Disability and Rehabilitation
ISSN: 0963-8288 (Print) 1464-5165 (Online) Journal homepage: http://www.tandfonline.com/loi/idre20
Combined transcranial direct current stimulation and home-based occupational therapy for upper limb motor impairment following intracerebral hemorrhage: a double-blind randomized controlled trial Jesper Mortensen, Krystian Figlewski & Henning Andersen To cite this article: Jesper Mortensen, Krystian Figlewski & Henning Andersen (2015): Combined transcranial direct current stimulation and home-based occupational therapy for upper limb motor impairment following intracerebral hemorrhage: a double-blind randomized controlled trial, Disability and Rehabilitation To link to this article: http://dx.doi.org/10.3109/09638288.2015.1055379
Published online: 16 Jun 2015.
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Date: 22 September 2015, At: 11:24
http://informahealthcare.com/dre ISSN 0963-8288 print/ISSN 1464-5165 online Disabil Rehabil, Early Online: 1–7 ! 2015 Informa UK Ltd. DOI: 10.3109/09638288.2015.1055379
RESEARCH PAPER
Combined transcranial direct current stimulation and home-based occupational therapy for upper limb motor impairment following intracerebral hemorrhage: a double-blind randomized controlled trial Downloaded by [Stockholm University Library] at 11:24 22 September 2015
Jesper Mortensen1,2, Krystian Figlewski2, and Henning Andersen2,3 1
Department of Public Health, University of Copenhagen, Copenhagen, Denmark, 2Hammel Neurorehabilitation Centre and University Research Clinic, Hammel, Denmark, and 3Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
Abstract
Keywords
Purpose: To investigate the combined effect of transcranial direct current stimulation (tDCS) and home-based occupational therapy on activities of daily living (ADL) and grip strength, in patients with upper limb motor impairment following intracerebral hemorrhage (ICH). Methods: A double-blind randomized controlled trial with one-week follow-up. Patients received five consecutive days of occupational therapy at home, combined with either anodal (n ¼ 8) or sham (n ¼ 7) tDCS. The primary outcome was ADL performance, which was assessed with the Jebsen–Taylor test (JTT). Results: Both groups improved JTT over time (p50.01). The anodal group improved grip strength compared with the sham group from baseline to postassessment (p ¼ 0.025). However, this difference was attenuated at one-week follow-up. There was a non-significant tendency for greater improvement in JTT in the anodal group compared with the sham group, from baseline to post-assessment (p ¼ 0.158). Conclusions: Five consecutive days of tDCS combined with occupational therapy provided greater improvements in grip strength compared with occupational therapy alone. tDCS is a promising add-on intervention regarding training of upper limb motor impairment. It is well tolerated by patients and can easily be applied for home-based training. Larger studies with long-term follow-up are needed to further explore possible effects of tDCS in patients with ICH.
ADL, home-based intervention, motor impairment, occupational therapy, stroke, tDCS, upper limb History Received 13 September 2014 Revised 9 May 2015 Accepted 22 May 2015 Published online 16 June 2015
ä Implications for Rehabilitation
Five consecutive days of tDCS combined with occupational therapy provided greater improvements in grip strength compared with occupational therapy alone. tDCS is well tolerated by patients and can easily be applied for home-based rehabilitation.
Introduction Stroke is one of the leading causes of disability and mortality [1], but due to improved acute therapy, more patients now survive a stroke [2]. This leads to an increasing number of patients with complex rehabilitation needs [2]. The most common disability caused by stroke is motor impairment, which can be regarded as a limitation in muscle control or movement [3,4]. Upper limb impairment affects patients’ participation in everyday life, which may lead to ‘‘learned nonuse’’, in which the affected upper limb is not being used for functional tasks and activities of daily living (ADL) [5]. In recent years, non-invasive brain stimulation modalities such as repetitive transcranial magnetic stimulation (rTMS) [6] and transcranial direct current stimulation (tDCS) [7,8] have been increasingly used as add-on therapy for upper limb motor impairment in patients with stroke. For rehabilitation purposes, Address for correspondence: Jesper Mortensen, Department of Public Health, University of Copenhagen, Gothersgade 160, Copenhagen, Denmark. Tel: +45-35337918. E-mail: [email protected]
tDCS has several advantages compared with rTMS. tDCS is easy to use, it is portable and it is better tolerated by patients [9,10]. tDCS is used to influence cortical excitability by polarization of brain regions [11]. This can be accomplished through various electrode montages [12]; anodal tDCS leads to increased cortical excitability by depolarization of brain regions, whereas cathodal tDCS decreases cortical excitability by hyperpolarization of brain regions. Furthermore, a combination of anodal and cathodal tDCS may be applied with dual tDCS. In general, only mild adverse effects are reported in healthy subjects and patients [13]. The most common adverse effects are transient itching, tingling and burning sensations at the place of the electrodes, headache and general discomfort [13]. A recent Cochrane review [14] reported low-quality evidence for the use of tDCS in combination with, e.g. occupational and physical therapy or robot-assisted training, but conclude that further studies are needed. Among the unanswered questions is the effect of tDCS in patients with intracerebral hemorrhage (ICH), as studies have mainly investigated the effect of tDCS in patients with ischemic stroke [14]. ICH accounts for only about 15% of stroke incidents, but is associated with a poorer prognosis
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than ischemic stroke, due to the severity of injuries [15]. Thus, many patients with ICH still suffer from upper limb impairment after discharge from a rehabilitation hospital [16,17]. To our knowledge, no previous studies have used tDCS as a rehabilitation intervention for home-based training in the chronic phase following stroke. However, a meta-analysis by Marquez et al. [7] has shown that there is a stronger evidence for the use of tDCS in patients with stroke in the chronic phase compared with the subacute phase. Furthermore, with tDCS being portable and easy-to-use, it could be a promising add-on therapy for occupational and physiotherapists in primary health care, for home-based training. The aim of this study was to investigate the combined effect of tDCS and home-based occupational therapy on ADL performance and grip strength, in patients with upper limb motor impairment following ICH.
