Most of the patients were righthanded, tremor more predominant in the right hand. Only a small number of patients had a family history of PD. The average age of onset and duration of the disease were 64.26 ± 11.98 and 4.4 ± 3.39 years, respectively. The main PD symptoms or signs included bradykinesia, rigidity, resting tremor and postural instability. The median of H&Y stage was 2. The mean UPDRS part III was 16.91 ± 4.91. The LED was 441.87 ± 304.27 mg/day, and the average MoCA score was 20.56 ± 4.33. Regarding the primary outcome, the improvement in the time used to complete the handwriting test from the baseline (time used to complete the 2nd handwriting test [T2] – time used to complete the 1st handwriting test [T1]) was significantly greater in the exercise group than the controls: 29.13 ± 27.17 vs. 5.17 ± 16.75 s, p < 0.001 (Table 2, Fig. 2A). Patients in the exercise group were able to write 16% faster on average after 4-weeks of the handwriting exercise, while the control group did not show improvement (3.63%, p < 0.001). After the exercise, the accuracy of the patients’ writing was not significantly different in both groups (Table 2, Fig. 2B). The average of the patients’ subjective rating of their handwriting after the intervention was significantly higher in the exercise group compared to the controls (2.78 ± 0.42 vs.
Time used to complete the 1st handwriting test (T1) (seconds), mean (SD) Time used to complete the 2nd handwriting test (T2) (seconds), mean (SD) Improvement in time (T2-T1) (seconds), mean (SD) Change in time used to complete (%), mean (SD) Accuracy 1st test (Good + Fair) (dots), mean (SD) Accuracy 2nd test (Good + Fair) (dots), mean (SD) Change in accuracy (%), mean (SD) Patient’s subjective rating scale 1st test (scores), mean (SD) Patient’s subjective rating scale 2nd test (scores), mean (SD) Change in patient’s subjective rating scale (%), mean (SD) UPDRS part III motor examination 1st test (scores), mean (SD) UPDRS part III motor examination 2nd test (scores), mean (SD) Change in UPDRS part III (%), mean (SD)
Exercise N = 23
Control N = 23
p-value
172.57 (38.53) 143.43 (34.02)
156.78 (56.19) 175 (48.88)
0.273
29.13 (27.17) 16.16 (13.07) 579.13 (105.41) 579.61 (104.35) 0.91 (13.15) 1.69 (0.47) 2.78 (0.42) 76.09 (54.08) 17.57 (4.52) 14.39 (4.30) 17.95 (14.25)
5.17 (16.75) 3.63 (9.05) 563 (125.33) 561.35 (115.11) 0.88 (9.13) 1.91 (0.52) 2.08 (0.60) 13.77 (36.46) 16.26 (5.30) 15.87 (5.62) 3.15 (9.14)
<0.001*
0.015*
<0.001* 0.639 0.576 0.835 0.142 <0.001* <0.001* 0.374 0.322 <0.001*
UPDRS III, Unified Parkinson Disease Rating Scale part III; T1, Time used to complete the 1st handwriting test; T2, Time used to complete the 2nd handwriting test. * Statistical significance (p < 0.05).
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
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Fig. 2. Comparison between exercise group versus control groups at baseline and after 4 weeks. (A) Time used to complete the handwriting test (seconds), (B) Improvement in time used to complete the handwriting test (T2-T1) (seconds), (C) Unified Parkinson Disease Rating Scale (UPDRS) part III motor examination (scores), (D) Change in UPDRS part III (%), (E) Patient’s subjective rating scale of their handwriting (scores), (F) Accuracy of the writing performance (Good + Fair) (dots) *Statistical significance (p < 0.05), ***Statistical significance (p < 0.001).
vs. 3.15 ± 9.14%, p < 0.001) (Table 2), in which all types of tremors of hands, rapid alternating movements of hands, rigidity and body bradykinesia were shown to be the most improvement categories (Table 3). 4. Discussion To the best of our knowledge, this is the first study which demonstrates the improvement in the handwriting of the PD
patients after the handwriting exercise facilitated by using visual cues and sensory feedback. Most of the patients had mild-tomoderate severity of the disease with a median H & Y stage of 2. This study demonstrated that the 4-week handwriting exercise could improve manual fine motor skill, especially the speed of writing, but not writing accuracy. The beneficial effects of the handwriting exercise in our study may be explained by visual cues and feedback [6,7]. Visual cues can facilitate locomotion and improve gait function in PD [21]. Rid-
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
N. Vorasoot et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 3 Change in UPDRS part III after 4 weeks. UPDRS part III (Motor examination)
Exercise mean (SD)
Control mean (SD)
pvalue
18. Speech
0.17 (0.39) 0.17 (0.39) 0.39 (0.78) 0.48 (0.67) 0.43 (0.66) 0.17 (0.49) 0.22 (0.52) 0.26 (0.54) 0.09 (0.29) 0.13 (0.34) 0.17 (0.39) 0.09 (0.42) 0.09 (0.29) 0.30 (0.47)
0 (0)
0.038*
0.04 (0.21) 0 (0.30)
0.159
0.04 (0.21) 0 (0)
0.004*
0.04 (0.37) 0 (0.43)
0.294
0.04 (0.37) 0.09 (0.29) 0.09 (0.29) 0 (0)
0.104
19. Facial expression 20. Tremor at rest 21. Action or postural tremor of hands 22. Rigidity 23. Finger taps 24. Hand movements 25. Rapid alternating movements of hands 26. Leg agility 27. Arising from chair 28. Posture 29. Gait 30. Postural stability 31. Body Bradykinesia and Hypokinesia *
0.026*
0.002*
0.121
1.000 0.639 0.038*
0 (0.30)
0.409
0.04 (0.21)
0.086
0.09 (0.29)
0.066
Statistical significance (p < 0.05).