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Methods Design The study was a double-blind sham-controlled RCT. The trial was approved by The Central Denmark Region Committees on Health Research Ethics (ID 1-10-72-251-13) and registered on clinicaltrials.gov before enrollment (ID NCT01992991). The power calculation was based on a study in which patients had a relative change in JTT following anodal tDCS of 6.80 SD 5.83% and a relative change following sham tDCS of 3.58 SD 5.11% [18]. The power calculation revealed that two groups of eight patients were necessary to achieve a statistical power of 95%, with a twosided significance level of a ¼ 0.05. Study population A total of 168 patients with ICH who had previously been admitted for rehabilitation in the region of Jutland, Denmark, were screened for eligibility in October–November 2013 (Figure 1). The Stroke Impact Scale (SIS) was mailed to 125 patients who met the following criteria. Inclusion: age 18–80 years, 46 months and 55 years from the initial ICH. Exclusion: Traumatic ICH, epilepsy, metal implants in the head, other neurological diseases, cognitive disabilities and residence 4100 km away from the rehabilitation hospital. The Stroke Impact Scale (SIS) questionnaire was applied to identify patients with upper limb impairment and the ability to complete the Jebsen–Taylor test (JTT), which was the primary outcome. A total of 16 patients fulfilled the above-mentioned criteria and gave informed consent. Patients were randomized to receive five consecutive days of occupational therapy combined with either anodal or sham tDCS (Figure 2). A stratified block randomization approach was used to ensure that patients with mild and moderate upper limb impairment were evenly distributed in the two treatment groups. The two strata were based on performance on the Box and Block Test (BBT) [19], which was assessed at a pre-trial assessment. Based on this, eight patients with a BBT score of 34–57 constituted the mild impairment stratum and eight patients with a BBT score of 4–34 constituted the moderate impairment stratum. Because two female patients both scored 34, the younger patient was placed in the moderate impairment stratum, as a younger person would be expected to perform better than an older person. One eligible female patient, who was randomized to sham tDCS, worsened from pre-trial assessment to initiation of the trial and was unable to complete baseline assessment. Thus, 15 patients were assessed at baseline and received the allocated treatment. All patients had suffered a first-ever stroke, except for patient 1, who had an ICH 2 years before the present injury. However, he did not suffer any motor or cognitive impairment from this prior incident. Patients 5,
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12 and 15 received antidepressants during the trial. As shown in Table 1, patients in the two treatment groups did not differ with regard to chosen characteristics. The online software GraphPad proposed by Suresh [20] was used for randomization. A colleague with no information about patients was given a list of numbers 1–8 for each stratum and randomized the 16 patients to the two treatment groups accordingly. The primary investigator then carried out data collection blind to treatment allocation. Treatment allocation was revealed after follow-up assessment of the last patient. tDCS tDCS was applied by an occupational therapist, using a NeuroConn DC-stimulatorÕ (NeuroConn, Ilmenau, Germany) with two salinesoaked electrodes (35 cm2). Primary motor cortex (M1) was localized using the international 10/20 EEG system, in which C3 and C4 correspond to left and right hemispheres of M1 [21]. For both anodal and sham tDCS, the anode was placed on the ipsilesional M1 and the cathode was placed over the contralesional supraorbital region. Anodal tDCS consisted of 20 min of stimulation with a 30-s fade in/fade out sequence. This duration was chosen to improve comparison with related studies [8]. The current was delivered at 1.5 mA, which gave a current density of 0.04 mA/ cm2. Sham tDCS consisted of a 30-s fade in/fade out sequence at the beginning of the session. Patients were asked after the fifth training session whether they thought they had received active or sham tDCS, in order to test if blinding was successful. Occupational therapy Patients received five consecutive days of occupational therapy at their own residence. Training lasted for 30 min and consisted of activity based and functional tasks within each patient’s capabilities. tDCS was delivered concurrent with training for the initial 20 min. The primary investigator supervised task performance and intervened when advice and correction in task performance was useful or required. Many tasks were timed to facilitate competitiveness and desire to improve performance. Patients were allowed small breaks during training sessions to prevent fatigue. During training, patients sat at the same table where they did the JTT. Test instruments The primary outcome was JTT [22], which covers the International Classification of Functioning, Disability and Health domains activity and function. JTT assess speed rather than quality of performance. It has been used in several studies of tDCS for upper limb motor impairment in patients with stroke [18,23–26]. The original version of JTT consists of seven tasks: (1) writing a short sentence, (2) turn over cards, (3) pick up small common objects, (4) pick up small objects with a spoon, (5) stacking checkers, (6) moving light cans and (7) moving heavy cans. As previously suggested, the writing task was not included, because of patients’ inability to complete this task with the impaired hand [18,23–26]. Each task was performed according to standardized written instructions. The mean of three JTT tests was used for assessment at baseline, post-intervention and one-week follow-up, respectively. Each of these assessments was preceded by a familiarization session, in which patients also completed the JTT three times. This number of practice sessions has been shown to be sufficient to reach a stable performance level [27]. The maximum time allowed for completion of each task was 180 s [28]. The Australian version of the JTT was used [29], in which the original subtests are supplemented by assessment of grip strength. Grip strength was measured in
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DOI: 10.3109/09638288.2015.1055379
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Patients with ICH assessed for eligibility (medical records screened), n=168
Epilepsy, n=13 Other comorbid disorders, n=16 Long driving distance, n=14 Mailed Stroke Impact Scale questionnaire, n=125
Did not reply, n=39
Returned questionnaires, n=86
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Refused to participate, n=22
Screened questionnaires, n=64
Patients with no impairment, n=3 Patients with paralysis, n=19 Phone contact with patient, n=42
Refused to participate, n=6 Patients with no impairment, n=9 Patients with paralysis, n=4 Metal implants, n=3 Epilepsy, n=3 Meningitis, n=1 Patients randomized to double-blind intervention, n=16
Anodal tDCS, n=8
Sham tDCS, n=8
Worsened hand function, n=1
Baseline examined, n=8
Baseline examined, n=7
Received treatment, n=8
Received treatment, n=7
Follow-up, n=8
Follow-up, n=7
Figure 1. Study flowchart.
kilogram with a Smedley digital handheld dynamometer. Patients sat on a chair positioned with the shoulder in 0 abduction, elbow in 90 flexion and wrist in 0–30 extension [30]. They were instructed to squeeze the handle as hard as they could for 3 s and relax for 20 s. The mean score of three trials was recorded for grip strength according to standardized written instructions [29].
The SIS version 3.0 is a stroke-specific self-reported health status measure with 60 items [31]. It was designed to assess multidimensional stroke outcomes, including strength (4 items), hand function (5 items), ADL (10 items), mobility (9 items), communication (7 items), emotion (9 items), memory and thinking (7 items) and participation (8 items). Each item is
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rated on a 5-point likert-scale from (1) Could not do it at all to (5) Not difficult at all. An additional question asks the patient to rate stroke recovery on a VAS scale from 0 to 100. The five items regarding hand function were used to screen for upper limb impairment. A hand function score of 25 was categorized as no impairment and a hand function score of 5 was categorized as paralysis. The SIS was chosen as a screening tool because scores on the hand function items are highly correlated with scores on JTT [32].
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Data analyses A between-subject group effect (anodal, sham) was analyzed by comparison of relative change (%) in JTT and grip strength from baseline to post intervention, with Welch’s and Student’s t test respectively. Relative change in grip strength was log-transformed by adding a constant (+5) to correct for negative values [33]. A within-subject time effect (baseline, post-intervention, follow-up) was analyzed with repeated-measure ANOVA in logJTT (seconds) and grip strength (kilogram). Furthermore, group (anodal, sham) by time (baseline, post-intervention, follow-up) interactions in logJTT (seconds) and grip strength were analyzed with repeatedmeasure ANOVA. Mauchley’s sphericity test was used to test for
compound symmetry, and to correct for dependent measures the Greenhouse–Geisser epsilon (") was used if "50.75 and the less conservative Hyund–Feldt epsilon was used if "40.75. Analyses were carried out using the statistical software package STATA v12/IC.
Results At baseline, patients in the anodal group completed JTT in 69.4 SD 28.5 s and patients in the sham group completed JTT in 54.6 SD 17.9 s, p ¼ 0.257. Furthermore, at baseline, patients in the anodal group had a grip strength of 20.8 SD 7.6 kg and patients in the sham group had a grip strength of 27.8 SD 15.3 kg, p ¼ 0.276. All 15 patients who were examined at baseline completed five consecutive days of occupational therapy with concurrent tDCS. As shown in Figure 3(a), there was a tendency for greater improvement in ADL performance in the anodal group compared with the sham group; patients in the anodal group improved 29.3 SD 5.6% in JTT from baseline to post-intervention, and patients in the sham group improved 23.4 SD 9.3%, p ¼ 0.179. From baseline to one-week follow-up, patients in the anodal group improved 30.5 SD 7.1% in JTT and patients in the sham group improved 24.2 SD 12.2%, p ¼ 0.259. As shown in Figure 3(b), there was a
Figure 2. Study protocol.
Table 1. Patient characteristics.
Sex
Months from injury
Dominant hand
Affected hand
Location of ICH
Emergent surgery
SIS, hand function
SIS, strength
SIS, Recovery
BBT
Anodal tDCS 1 69 2 44 3 71 4 65 5 73 6 76 7 56 8 70
M F F F M F M M
41 16 57 18 37 33 09 45
R R R R L R R R
R R L R L L R L
Fossa posterior Basal ganglia Frontal lobe Basal ganglia Thalamus Mesencephalon Thalamus Basal ganglia
Yes No No No No Yes No No
08 14 11 17 13 22 21 24
5 8 6 7 4 7 7 7
60 61 38 65 73 70 50 85
23 43 34 34 30 39 32 47
Sham tDCS 9 10 11 12 13 14 15 16y
47 46 69 61 70 63 59 71
M F M M M M F F
39 43 46 40 12 21 06 21
L L L R R R R R
R R L L R R L L
Basal ganglia Basal ganglia Basal ganglia Mesencephalon Basal ganglia Parietal lobe Basal ganglia Basal ganglia
No No No No No Yes No No
12 10 22 21 17 19 11 06
6 4 8 8 4 5 5 3
60 30 70 80 41 50 40 50
57 30 41 41 28 27 53 04
p ¼ 0.26
p ¼ 0.61
p ¼ 0.78
p ¼ 0.28
p ¼ 1.00
p ¼ 1.00
p ¼ 1.00
p ¼ 0.41
p ¼ 0.26
p ¼ 0.43
Patient
Age
ICH: intracerebral hemorrhage; SIS: Stroke Impact Scale; BBT: Box and Block Test. Continuous data were tested with two-sample t test and categorical data were tested with Fisher’s exact test. yPatient was not included in any analyses because her hand function was too poor at baseline.
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(a)
(b)
Figure 3. (a) Relative change in JTT from baseline to post-intervention. Anodal: n ¼ 8, Sham: n ¼ 7. JTT: Jebsen–Taylor test. Presented as mean ± SD. Positive change represents improvement. (b) Relative change in grip strength from baseline to post-intervention. Anodal: n ¼ 8, Sham: n ¼ 7. Presented as geometric mean (IQR). Positive change represents improvement. *p50.05.
Figure 4. JTT familirization and test sessions at baseline, post-intervention and follow-up. n ¼ 15. JTT: Jebsen–Taylor test; F: familiarization session; T: Test. Data presented as mean ± SD.
Figure 5. Adverse effects of tDCS.
120 Baseline
Post
Follow−up
100 JTT (seconds)
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5
80 60 40 20 0 F1
F2
F3
T1
statistically significant improvement in grip strength in the anodal group compared with the sham group; patients in the anodal group improved 12% IQR(3.7–23.0) in grip strength from baseline to post-intervention, whereas patients in the sham group had a decrease 1.3% IQR(4.4–10.6), p ¼ 0.025. From baseline to one-week follow-up, patients in the anodal group improved 23% IQR(5.0–35.2) in grip strength and patients in the sham group improved 12.2% IQR(4.8–18.1), p ¼ 0.369. Due to a tendency for greater grip strength at baseline in the sham group compared with the anodal group, a covariance analysis was done to investigate whether grip strength at baseline was a confounder on improvement in grip strength from baseline to post-intervention. This analysis showed a crude coefficient of log b: 1.53, 95% CI [0.22; 2.84], p ¼ 0.025 and after adjustment for baseline grip strength, a coefficient of log b: 1.50, 95% CI [0.08; 2.92], p ¼ 0.040. Based on this, baseline grip strength did not confound the group effect on relative change in grip strength. Both the anodal [F(2,14) ¼ 86.48, p ¼ 0.000] and the sham groups [F(2,12) ¼ 24.46, p ¼ 0.002] improved in log JTT over time. The anodal group [F(2,14) ¼ 10.22, p ¼ 0.005] improved grip strength over time, whereas the sham group did not [F(2,12) ¼ 2.51, p ¼ 0.155]. There was no interaction between treatment group and improvement over time, neither for log JTT [F(2,26) ¼ 1.26, p ¼ 0.295] nor grip strength [F(2,26) ¼ 1.09, p ¼ 0.333]. Post-hoc analyses revealed that patients in the moderate impairment stratum and the mild impairment stratum did not differ with regard to improvement following training. The moderate impairment stratum improved 27.3 SD 8.3% in JTT and the mild impairment stratum improved 25.9 SD 8.0%, p ¼ 0.749. In grip strength, the moderate impairment stratum improved 3.9% IQR(1.7–10.6) and in the mild impairment stratum improved 8.5% IQR(1.5–21.3), p ¼ 0.643. In other posthoc analyses, we excluded patient 1 from the anodal group, as he
T2
T3
F1
F2
F3
T1
T3
T3
F1
F2
F3
T1
T2
T3
had suffered a prior ICH. These analyses attenuated group differences in change in JTT with p ¼ 0.249 and attenuated differences in change in grip strength with p ¼ 0.043. However, conclusions did not change. As previously suggested, familiarization sessions in JTT were applied to facilitate that patients had the opportunity to practice before test. As shown in Figure 4, the chosen three familiarization sessions before assessment at baseline, post-intervention and oneweek follow-up were sufficient for patients (across intervention groups) to reach a stable performance level. tDCS was well tolerated by patients with only mild transient adverse effects, such as itching, tingling, burning sensation, headache and sleepiness. These adverse effects were reported in both treatment groups, but were more prominent in the active group, as shown in Figure 5. However, the blinding control revealed that patients were unable to guess treatment allocation. A total of eight patients guessed the right treatment allocation group, but four patients who had received anodal tDCS thought they had received sham tDCS, and three patients who had received sham tDCS thought they had received anodal tDCS, p ¼ 1.00.