gel et al evaluated the effects of passive leg cycling on upper extremity motor function in PD patients, and found significant improvement in tremor and bradykinesia. This was thought to be due to the effect of the afferent input from the lower extremities on, corticomotor excitability. This sensory feedback loop played a role in the improvement of upper extremity motor function [15]. Subsequent study on active-assisted cycling also demonstrated that the high-intensity exercise could ameliorate motor symptoms of PD, and the role of exercise-induced neuroplasticity was introduced [14,22]. Motor benefits of leg cycling and exercise-induced neuroplasticity were also demonstrated in spinocerebellar ataxia [17]. Comparably, the dots, which are the framework of the alphabets in our handwriting exercise, serve as visual cues. Writing the same letters several times may provide repetitive stimulation of the sensory feedback loops which, in turn, facilitates corticomotor excitation and induced neuroplasticity. Improvement in the speed of writing in the exercise group may be attributed to the effect of sensory feedback on motor learning and plasticity. In addition to the improvement in writing speed, our study demonstrated that the reduction in the UPDRS part III scores was also significantly greater in the exercise group. This is in line with one recent study which showed that progressive cycling exercise could improve both UPDRS part III and MoCA scores, indicating improvement in both motor and cognitive functions [23]. Furthermore, intensive multidisciplinary rehabilitation, including active and passive exercise, treadmill training, hand dexterity training and speech therapy, was demonstrated to improve quality of life in PD patients [24]. This study also provided an indirect evidence of some improvement in the quality of life of the PD patients through the more appreciation in the patient’s subjective rating after the writing exercise. One of the well-recognized handwriting difficulties in PD is micrographia. Progressive micrographia was evident in horizontal but not vertical writing [25]. One hypothesis was that micrographia might be attributed to poor coordination between wrist
5
and finger movements, and wrist extension stiffness. There was also a strong correlation between activity in the posterior putamen on functional MRI and writing size in PD patients, and impaired habitual control was proposed to be a mechanism of micrographia [26]. While the exact mechanisms of micrographia are unclear, handwriting rehabilitation has been found to improve handwriting skills. Ziliotto et al reported a benefit from after a 10-week handwriting rehabilitation training [27]. The recent study of the sixweek intensive writing amplitude training improved amplitude and amplitude variability, and proposed the role of consolidation of motor learning in PD [28]. The handwriting exercise in this study can also serve as one of the rehabilitative approaches to consolidate motor learning and neuroplasticity. While the improvement in size of handwriting cannot be evaluated in the study given the fixed prespecified size of the alphabets in the handwriting exercise book, additional writing parameters such as pressure on a writing surface or amplitude on free writing, can be incorporated in future studies. In the present study, all recruited patients had excellent adherence to protocol including 100% follow-up rate at the outpatient clinic. All subjects in the exercise group had an excellent compliance in performing the handwriting exercise and expressed satisfaction. One of the limitations of this study is that the effects of handwriting exercise may be different in other languages, and future trials in a variety of languages may be required before there are applications to each individual language or generalization. Additionally, we conducted this trial in the tertiary hospital, and the patients might not represent PD patients in the entire Thai population. High level of education in the patients can have a positive impact to the adherence of this relatively intensive writing exercise. 5. Conclusions The current study revealed that the 4-week handwriting exercise with our handwriting practice book appeared to improve writing speed and fine motor function of hands. The optimum duration of the exercise, the frequency of the exercise, the quantity and the characteristic of the letters in the handwriting practice book will need to be studied further to increase the benefit received from the exercise. Sources of support This study was supported by the Ramathibodi Research Fund. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements We thank the patients for taking part in this study, neurology residents for helping in recruiting study participants, and Mr. Jate Jindaroj for helping in designing the handwriting practice form. We acknowledge Miss Fasai Pulkes for English editing. Authors’ contributions NV contributed to data collection, analysis and interpretation, as well as writing of the first draft and manuscript revision. PT contributed to data interpretation and manuscript revision. KT contributed to methods and manuscript revision regarding statistical
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
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analysis. TP contributed to study design and conceptualization, as well as data interpretation and manuscript revision. All authors read and approve the final manuscript. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.08.119. References [1] Shukla AW, Ounpraseuth S, Okun MS, Gray V, Schwankhaus J, Metzer WS. Micrographia and related deficits in Parkinson’s disease: a cross-sectional study. BMJ Open 2012;2(3). pii: e000628. [2] Ishihara LS, Khaw K-T, Luben R, et al. Self-reported parkinsonian symptoms in the EPIC-Norfolk cohort. BMC Neurol 2005;5:15. [3] Jarzebska E. Evaluation of effectiveness of the micrographia’s therapy in Parkinson’s disease patients. Pol Merkur Lek organ Pol Tow Lek 2006;20 (120):688–90. [4] McLennan JE, Nakano K, Tyler HR, Schwab RS. Micrographia in Parkinson’s disease. J Neurol Sci 1972;15(2):141–52. [5] Tomlinson CL, Patel S, Meek C. Physiotherapy versus placebo or no intervention in Parkinson’s disease. In: Tomlinson CL, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2012. p. CD002817. [6] Nieuwboer A, Rochester L, Müncks L, Swinnen SP. Motor learning in Parkinson’s disease: limitations and potential for rehabilitation. Parkinsonism Relat Disord 2009;15:S53–8. [7] Cassimatis C, Liu KPY, Fahey P, Bissett M. The effectiveness of external sensory cues in improving functional performance in individuals with Parkinson’s disease. Int J Rehabil Res 2016;39(3):211–8. [8] Nieuwboer A, Kwakkel G, Rochester L, et al. Cueing training in the home improves gait-related mobility in Parkinson’s disease: the RESCUE trial. J Neurol Neurosurg Psychiatry 2007;78(2):134–40. [9] Schmidt RA, Motor Lee TD. Control and learning: a behavioral emphasis. Hum Kinet 1999. [10] Oliveira RM, Gurd JM, Nixon P, Marshall JC, Passingham RE. Micrographia in Parkinson’s disease: the effect of providing external cues. J Neurol Neurosurg Psychiatry 1997;63(4):429–33. [11] Bryant MS, Rintala DH, Lai EC, Protas EJ. An investigation of two interventions for micrographia in individuals with Parkinson’s disease. Clin Rehabil 2010;24 (11):1021–6. [12] Spaulding SJ, Barber B, Colby M, Cormack B, Mick T, Jenkins ME. Cueing and gait improvement among people with Parkinson’s disease: a meta-analysis. Arch Phys Med Rehabil 2013;94(3):562–70.
[13] Rocha PA, Porfírio GM, Ferraz HB, Trevisani VFM. Effects of external cues on gait parameters of Parkinson’s disease patients: a systematic review. Clin Neurol Neurosurg 2014;124:127–34. [14] Ridgel AL, Peacock CA, Fickes EJ, Kim CH. Active-assisted cycling improves tremor and bradykinesia in Parkinson’s disease. Arch Phys Med Rehabil 2012;93(11):2049–54. [15] Ridgel AL, Muller MD, Kim CH, Fickes EJ, Mera TO. Acute effects of passive leg cycling on upper extremity tremor and bradykinesia in Parkinson’s disease. Phys Sportsmed. 2011;39(3):83–93. [16] Ridgel AL, Abdar HM, Alberts JL, Discenzo FM, Loparo KA. Variability in cadence during forced cycling predicts motor improvement in individuals with Parkinson’s disease. IEEE Trans Neural Syst Rehabil Eng 2013;21(3):481–9. [17] Chang YJ, Chou CC, Huang WT, Lu CS, Wong AM, Hsu MJ. Cycling regimen induces spinal circuitry plasticity and improves leg muscle coordination in individuals with spinocerebellar ataxia. Arch Phys Med Rehabil 2015;96 (6):1006–13. [18] McGough EL, Robinson CA, Nelson MD, et al. A tandem cycling program: feasibility and physical performance outcomes in people with Parkinson disease. J Neurol Phys Ther. 2016;40(4):223–9. [19] Mohammadi-Abdar H, Ridgel AL, Discenzo FM, Phillips RS, Walter BL, Loparo KA. Test and validation of a smart exercise bike for motor rehabilitation in individuals with Parkinson’s disease. IEEE Trans Neural Syst Rehabil Eng 2016;24(11):1254–64. [20] Nackaerts E, Nieuwboer A, Broeder S, et al. Opposite effects of visual cueing during writing-like movements of different amplitudes in Parkinson’s disease. Neurorehabil Neural Repair 2016;30(5):431–9. [21] Azulay J-P, Mesure S, Amblard B, Blin O, Sangla I, Pouget J. Visual control of locomotion in PD. Brain 1999;122:111–20. [22] Snijders AH, van Kesteren M, Bloem BR. Cycling is less affected than walking in freezers of gait. J Neurol Neurosurg Psychiatry 2011;83(5):575–6. [23] Changa H-C, Lua C-S, Chioub W-D, Chena C-C, Wenga Y-H, Chang Y-J. An 8week low-intensity progressive cycling training improves motor functions in patients with early-stage Parkinson’s disease. J Clin Neurol. 2018;14 (2):225–33. [24] Ferrazzoli D, Ortelli P, Zivi I, et al. Efficacy of intensive multidisciplinary rehabilitation in Parkinson’s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2018;89(8):828–35. [25] Ma H, Hwang W, Chang S, Wang T. Progressive micrographia shown in horizontal, but not vertical, writing in Parkinson’s disease. Behav Neurol 2013;27:169–74. [26] Wu T, Zhang J, Hallett M, Feng T, Hou Y, Chan P. Neural correlates underlying micrographia in Parkinson’s disease. Brain 2016;139(1):144–60. [27] Ziliotto A, Cersosimo MG, Micheli FE. Handwriting rehabilitation in parkinson disease: a pilot study. Ann Rehabil Med 2015;39(4):586–91. [28] Nackaerts E, Heremans E, Vervoort G, et al. Relearning of writing skills in Parkinson’s disease after intensive amplitude training. Mov Disord 2016;31 (8):1209–16.