Discussion Improved grip strength following active tDCS compared with sham tDCS is in line with a study by Bolognini et al. [26]. In this study, 14 patients with stroke were randomized to dual or sham tDCS, which was given in combination with two weeks of constrained-induced movement therapy [26]. Similar to the results from the present study, Bolognini et al. found improved grip strength in the active-treated group and a slight decrease in the sham group from baseline to post-intervention. The same method for assessment of grip strength was used by taking the mean of three measures, but raw change where reported instead of relative
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change. Another study by Fusco et al. [34] found only borderline significant improvement following active tDCS compared with sham. However, they had conducted a crossover study with anodal, cathodal, dual and sham tDCS in nine patients only. In this study, raw change in grip strength was also reported. Both studies did not provide any information on the dynamometer used for assessment. A large three-armed RCT by Khedr et al. [35] found a non-significant tendency for greater improvement in grip strength following anodal or cathodal tDCS compared with sham tDCS, but in this study a neurologist assessed grip strength manually, using a 5-point likert scale. In general, comparison with these studies should be made with caution as they primarily included patients with ischemic stroke [26,34,35]. Furthermore, studies by Fusco et al. [34] and Khedr et al. [35] included patients in the subacute phase following injury, whereas the present study investigated patients in the chronic phase. In the present study, patients in the sham group may have experienced supraspinal fatigue following five consecutive days of training, which may be a possible explanation for the lack of improvement in grip strength at post assessment [36]. Whereas prolonged facilitation of corticospinal neurons following anodal tDCS may have alleviated possible fatigue [37]. However, the difference in performance could not be detected at one-week follow-up, because of greater improvement in the sham group from post-intervention to one-week follow-up compared with the anodal group. Thus, it is likely that facilitation of corticospinal neurons following anodal tDCS is a transient effect. Baseline grip strength was slightly higher in the sham group compared with the anodal group. However, grip strength at baseline was not a confounder on the effect of relative change in grip strength. Nonetheless, it should be considered that results could be influenced by a regression towards the mean effect. However, there was an uneven distribution of male and female patients in the two treatment groups, which is likely to account for differences in grip strength at baseline, rather than extreme values. Furthermore, the mean of three measures was used to account for individual variance in grip strength. There was only a tendency for greater improvement in ADL performance in the anodal group compared with the sham group. This result differs from previous studies which have used JTT as an outcome, as they have all found significant improvement following active tDCS compared with sham tDCS [18,23–26]. Four of these studies had used a crossover design in 4–10 patients with ischemic stroke [18,23–25] and the fifth study was the aforementioned study by Bolognini et al. [26]. In line with results on grip strength in the present study, three of these studies found no improvement in ADL performance following sham tDCS. As with grip strength, a possible explanation may be due to muscle fatigue in the sham group, which may be alleviated by active tDCS [37]. In the present study, there was a tendency for greater improvement in the anodal group, and the non-significant result may be due to a type-II error caused by the small sample size. Thus, a post-hoc power calculation was carried out, which showed that two groups of 27 patients were necessary to achieve a statistical significant difference between groups, with a power of 80% and a two-sided significance level of a ¼ 0.05. However, it should also be considered that two patients in the anodal group had suffered injuries in infratentorial brain regions, which may account for lack of a statistically significant result in favor of anodal tDCS. tDCS provides a weak current which alters neuronal excitability in cortical regions and surrounding areas [11], and thus patients with impairments following ICH in infratentorial brain regions are perhaps less likely to benefit from tDCS compared with patients who have cortical or subcortical ICH. Based on this, there is a need for studies evaluating the influence of the location of lesions, on the effect of tDCS [11]. Another
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possible explanation for the non-significant result may be that some patients may not have responded to tDCS. Thus, a recently published study showed that approximately 50% of healthy participants had poor or absent response to tDCS, when measured with TMS [38]. Based on this, a limitation in the present study is that TMS or neuroimaging techniques were not used to confirm alterations of cortical excitability, and thus it is unsure whether M1 was sufficiently stimulated. Because most patients no longer had structured training of the impaired hand, learned nonuse had become the natural state in daily living. In general, patients felt that the present training program was a reminder for them to use the impaired hand in ADL. Even minor progress in performance strengthened them in believing that it was still possible to improve motor functions, even several years after an ICH. In addition to benefits from occupational therapy, this study contributes to the pool of evidence, which has shown tDCS as a promising intervention for upper limb motor impairment. tDCS can easily be applied for home-based training by occupational- and physiotherapists, following a practical and theoretical instruction. Furthermore, tDCS was well tolerated by patients in the present study, which is in line with previous reports on adverse effects [13]. All training sessions and performance tests were supervised by the primary investigator, which ensured a high degree of reliability and internal validity in administration. It could be argued that the therapist, who carried out the training, should not apply the performance tests, due to potential bias introduced by observing progress following the respective intervention. However, the main purpose was to investigate whether patients who receive active tDCS would improve more in ADL performance compared with patients who receive sham tDCS. Because performance tests were done blind to treatment allocation, the primary investigator was unbiased during assessments. Furthermore, JTT and assessment of grip strength with a dynamometer are very simple and standardized tests, ensuring that assessment can be made the exact same manner every time. The screening process of eligible patients included only patients who were registered in a clinical database at a specialized neurorehabilitation hospital. Thus, a potential selection bias could be present, as patients with mild impairments would not be referred to this neurorehabilitation hospital. However, patients who are not referred to this hospital are perhaps unlikely to have any noteworthy upper limb impairment 6 months from the primary ICH. Based on this, we consider the external validity of the study to be high.
Implications This study shows that five consecutive days of focused occupational therapy provides effects in ADL performance, which last at one-week follow-up. Furthermore, results support previous findings from studies on patients with ischemic stroke, which have shown tDCS as a promising add-on therapy for training of upper limb motor function. In the present study, anodal tDCS resulted in increased grip strength and a non-significant tendency for greater ADL improvement compared with sham tDCS. tDCS can easily be applied for home-based training by occupationaland physiotherapists in primary care. Also, tDCS is well tolerated by patients and is a suitable intervention for blinded clinical trials. Larger studies investigating the effect of tDCS on motor impairment following ICH are warranted. Additionally, longterm effects and adverse effects following tDCS should be investigated.
Declaration of interest This study was financially supported by the BEVICA foundation.