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
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Clinical study
Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial Nisa Vorasoot a, Pichet Termsarasab a, Kunlawat Thadanipon b, Teeratorn Pulkes a,⇑ a b
Division of Neurology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
a r t i c l e
i n f o
Article history: Received 24 July 2019 Accepted 25 August 2019 Available online xxxx Keywords: Parkinson disease Micrographia Handwriting Handwriting exercise Fine motor function Visual cue Neuroplasticity
a b s t r a c t Parkinson disease (PD) patients frequently experience micrographia and difficulty writing, which could potentially impact their quality of life. This study aimed to determine whether handwriting exercise could improve fine manual motor function in PD. The study was a randomized controlled trial assessing the efficacy of a 4-week handwriting exercise using a newly developed handwriting practice book. The primary endpoint was an improvement in the time used to complete the handwriting test. Secondary endpoints were accuracy of the writing performance, patient’s subjective rating scale of their handwriting and a UPDRS part III motor examination. Of a total of 46 subjects, 23 were randomly assigned to the handwriting exercise group. After 4 weeks, the mean time used to complete the test was significantly lower in the exercise group, compared to the control group (143.43 ± 34.02 vs. 175 ± 48.88 s, p = 0.015). Mean time used to complete the handwriting test decreased from the baseline by 16.16% in the exercise group, but increased by 3.63% in the control group (p < 0.001). Significant improvements were also observed by assessing the subjective rating scale and the UPDRS part III scores. The 4-week handwriting exercise using the studied handwriting practice book appears to promote an improvement in writing speed and motor function of hands. The optimal duration and frequency of the exercise, the quantity and characteristic of the letters in the handwriting practice book, and the benefits of the exercise in other languages merit further studies. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Handwriting abnormality is a common feature in PD. In addition to small handwriting, micrographia in PD is also characterized by a progressive reduction in amplitude during a writing task [1]. The exact prevalence of micrographia in PD has not been clearly established in the literature, varying widely from 9% to 75% [2– 4]. Micrographia, as well as difficulty writing and signing, can potentially have negative impacts on quality of life. While levodopa remains a mainstay of pharmacological therapy for PD, motor rehabilitation can serve as an adjunctive nonpharmacological therapy [5]. Several studies have shown that motor learning in PD can be improved by means of cueing and feedback strategies [6,7]. Cues are a reference or trigger for movement generation which, in the case of PD, can be either visual or auditory [8], and feedback refers to the provision of external information which supplements the internal sensory pathways to guide learning [9]. Several studies have shown benefits of short-term ⇑ Corresponding author at: 270 Rama 6 Road, Ratchathewi, Bangkok, Thailand. E-mail address: [email protected] (T. Pulkes).
training with visual cues and feedback, especially for gait in PD [10–13]. Examples include treadmill walking and cycling exercises with visual cues [14–19]. One recent study demonstrated improvement in the upper limb task from technology-assisted rehabilitation with visual cues [20]. Our study aimed to determine whether handwriting exercise could improve writing skills and motor function in PD patients. We developed a handwriting practice book which consisted of the 44 letters in the Thai alphabet. It was hypothesized that the book would improve patients’ writing by visual cues. The results of the 4-week handwriting exercise were then compared to the results of the control group.
2. Methods 2.1. Study design The study was a single center, evaluator-blinded, randomized controlled trial conducted in the neurology clinic at Ramathibodi Hospital, Mahidol University. It was carried out from June 2018
https://doi.org/10.1016/j.jocn.2019.08.119 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
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to December 2018. The study was registered on Thai Clinical Trials Registry (http://www.clinicaltrials.in.th).
size of four. The handwriting exercise group performed handwriting exercises using the handwriting practice book for 4 weeks.
2.2. Ethics and consent
2.5. Intervention
This study was undertaken according to the principles of the Declaration of Helsinki. The research protocol was approved by the Ethical Committee of Ramathibodi Hospital (ID04-61–19). All participants were informed and gave written and verbal consents.
The handwriting practice book consisted of 44 Thai alphabets. Each letter, approximately 1.5x1.5 cm in size, was in the form of dotted framework: each dot was 1 mm in diameter and the diameter-to-diameter distance between each dot was 0.5 mm. Each page contained 30 copies of the identical letter of the alphabet. Patients in the exercise group were informed to do 5 pages in the handwriting practice book every day for 4 weeks. After the 4 weeks, patients returned the handwriting practice book for compliance evaluation.
2.3. Participants The diagnosis of Parkinson disease was made according to United Kingdom Parkinson Disease Society Brain Bank criteria, however family history of PD was allowed. Inclusion criteria included that patients must be at least 18 years of age, Hoehn and Yahr (H&Y) stage 1–3 during an on-medication period, on stable pharmacological treatment without motor fluctuations at least for the past 6 weeks, and able to write. Patients with coexisting neurological or musculoskeletal disorders affecting writing movement and patients who underwent deep brain stimulation were excluded. 2.4. Randomization Patients were randomly allocated in a 1:1 ratio into two groups according to a computer-generated random sequence with a block
2.6. Outcomes measurement All measurements were taken at the baseline and at 4 weeks after the intervention. The primary endpoint was an improvement in the time taken to complete the 1-page handwriting test, which consisted of 25 different letters of the Thai alphabet (Supplementary Material). The secondary endpoints included the following parameters and their change from the baseline: time used to complete the test, accuracy of writing, patient’s subjective rating their writing on scale and Unified Parkinson Disease Rating Scale (UPDRS) part III (motor examination). The accuracy of writing
Fig. 1. Flowchart of the experimental procedures.
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
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was assessed by looking at how well the patients’ handwriting matched the dotted framework of each letter: (a) ‘good’ when it passed through the center of the dot; (b) ‘fair’ when it partially passed the dot; (c) ‘poor’ when it did not touch the dot. The blinded author (N.V.) would then count the total numbers of dots categorized into the above conditions. Patients’ subjective rating scale was determined by their perception of their writing ability (categorized into 4 levels: 4 = excellent; 3 = good; 2 = fair; and 1 = poor). 2.7. Statistical analysis To calculate the optimal sample size, a pilot study was conducted to evaluate the writing skills of 20 PD patients in order. Time used to complete the handwriting test was recorded. In the pilot study, the mean ± standard deviation (SD) of the time used to complete the test was 142.3 ± 16.53 s. The sample size was calculated using the formula below.
n¼
z1a2 þ z1b
2
ð2r2 Þ
D2
To detect at least 10% (i.e., 14 s) improvement in the average time used to complete the test with 80% power and a two-tailed significance level of 0.05, the calculated sample size was 21 patients in each group. In order to allow 10% loss-to-follow up rate, we aimed to recruit 23 patients in each group. All information including demographic data, clinical features, H&Y stage, UPDRS part III, levodopa equivalent dose (LED), Montreal Cognitive Assessment (MoCA), time used to complete the handwriting examination, accuracy of the writing and patient’s subjective rating of their handwriting were recorded. Depending on the distribution of data, independent t-test or non-parametric Mann-Whitney U test was employed for comparison of continuous variables, and v2 test or Fisher’s exact test for categorical variables. Statistical significance was defined as p-value < 0.05. The data were analyzed using Stata version 15 (College Station, TX) by K.T. who was blinded to the treatment allocation.
2.08 ± 0.60, p < 0.001) (Table 2, Fig. 2C). UPDRS part III scores after the writing exercise were not different in both groups, (exercise vs. control = 14.39 ± 4.30 vs. 15.87 ± 5.62, p = 0.322) (Table 2, Fig. 2D). However the percentage of reduction of the scores from the baseline was significantly higher in the exercise group (-17.95 ± 14.25%
Table 1 Demographic Characteristics. Characteristics
Exercise N = 23 N (%)
Control N = 23 N (%)
Male Age (yr), mean (SD) Ethnics - Thai - Chinese - Mixed Thai and Chinese Family history of Parkinson disease Smoking Education (yr), mean (SD) Right-handed Right handwriting Right dominant hand tremor or dyskinesia Age onset (yr), mean (SD) Disease duration (yr), mean (SD) Bradykinesia Rigidity Rest tremor Postural instability H&Y (1–3), median (IQR) UPDRS III on medication (0–132), mean (SD) LED (mg/24 hr), mean (SD)
12 (52.17) 66.74 (10.82)
13 (56.52) 69.52 (10.31)
17 (73.91) 0 (0) 6 (26.09) 4 (17.39) 3 (13.04) 10.09 (6.45) 22 (95.65) 22 (95.65) 13 (56.52) 62.30 (12.61) 4.41 (4.23) 23 (100) 22 (95.65) 16 (69.57) 5 (21.74) 2 (2, 2.5) 17.57 (4.52)
17 (73.91) 1 (4.35) 5 (21.74) 3 (13.04) 6 (26.09) 10.04 (4.82) 23 (100) 23 (100) 13 (56.52) 66.22 (11.25) 3.37 (2.36) 23 (100) 23 (100) 20 (86.96) 7 (30.43) 2 (2, 2.5) 16.26 (5.30)
370.79 (252.31) 20.74 (5.08)
512.96 (339.33) 20.39 (3.53)
MoCA (30), mean (SD)
H&Y, Hoehn and Yahr stage; UPDRS III, Unified Parkinson Disease Rating Scale part III; LED, Levodopa equivalent dose; MoCA, Montreal Cognitive Assessment.
Table 2 Comparison between exercise group versus control groups at baseline and after 4 weeks.