DOI: 10.3109/09638288.2015.1055379
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21. DaSilva AF, Volz MS, Bikson M, Fregni F. Electrode positioning and montage in transcranial direct current stimulation. J Vis Exp 2011;pii:2744. 22. Jebsen RH, Taylor N, Trieschmann RB. An objective and standardized test of hand function. Arch Phys Med Rehabil 1969; 50:311–19. 23. Hummel F, Celnik P, Giraux P, et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain 2005; 128:490–9. 24. Mahmoudi H, Borhani Haghighi A, Petramfar P, et al. Transcranial direct current stimulation: electrode montage in stroke. Disabil Rehabil 2011;33:1383–8. 25. Boggio PS, Nunes A, Rigonatti SP, et al. Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients. Restor Neurol Neurosci 2007;25: 123–9. 26. Bolognini N, Vallar G, Casati C, et al. Neurophysiological and behavioral effects of tDCS combined with constraint-induced movement therapy in poststroke patients. Neurorehabil Neural Repair 2011;25:819–29. 27. Talelli P, Wallace A, Dileone M, et al. Theta burst stimulation in the rehabilitation of the upper limb: a semirandomized, placebocontrolled trial in chronic stroke patients. Neurorehabil Neural Repair 2013;26:976–87. 28. Carey JR, Durfee WK, Bhatt E, et al. Comparison of finger tracking versus simple movement training via telerehabilitation to alter hand function and cortical reorganization after stroke. Neurorehabil Neural Repair 2007;21:216–32. 29. Agnew P, Maas F. An interim Australian version of the Jebsen test of hand function. Aust J Physiother 1982;28:23–9. 30. Roberts HC, Denison HJ, Martin HJ, et al. A review of the measurement of grip strength in clinical and epidemiological studies: towards a standardised approach. Age Ageing 2011;40: 423–9. 31. Duncan PW, Bode RK, Min Lai S, Perera S. Rasch analysis of a new stroke-specific outcome scale: the stroke impact scale. Arch Phys Med Rehabil 2003;84:950–63. 32. Beebe JA, Lang CE. Relationships and responsiveness of six upper extremity function tests during the first 6 months of recovery after stroke. J Neurol Phys Ther 2010;33: 96–103. 33. McDonald JH. Handbook of biological statistics: data transformations [Internet] Available from: http://udel.edu/mcdonald/ stattransform.html [last accessed 12 May 2014]. 34. Fusco A, De Angelis D, Morone G, et al. The ABC of tDCS: effects of anodal, bilateral and cathodal montages of transcranial direct current stimulation in patients with stroke – a pilot study. Stroke Res Treat 2013;2013:837595. 35. Khedr EM, Shawky OA, El-Hammady DH, et al. Effect of anodal versus cathodal transcranial direct current stimulation on stroke rehabilitation: a pilot randomized controlled trial. Neurorehabil Neural Repair 2013;27:592–601. 36. Gandevia SC. Spinal and supraspinal factors in human muscle fatigue. Physiol Rev 2001;81:1725–89. 37. Cogiamanian F, Marceglia S, Ardolino G, et al. Improved isometric force endurance after transcranial direct current stimulation over the human motor cortical areas. Eur J Neurosci 2007; 26:242–9. 38. Wiethoff S, Hamada M, Rothwell JC. Variability in response to transcranial direct current stimulation of the motor cortex. Brain Stimul 2014;7:468–75.
ISSN: 0963-8288 (Print) 1464-5165 (Online) Journal homepage: http://www.tandfonline.com/loi/idre20
Combined transcranial direct current stimulation and home-based occupational therapy for upper limb motor impairment following intracerebral hemorrhage: a double-blind randomized controlled trial Jesper Mortensen, Krystian Figlewski & Henning Andersen To cite this article: Jesper Mortensen, Krystian Figlewski & Henning Andersen (2015): Combined transcranial direct current stimulation and home-based occupational therapy for upper limb motor impairment following intracerebral hemorrhage: a double-blind randomized controlled trial, Disability and Rehabilitation To link to this article: http://dx.doi.org/10.3109/09638288.2015.1055379
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Date: 22 September 2015, At: 11:24
http://informahealthcare.com/dre ISSN 0963-8288 print/ISSN 1464-5165 online Disabil Rehabil, Early Online: 1–7 ! 2015 Informa UK Ltd. DOI: 10.3109/09638288.2015.1055379
RESEARCH PAPER
Combined transcranial direct current stimulation and home-based occupational therapy for upper limb motor impairment following intracerebral hemorrhage: a double-blind randomized controlled trial Downloaded by [Stockholm University Library] at 11:24 22 September 2015
Jesper Mortensen1,2, Krystian Figlewski2, and Henning Andersen2,3 1
Department of Public Health, University of Copenhagen, Copenhagen, Denmark, 2Hammel Neurorehabilitation Centre and University Research Clinic, Hammel, Denmark, and 3Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
Abstract
Keywords
Purpose: To investigate the combined effect of transcranial direct current stimulation (tDCS) and home-based occupational therapy on activities of daily living (ADL) and grip strength, in patients with upper limb motor impairment following intracerebral hemorrhage (ICH). Methods: A double-blind randomized controlled trial with one-week follow-up. Patients received five consecutive days of occupational therapy at home, combined with either anodal (n ¼ 8) or sham (n ¼ 7) tDCS. The primary outcome was ADL performance, which was assessed with the Jebsen–Taylor test (JTT). Results: Both groups improved JTT over time (p50.01). The anodal group improved grip strength compared with the sham group from baseline to postassessment (p ¼ 0.025). However, this difference was attenuated at one-week follow-up. There was a non-significant tendency for greater improvement in JTT in the anodal group compared with the sham group, from baseline to post-assessment (p ¼ 0.158). Conclusions: Five consecutive days of tDCS combined with occupational therapy provided greater improvements in grip strength compared with occupational therapy alone. tDCS is a promising add-on intervention regarding training of upper limb motor impairment. It is well tolerated by patients and can easily be applied for home-based training. Larger studies with long-term follow-up are needed to further explore possible effects of tDCS in patients with ICH.
ADL, home-based intervention, motor impairment, occupational therapy, stroke, tDCS, upper limb History Received 13 September 2014 Revised 9 May 2015 Accepted 22 May 2015 Published online 16 June 2015
ä Implications for Rehabilitation
Five consecutive days of tDCS combined with occupational therapy provided greater improvements in grip strength compared with occupational therapy alone. tDCS is well tolerated by patients and can easily be applied for home-based rehabilitation.