3. Results Forty-six patients were enrolled and randomly assigned into either the exercise or control group (Fig. 1). There were 23 patients in each group. The baseline demographic information was similar in both groups, as summarized in Table 1. Overall, the average age was 68.13 ± 10.54 years. Most of the patients were righthanded, tremor more predominant in the right hand. Only a small number of patients had a family history of PD. The average age of onset and duration of the disease were 64.26 ± 11.98 and 4.4 ± 3.39 years, respectively. The main PD symptoms or signs included bradykinesia, rigidity, resting tremor and postural instability. The median of H&Y stage was 2. The mean UPDRS part III was 16.91 ± 4.91. The LED was 441.87 ± 304.27 mg/day, and the average MoCA score was 20.56 ± 4.33. Regarding the primary outcome, the improvement in the time used to complete the handwriting test from the baseline (time used to complete the 2nd handwriting test [T2] – time used to complete the 1st handwriting test [T1]) was significantly greater in the exercise group than the controls: 29.13 ± 27.17 vs. 5.17 ± 16.75 s, p < 0.001 (Table 2, Fig. 2A). Patients in the exercise group were able to write 16% faster on average after 4-weeks of the handwriting exercise, while the control group did not show improvement (3.63%, p < 0.001). After the exercise, the accuracy of the patients’ writing was not significantly different in both groups (Table 2, Fig. 2B). The average of the patients’ subjective rating of their handwriting after the intervention was significantly higher in the exercise group compared to the controls (2.78 ± 0.42 vs.
Time used to complete the 1st handwriting test (T1) (seconds), mean (SD) Time used to complete the 2nd handwriting test (T2) (seconds), mean (SD) Improvement in time (T2-T1) (seconds), mean (SD) Change in time used to complete (%), mean (SD) Accuracy 1st test (Good + Fair) (dots), mean (SD) Accuracy 2nd test (Good + Fair) (dots), mean (SD) Change in accuracy (%), mean (SD) Patient’s subjective rating scale 1st test (scores), mean (SD) Patient’s subjective rating scale 2nd test (scores), mean (SD) Change in patient’s subjective rating scale (%), mean (SD) UPDRS part III motor examination 1st test (scores), mean (SD) UPDRS part III motor examination 2nd test (scores), mean (SD) Change in UPDRS part III (%), mean (SD)
Exercise N = 23
Control N = 23
p-value
172.57 (38.53) 143.43 (34.02)
156.78 (56.19) 175 (48.88)
0.273
29.13 (27.17) 16.16 (13.07) 579.13 (105.41) 579.61 (104.35) 0.91 (13.15) 1.69 (0.47) 2.78 (0.42) 76.09 (54.08) 17.57 (4.52) 14.39 (4.30) 17.95 (14.25)
5.17 (16.75) 3.63 (9.05) 563 (125.33) 561.35 (115.11) 0.88 (9.13) 1.91 (0.52) 2.08 (0.60) 13.77 (36.46) 16.26 (5.30) 15.87 (5.62) 3.15 (9.14)
<0.001*
0.015*
<0.001* 0.639 0.576 0.835 0.142 <0.001* <0.001* 0.374 0.322 <0.001*
UPDRS III, Unified Parkinson Disease Rating Scale part III; T1, Time used to complete the 1st handwriting test; T2, Time used to complete the 2nd handwriting test. * Statistical significance (p < 0.05).
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
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Fig. 2. Comparison between exercise group versus control groups at baseline and after 4 weeks. (A) Time used to complete the handwriting test (seconds), (B) Improvement in time used to complete the handwriting test (T2-T1) (seconds), (C) Unified Parkinson Disease Rating Scale (UPDRS) part III motor examination (scores), (D) Change in UPDRS part III (%), (E) Patient’s subjective rating scale of their handwriting (scores), (F) Accuracy of the writing performance (Good + Fair) (dots) *Statistical significance (p < 0.05), ***Statistical significance (p < 0.001).
vs. 3.15 ± 9.14%, p < 0.001) (Table 2), in which all types of tremors of hands, rapid alternating movements of hands, rigidity and body bradykinesia were shown to be the most improvement categories (Table 3). 4. Discussion To the best of our knowledge, this is the first study which demonstrates the improvement in the handwriting of the PD
patients after the handwriting exercise facilitated by using visual cues and sensory feedback. Most of the patients had mild-tomoderate severity of the disease with a median H & Y stage of 2. This study demonstrated that the 4-week handwriting exercise could improve manual fine motor skill, especially the speed of writing, but not writing accuracy. The beneficial effects of the handwriting exercise in our study may be explained by visual cues and feedback [6,7]. Visual cues can facilitate locomotion and improve gait function in PD [21]. Rid-
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
N. Vorasoot et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 3 Change in UPDRS part III after 4 weeks. UPDRS part III (Motor examination)
Exercise mean (SD)
Control mean (SD)
pvalue
18. Speech
0.17 (0.39) 0.17 (0.39) 0.39 (0.78) 0.48 (0.67) 0.43 (0.66) 0.17 (0.49) 0.22 (0.52) 0.26 (0.54) 0.09 (0.29) 0.13 (0.34) 0.17 (0.39) 0.09 (0.42) 0.09 (0.29) 0.30 (0.47)
0 (0)
0.038*
0.04 (0.21) 0 (0.30)
0.159
0.04 (0.21) 0 (0)
0.004*
0.04 (0.37) 0 (0.43)
0.294
0.04 (0.37) 0.09 (0.29) 0.09 (0.29) 0 (0)
0.104
19. Facial expression 20. Tremor at rest 21. Action or postural tremor of hands 22. Rigidity 23. Finger taps 24. Hand movements 25. Rapid alternating movements of hands 26. Leg agility 27. Arising from chair 28. Posture 29. Gait 30. Postural stability 31. Body Bradykinesia and Hypokinesia *
0.026*
0.002*
0.121
1.000 0.639 0.038*
0 (0.30)
0.409
0.04 (0.21)
0.086
0.09 (0.29)
0.066
Statistical significance (p < 0.05).
gel et al evaluated the effects of passive leg cycling on upper extremity motor function in PD patients, and found significant improvement in tremor and bradykinesia. This was thought to be due to the effect of the afferent input from the lower extremities on, corticomotor excitability. This sensory feedback loop played a role in the improvement of upper extremity motor function [15]. Subsequent study on active-assisted cycling also demonstrated that the high-intensity exercise could ameliorate motor symptoms of PD, and the role of exercise-induced neuroplasticity was introduced [14,22]. Motor benefits of leg cycling and exercise-induced neuroplasticity were also demonstrated in spinocerebellar ataxia [17]. Comparably, the dots, which are the framework of the alphabets in our handwriting exercise, serve as visual cues. Writing the same letters several times may provide repetitive stimulation of the sensory feedback loops which, in turn, facilitates corticomotor excitation and induced neuroplasticity. Improvement in the speed of writing in the exercise group may be attributed to the effect of sensory feedback on motor learning and plasticity. In addition to the improvement in writing speed, our study demonstrated that the reduction in the UPDRS part III scores was also significantly greater in the exercise group. This is in line with one recent study which showed that progressive cycling exercise could improve both UPDRS part III and MoCA scores, indicating improvement in both motor and cognitive functions [23]. Furthermore, intensive multidisciplinary rehabilitation, including active and passive exercise, treadmill training, hand dexterity training and speech therapy, was demonstrated to improve quality of life in PD patients [24]. This study also provided an indirect evidence of some improvement in the quality of life of the PD patients through the more appreciation in the patient’s subjective rating after the writing exercise. One of the well-recognized handwriting difficulties in PD is micrographia. Progressive micrographia was evident in horizontal but not vertical writing [25]. One hypothesis was that micrographia might be attributed to poor coordination between wrist
5
and finger movements, and wrist extension stiffness. There was also a strong correlation between activity in the posterior putamen on functional MRI and writing size in PD patients, and impaired habitual control was proposed to be a mechanism of micrographia [26]. While the exact mechanisms of micrographia are unclear, handwriting rehabilitation has been found to improve handwriting skills. Ziliotto et al reported a benefit from after a 10-week handwriting rehabilitation training [27]. The recent study of the sixweek intensive writing amplitude training improved amplitude and amplitude variability, and proposed the role of consolidation of motor learning in PD [28]. The handwriting exercise in this study can also serve as one of the rehabilitative approaches to consolidate motor learning and neuroplasticity. While the improvement in size of handwriting cannot be evaluated in the study given the fixed prespecified size of the alphabets in the handwriting exercise book, additional writing parameters such as pressure on a writing surface or amplitude on free writing, can be incorporated in future studies. In the present study, all recruited patients had excellent adherence to protocol including 100% follow-up rate at the outpatient clinic. All subjects in the exercise group had an excellent compliance in performing the handwriting exercise and expressed satisfaction. One of the limitations of this study is that the effects of handwriting exercise may be different in other languages, and future trials in a variety of languages may be required before there are applications to each individual language or generalization. Additionally, we conducted this trial in the tertiary hospital, and the patients might not represent PD patients in the entire Thai population. High level of education in the patients can have a positive impact to the adherence of this relatively intensive writing exercise. 5. Conclusions The current study revealed that the 4-week handwriting exercise with our handwriting practice book appeared to improve writing speed and fine motor function of hands. The optimum duration of the exercise, the frequency of the exercise, the quantity and the characteristic of the letters in the handwriting practice book will need to be studied further to increase the benefit received from the exercise. Sources of support This study was supported by the Ramathibodi Research Fund. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements We thank the patients for taking part in this study, neurology residents for helping in recruiting study participants, and Mr. Jate Jindaroj for helping in designing the handwriting practice form. We acknowledge Miss Fasai Pulkes for English editing. Authors’ contributions NV contributed to data collection, analysis and interpretation, as well as writing of the first draft and manuscript revision. PT contributed to data interpretation and manuscript revision. KT contributed to methods and manuscript revision regarding statistical
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119
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analysis. TP contributed to study design and conceptualization, as well as data interpretation and manuscript revision. All authors read and approve the final manuscript. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.08.119. References [1] Shukla AW, Ounpraseuth S, Okun MS, Gray V, Schwankhaus J, Metzer WS. Micrographia and related deficits in Parkinson’s disease: a cross-sectional study. BMJ Open 2012;2(3). pii: e000628. [2] Ishihara LS, Khaw K-T, Luben R, et al. Self-reported parkinsonian symptoms in the EPIC-Norfolk cohort. BMC Neurol 2005;5:15. [3] Jarzebska E. Evaluation of effectiveness of the micrographia’s therapy in Parkinson’s disease patients. Pol Merkur Lek organ Pol Tow Lek 2006;20 (120):688–90. [4] McLennan JE, Nakano K, Tyler HR, Schwab RS. Micrographia in Parkinson’s disease. J Neurol Sci 1972;15(2):141–52. [5] Tomlinson CL, Patel S, Meek C. Physiotherapy versus placebo or no intervention in Parkinson’s disease. In: Tomlinson CL, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2012. p. CD002817. [6] Nieuwboer A, Rochester L, Müncks L, Swinnen SP. Motor learning in Parkinson’s disease: limitations and potential for rehabilitation. Parkinsonism Relat Disord 2009;15:S53–8. [7] Cassimatis C, Liu KPY, Fahey P, Bissett M. The effectiveness of external sensory cues in improving functional performance in individuals with Parkinson’s disease. Int J Rehabil Res 2016;39(3):211–8. [8] Nieuwboer A, Kwakkel G, Rochester L, et al. Cueing training in the home improves gait-related mobility in Parkinson’s disease: the RESCUE trial. J Neurol Neurosurg Psychiatry 2007;78(2):134–40. [9] Schmidt RA, Motor Lee TD. Control and learning: a behavioral emphasis. Hum Kinet 1999. [10] Oliveira RM, Gurd JM, Nixon P, Marshall JC, Passingham RE. Micrographia in Parkinson’s disease: the effect of providing external cues. J Neurol Neurosurg Psychiatry 1997;63(4):429–33. [11] Bryant MS, Rintala DH, Lai EC, Protas EJ. An investigation of two interventions for micrographia in individuals with Parkinson’s disease. Clin Rehabil 2010;24 (11):1021–6. [12] Spaulding SJ, Barber B, Colby M, Cormack B, Mick T, Jenkins ME. Cueing and gait improvement among people with Parkinson’s disease: a meta-analysis. Arch Phys Med Rehabil 2013;94(3):562–70.