Introduction Stroke is one of the leading causes of disability and mortality [1], but due to improved acute therapy, more patients now survive a stroke [2]. This leads to an increasing number of patients with complex rehabilitation needs [2]. The most common disability caused by stroke is motor impairment, which can be regarded as a limitation in muscle control or movement [3,4]. Upper limb impairment affects patients’ participation in everyday life, which may lead to ‘‘learned nonuse’’, in which the affected upper limb is not being used for functional tasks and activities of daily living (ADL) [5]. In recent years, non-invasive brain stimulation modalities such as repetitive transcranial magnetic stimulation (rTMS) [6] and transcranial direct current stimulation (tDCS) [7,8] have been increasingly used as add-on therapy for upper limb motor impairment in patients with stroke. For rehabilitation purposes, Address for correspondence: Jesper Mortensen, Department of Public Health, University of Copenhagen, Gothersgade 160, Copenhagen, Denmark. Tel: +45-35337918. E-mail: [email protected]
tDCS has several advantages compared with rTMS. tDCS is easy to use, it is portable and it is better tolerated by patients [9,10]. tDCS is used to influence cortical excitability by polarization of brain regions [11]. This can be accomplished through various electrode montages [12]; anodal tDCS leads to increased cortical excitability by depolarization of brain regions, whereas cathodal tDCS decreases cortical excitability by hyperpolarization of brain regions. Furthermore, a combination of anodal and cathodal tDCS may be applied with dual tDCS. In general, only mild adverse effects are reported in healthy subjects and patients [13]. The most common adverse effects are transient itching, tingling and burning sensations at the place of the electrodes, headache and general discomfort [13]. A recent Cochrane review [14] reported low-quality evidence for the use of tDCS in combination with, e.g. occupational and physical therapy or robot-assisted training, but conclude that further studies are needed. Among the unanswered questions is the effect of tDCS in patients with intracerebral hemorrhage (ICH), as studies have mainly investigated the effect of tDCS in patients with ischemic stroke [14]. ICH accounts for only about 15% of stroke incidents, but is associated with a poorer prognosis
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than ischemic stroke, due to the severity of injuries [15]. Thus, many patients with ICH still suffer from upper limb impairment after discharge from a rehabilitation hospital [16,17]. To our knowledge, no previous studies have used tDCS as a rehabilitation intervention for home-based training in the chronic phase following stroke. However, a meta-analysis by Marquez et al. [7] has shown that there is a stronger evidence for the use of tDCS in patients with stroke in the chronic phase compared with the subacute phase. Furthermore, with tDCS being portable and easy-to-use, it could be a promising add-on therapy for occupational and physiotherapists in primary health care, for home-based training. The aim of this study was to investigate the combined effect of tDCS and home-based occupational therapy on ADL performance and grip strength, in patients with upper limb motor impairment following ICH.
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Methods Design The study was a double-blind sham-controlled RCT. The trial was approved by The Central Denmark Region Committees on Health Research Ethics (ID 1-10-72-251-13) and registered on clinicaltrials.gov before enrollment (ID NCT01992991). The power calculation was based on a study in which patients had a relative change in JTT following anodal tDCS of 6.80 SD 5.83% and a relative change following sham tDCS of 3.58 SD 5.11% [18]. The power calculation revealed that two groups of eight patients were necessary to achieve a statistical power of 95%, with a twosided significance level of a ¼ 0.05. Study population A total of 168 patients with ICH who had previously been admitted for rehabilitation in the region of Jutland, Denmark, were screened for eligibility in October–November 2013 (Figure 1). The Stroke Impact Scale (SIS) was mailed to 125 patients who met the following criteria. Inclusion: age 18–80 years, 46 months and 55 years from the initial ICH. Exclusion: Traumatic ICH, epilepsy, metal implants in the head, other neurological diseases, cognitive disabilities and residence 4100 km away from the rehabilitation hospital. The Stroke Impact Scale (SIS) questionnaire was applied to identify patients with upper limb impairment and the ability to complete the Jebsen–Taylor test (JTT), which was the primary outcome. A total of 16 patients fulfilled the above-mentioned criteria and gave informed consent. Patients were randomized to receive five consecutive days of occupational therapy combined with either anodal or sham tDCS (Figure 2). A stratified block randomization approach was used to ensure that patients with mild and moderate upper limb impairment were evenly distributed in the two treatment groups. The two strata were based on performance on the Box and Block Test (BBT) [19], which was assessed at a pre-trial assessment. Based on this, eight patients with a BBT score of 34–57 constituted the mild impairment stratum and eight patients with a BBT score of 4–34 constituted the moderate impairment stratum. Because two female patients both scored 34, the younger patient was placed in the moderate impairment stratum, as a younger person would be expected to perform better than an older person. One eligible female patient, who was randomized to sham tDCS, worsened from pre-trial assessment to initiation of the trial and was unable to complete baseline assessment. Thus, 15 patients were assessed at baseline and received the allocated treatment. All patients had suffered a first-ever stroke, except for patient 1, who had an ICH 2 years before the present injury. However, he did not suffer any motor or cognitive impairment from this prior incident. Patients 5,
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12 and 15 received antidepressants during the trial. As shown in Table 1, patients in the two treatment groups did not differ with regard to chosen characteristics. The online software GraphPad proposed by Suresh [20] was used for randomization. A colleague with no information about patients was given a list of numbers 1–8 for each stratum and randomized the 16 patients to the two treatment groups accordingly. The primary investigator then carried out data collection blind to treatment allocation. Treatment allocation was revealed after follow-up assessment of the last patient. tDCS tDCS was applied by an occupational therapist, using a NeuroConn DC-stimulatorÕ (NeuroConn, Ilmenau, Germany) with two salinesoaked electrodes (35 cm2). Primary motor cortex (M1) was localized using the international 10/20 EEG system, in which C3 and C4 correspond to left and right hemispheres of M1 [21]. For both anodal and sham tDCS, the anode was placed on the ipsilesional M1 and the cathode was placed over the contralesional supraorbital region. Anodal tDCS consisted of 20 min of stimulation with a 30-s fade in/fade out sequence. This duration was chosen to improve comparison with related studies [8]. The current was delivered at 1.5 mA, which gave a current density of 0.04 mA/ cm2. Sham tDCS consisted of a 30-s fade in/fade out sequence at the beginning of the session. Patients were asked after the fifth training session whether they thought they had received active or sham tDCS, in order to test if blinding was successful. Occupational therapy Patients received five consecutive days of occupational therapy at their own residence. Training lasted for 30 min and consisted of activity based and functional tasks within each patient’s capabilities. tDCS was delivered concurrent with training for the initial 20 min. The primary investigator supervised task performance and intervened when advice and correction in task performance was useful or required. Many tasks were timed to facilitate competitiveness and desire to improve performance. Patients were allowed small breaks during training sessions to prevent fatigue. During training, patients sat at the same table where they did the JTT. Test instruments The primary outcome was JTT [22], which covers the International Classification of Functioning, Disability and Health domains activity and function. JTT assess speed rather than quality of performance. It has been used in several studies of tDCS for upper limb motor impairment in patients with stroke [18,23–26]. The original version of JTT consists of seven tasks: (1) writing a short sentence, (2) turn over cards, (3) pick up small common objects, (4) pick up small objects with a spoon, (5) stacking checkers, (6) moving light cans and (7) moving heavy cans. As previously suggested, the writing task was not included, because of patients’ inability to complete this task with the impaired hand [18,23–26]. Each task was performed according to standardized written instructions. The mean of three JTT tests was used for assessment at baseline, post-intervention and one-week follow-up, respectively. Each of these assessments was preceded by a familiarization session, in which patients also completed the JTT three times. This number of practice sessions has been shown to be sufficient to reach a stable performance level [27]. The maximum time allowed for completion of each task was 180 s [28]. The Australian version of the JTT was used [29], in which the original subtests are supplemented by assessment of grip strength. Grip strength was measured in
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Patients with ICH assessed for eligibility (medical records screened), n=168
Epilepsy, n=13 Other comorbid disorders, n=16 Long driving distance, n=14 Mailed Stroke Impact Scale questionnaire, n=125
Did not reply, n=39
Returned questionnaires, n=86
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Refused to participate, n=22
Screened questionnaires, n=64
Patients with no impairment, n=3 Patients with paralysis, n=19 Phone contact with patient, n=42
Refused to participate, n=6 Patients with no impairment, n=9 Patients with paralysis, n=4 Metal implants, n=3 Epilepsy, n=3 Meningitis, n=1 Patients randomized to double-blind intervention, n=16
Anodal tDCS, n=8
Sham tDCS, n=8
Worsened hand function, n=1
Baseline examined, n=8
Baseline examined, n=7
Received treatment, n=8
Received treatment, n=7
Follow-up, n=8
Follow-up, n=7
Figure 1. Study flowchart.