[13] Rocha PA, Porfírio GM, Ferraz HB, Trevisani VFM. Effects of external cues on gait parameters of Parkinson’s disease patients: a systematic review. Clin Neurol Neurosurg 2014;124:127–34. [14] Ridgel AL, Peacock CA, Fickes EJ, Kim CH. Active-assisted cycling improves tremor and bradykinesia in Parkinson’s disease. Arch Phys Med Rehabil 2012;93(11):2049–54. [15] Ridgel AL, Muller MD, Kim CH, Fickes EJ, Mera TO. Acute effects of passive leg cycling on upper extremity tremor and bradykinesia in Parkinson’s disease. Phys Sportsmed. 2011;39(3):83–93. [16] Ridgel AL, Abdar HM, Alberts JL, Discenzo FM, Loparo KA. Variability in cadence during forced cycling predicts motor improvement in individuals with Parkinson’s disease. IEEE Trans Neural Syst Rehabil Eng 2013;21(3):481–9. [17] Chang YJ, Chou CC, Huang WT, Lu CS, Wong AM, Hsu MJ. Cycling regimen induces spinal circuitry plasticity and improves leg muscle coordination in individuals with spinocerebellar ataxia. Arch Phys Med Rehabil 2015;96 (6):1006–13. [18] McGough EL, Robinson CA, Nelson MD, et al. A tandem cycling program: feasibility and physical performance outcomes in people with Parkinson disease. J Neurol Phys Ther. 2016;40(4):223–9. [19] Mohammadi-Abdar H, Ridgel AL, Discenzo FM, Phillips RS, Walter BL, Loparo KA. Test and validation of a smart exercise bike for motor rehabilitation in individuals with Parkinson’s disease. IEEE Trans Neural Syst Rehabil Eng 2016;24(11):1254–64. [20] Nackaerts E, Nieuwboer A, Broeder S, et al. Opposite effects of visual cueing during writing-like movements of different amplitudes in Parkinson’s disease. Neurorehabil Neural Repair 2016;30(5):431–9. [21] Azulay J-P, Mesure S, Amblard B, Blin O, Sangla I, Pouget J. Visual control of locomotion in PD. Brain 1999;122:111–20. [22] Snijders AH, van Kesteren M, Bloem BR. Cycling is less affected than walking in freezers of gait. J Neurol Neurosurg Psychiatry 2011;83(5):575–6. [23] Changa H-C, Lua C-S, Chioub W-D, Chena C-C, Wenga Y-H, Chang Y-J. An 8week low-intensity progressive cycling training improves motor functions in patients with early-stage Parkinson’s disease. J Clin Neurol. 2018;14 (2):225–33. [24] Ferrazzoli D, Ortelli P, Zivi I, et al. Efficacy of intensive multidisciplinary rehabilitation in Parkinson’s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2018;89(8):828–35. [25] Ma H, Hwang W, Chang S, Wang T. Progressive micrographia shown in horizontal, but not vertical, writing in Parkinson’s disease. Behav Neurol 2013;27:169–74. [26] Wu T, Zhang J, Hallett M, Feng T, Hou Y, Chan P. Neural correlates underlying micrographia in Parkinson’s disease. Brain 2016;139(1):144–60. [27] Ziliotto A, Cersosimo MG, Micheli FE. Handwriting rehabilitation in parkinson disease: a pilot study. Ann Rehabil Med 2015;39(4):586–91. [28] Nackaerts E, Heremans E, Vervoort G, et al. Relearning of writing skills in Parkinson’s disease after intensive amplitude training. Mov Disord 2016;31 (8):1209–16.
Please cite this article as: N. Vorasoot, P. Termsarasab, K. Thadanipon et al., Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.119