kilogram with a Smedley digital handheld dynamometer. Patients sat on a chair positioned with the shoulder in 0 abduction, elbow in 90 flexion and wrist in 0–30 extension [30]. They were instructed to squeeze the handle as hard as they could for 3 s and relax for 20 s. The mean score of three trials was recorded for grip strength according to standardized written instructions [29].
The SIS version 3.0 is a stroke-specific self-reported health status measure with 60 items [31]. It was designed to assess multidimensional stroke outcomes, including strength (4 items), hand function (5 items), ADL (10 items), mobility (9 items), communication (7 items), emotion (9 items), memory and thinking (7 items) and participation (8 items). Each item is
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rated on a 5-point likert-scale from (1) Could not do it at all to (5) Not difficult at all. An additional question asks the patient to rate stroke recovery on a VAS scale from 0 to 100. The five items regarding hand function were used to screen for upper limb impairment. A hand function score of 25 was categorized as no impairment and a hand function score of 5 was categorized as paralysis. The SIS was chosen as a screening tool because scores on the hand function items are highly correlated with scores on JTT [32].
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Data analyses A between-subject group effect (anodal, sham) was analyzed by comparison of relative change (%) in JTT and grip strength from baseline to post intervention, with Welch’s and Student’s t test respectively. Relative change in grip strength was log-transformed by adding a constant (+5) to correct for negative values [33]. A within-subject time effect (baseline, post-intervention, follow-up) was analyzed with repeated-measure ANOVA in logJTT (seconds) and grip strength (kilogram). Furthermore, group (anodal, sham) by time (baseline, post-intervention, follow-up) interactions in logJTT (seconds) and grip strength were analyzed with repeatedmeasure ANOVA. Mauchley’s sphericity test was used to test for
compound symmetry, and to correct for dependent measures the Greenhouse–Geisser epsilon (") was used if "50.75 and the less conservative Hyund–Feldt epsilon was used if "40.75. Analyses were carried out using the statistical software package STATA v12/IC.
Results At baseline, patients in the anodal group completed JTT in 69.4 SD 28.5 s and patients in the sham group completed JTT in 54.6 SD 17.9 s, p ¼ 0.257. Furthermore, at baseline, patients in the anodal group had a grip strength of 20.8 SD 7.6 kg and patients in the sham group had a grip strength of 27.8 SD 15.3 kg, p ¼ 0.276. All 15 patients who were examined at baseline completed five consecutive days of occupational therapy with concurrent tDCS. As shown in Figure 3(a), there was a tendency for greater improvement in ADL performance in the anodal group compared with the sham group; patients in the anodal group improved 29.3 SD 5.6% in JTT from baseline to post-intervention, and patients in the sham group improved 23.4 SD 9.3%, p ¼ 0.179. From baseline to one-week follow-up, patients in the anodal group improved 30.5 SD 7.1% in JTT and patients in the sham group improved 24.2 SD 12.2%, p ¼ 0.259. As shown in Figure 3(b), there was a
Figure 2. Study protocol.
Table 1. Patient characteristics.
Sex
Months from injury
Dominant hand
Affected hand
Location of ICH
Emergent surgery
SIS, hand function
SIS, strength
SIS, Recovery
BBT
Anodal tDCS 1 69 2 44 3 71 4 65 5 73 6 76 7 56 8 70
M F F F M F M M
41 16 57 18 37 33 09 45
R R R R L R R R
R R L R L L R L
Fossa posterior Basal ganglia Frontal lobe Basal ganglia Thalamus Mesencephalon Thalamus Basal ganglia
Yes No No No No Yes No No
08 14 11 17 13 22 21 24
5 8 6 7 4 7 7 7
60 61 38 65 73 70 50 85
23 43 34 34 30 39 32 47
Sham tDCS 9 10 11 12 13 14 15 16y
47 46 69 61 70 63 59 71
M F M M M M F F
39 43 46 40 12 21 06 21
L L L R R R R R
R R L L R R L L
Basal ganglia Basal ganglia Basal ganglia Mesencephalon Basal ganglia Parietal lobe Basal ganglia Basal ganglia
No No No No No Yes No No
12 10 22 21 17 19 11 06
6 4 8 8 4 5 5 3
60 30 70 80 41 50 40 50
57 30 41 41 28 27 53 04
p ¼ 0.26
p ¼ 0.61
p ¼ 0.78
p ¼ 0.28
p ¼ 1.00
p ¼ 1.00
p ¼ 1.00
p ¼ 0.41
p ¼ 0.26
p ¼ 0.43
Patient
Age
ICH: intracerebral hemorrhage; SIS: Stroke Impact Scale; BBT: Box and Block Test. Continuous data were tested with two-sample t test and categorical data were tested with Fisher’s exact test. yPatient was not included in any analyses because her hand function was too poor at baseline.
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(a)
(b)
Figure 3. (a) Relative change in JTT from baseline to post-intervention. Anodal: n ¼ 8, Sham: n ¼ 7. JTT: Jebsen–Taylor test. Presented as mean ± SD. Positive change represents improvement. (b) Relative change in grip strength from baseline to post-intervention. Anodal: n ¼ 8, Sham: n ¼ 7. Presented as geometric mean (IQR). Positive change represents improvement. *p50.05.
Figure 4. JTT familirization and test sessions at baseline, post-intervention and follow-up. n ¼ 15. JTT: Jebsen–Taylor test; F: familiarization session; T: Test. Data presented as mean ± SD.
Figure 5. Adverse effects of tDCS.
120 Baseline
Post
Follow−up
100 JTT (seconds)
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80 60 40 20 0 F1
F2
F3
T1
statistically significant improvement in grip strength in the anodal group compared with the sham group; patients in the anodal group improved 12% IQR(3.7–23.0) in grip strength from baseline to post-intervention, whereas patients in the sham group had a decrease 1.3% IQR(4.4–10.6), p ¼ 0.025. From baseline to one-week follow-up, patients in the anodal group improved 23% IQR(5.0–35.2) in grip strength and patients in the sham group improved 12.2% IQR(4.8–18.1), p ¼ 0.369. Due to a tendency for greater grip strength at baseline in the sham group compared with the anodal group, a covariance analysis was done to investigate whether grip strength at baseline was a confounder on improvement in grip strength from baseline to post-intervention. This analysis showed a crude coefficient of log b: 1.53, 95% CI [0.22; 2.84], p ¼ 0.025 and after adjustment for baseline grip strength, a coefficient of log b: 1.50, 95% CI [0.08; 2.92], p ¼ 0.040. Based on this, baseline grip strength did not confound the group effect on relative change in grip strength. Both the anodal [F(2,14) ¼ 86.48, p ¼ 0.000] and the sham groups [F(2,12) ¼ 24.46, p ¼ 0.002] improved in log JTT over time. The anodal group [F(2,14) ¼ 10.22, p ¼ 0.005] improved grip strength over time, whereas the sham group did not [F(2,12) ¼ 2.51, p ¼ 0.155]. There was no interaction between treatment group and improvement over time, neither for log JTT [F(2,26) ¼ 1.26, p ¼ 0.295] nor grip strength [F(2,26) ¼ 1.09, p ¼ 0.333]. Post-hoc analyses revealed that patients in the moderate impairment stratum and the mild impairment stratum did not differ with regard to improvement following training. The moderate impairment stratum improved 27.3 SD 8.3% in JTT and the mild impairment stratum improved 25.9 SD 8.0%, p ¼ 0.749. In grip strength, the moderate impairment stratum improved 3.9% IQR(1.7–10.6) and in the mild impairment stratum improved 8.5% IQR(1.5–21.3), p ¼ 0.643. In other posthoc analyses, we excluded patient 1 from the anodal group, as he
T2
T3
F1
F2
F3
T1
T3
T3
F1
F2
F3
T1
T2
T3
had suffered a prior ICH. These analyses attenuated group differences in change in JTT with p ¼ 0.249 and attenuated differences in change in grip strength with p ¼ 0.043. However, conclusions did not change. As previously suggested, familiarization sessions in JTT were applied to facilitate that patients had the opportunity to practice before test. As shown in Figure 4, the chosen three familiarization sessions before assessment at baseline, post-intervention and oneweek follow-up were sufficient for patients (across intervention groups) to reach a stable performance level. tDCS was well tolerated by patients with only mild transient adverse effects, such as itching, tingling, burning sensation, headache and sleepiness. These adverse effects were reported in both treatment groups, but were more prominent in the active group, as shown in Figure 5. However, the blinding control revealed that patients were unable to guess treatment allocation. A total of eight patients guessed the right treatment allocation group, but four patients who had received anodal tDCS thought they had received sham tDCS, and three patients who had received sham tDCS thought they had received anodal tDCS, p ¼ 1.00.
Discussion Improved grip strength following active tDCS compared with sham tDCS is in line with a study by Bolognini et al. [26]. In this study, 14 patients with stroke were randomized to dual or sham tDCS, which was given in combination with two weeks of constrained-induced movement therapy [26]. Similar to the results from the present study, Bolognini et al. found improved grip strength in the active-treated group and a slight decrease in the sham group from baseline to post-intervention. The same method for assessment of grip strength was used by taking the mean of three measures, but raw change where reported instead of relative
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change. Another study by Fusco et al. [34] found only borderline significant improvement following active tDCS compared with sham. However, they had conducted a crossover study with anodal, cathodal, dual and sham tDCS in nine patients only. In this study, raw change in grip strength was also reported. Both studies did not provide any information on the dynamometer used for assessment. A large three-armed RCT by Khedr et al. [35] found a non-significant tendency for greater improvement in grip strength following anodal or cathodal tDCS compared with sham tDCS, but in this study a neurologist assessed grip strength manually, using a 5-point likert scale. In general, comparison with these studies should be made with caution as they primarily included patients with ischemic stroke [26,34,35]. Furthermore, studies by Fusco et al. [34] and Khedr et al. [35] included patients in the subacute phase following injury, whereas the present study investigated patients in the chronic phase. In the present study, patients in the sham group may have experienced supraspinal fatigue following five consecutive days of training, which may be a possible explanation for the lack of improvement in grip strength at post assessment [36]. Whereas prolonged facilitation of corticospinal neurons following anodal tDCS may have alleviated possible fatigue [37]. However, the difference in performance could not be detected at one-week follow-up, because of greater improvement in the sham group from post-intervention to one-week follow-up compared with the anodal group. Thus, it is likely that facilitation of corticospinal neurons following anodal tDCS is a transient effect. Baseline grip strength was slightly higher in the sham group compared with the anodal group. However, grip strength at baseline was not a confounder on the effect of relative change in grip strength. Nonetheless, it should be considered that results could be influenced by a regression towards the mean effect. However, there was an uneven distribution of male and female patients in the two treatment groups, which is likely to account for differences in grip strength at baseline, rather than extreme values. Furthermore, the mean of three measures was used to account for individual variance in grip strength. There was only a tendency for greater improvement in ADL performance in the anodal group compared with the sham group. This result differs from previous studies which have used JTT as an outcome, as they have all found significant improvement following active tDCS compared with sham tDCS [18,23–26]. Four of these studies had used a crossover design in 4–10 patients with ischemic stroke [18,23–25] and the fifth study was the aforementioned study by Bolognini et al. [26]. In line with results on grip strength in the present study, three of these studies found no improvement in ADL performance following sham tDCS. As with grip strength, a possible explanation may be due to muscle fatigue in the sham group, which may be alleviated by active tDCS [37]. In the present study, there was a tendency for greater improvement in the anodal group, and the non-significant result may be due to a type-II error caused by the small sample size. Thus, a post-hoc power calculation was carried out, which showed that two groups of 27 patients were necessary to achieve a statistical significant difference between groups, with a power of 80% and a two-sided significance level of a ¼ 0.05. However, it should also be considered that two patients in the anodal group had suffered injuries in infratentorial brain regions, which may account for lack of a statistically significant result in favor of anodal tDCS. tDCS provides a weak current which alters neuronal excitability in cortical regions and surrounding areas [11], and thus patients with impairments following ICH in infratentorial brain regions are perhaps less likely to benefit from tDCS compared with patients who have cortical or subcortical ICH. Based on this, there is a need for studies evaluating the influence of the location of lesions, on the effect of tDCS [11]. Another
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possible explanation for the non-significant result may be that some patients may not have responded to tDCS. Thus, a recently published study showed that approximately 50% of healthy participants had poor or absent response to tDCS, when measured with TMS [38]. Based on this, a limitation in the present study is that TMS or neuroimaging techniques were not used to confirm alterations of cortical excitability, and thus it is unsure whether M1 was sufficiently stimulated. Because most patients no longer had structured training of the impaired hand, learned nonuse had become the natural state in daily living. In general, patients felt that the present training program was a reminder for them to use the impaired hand in ADL. Even minor progress in performance strengthened them in believing that it was still possible to improve motor functions, even several years after an ICH. In addition to benefits from occupational therapy, this study contributes to the pool of evidence, which has shown tDCS as a promising intervention for upper limb motor impairment. tDCS can easily be applied for home-based training by occupational- and physiotherapists, following a practical and theoretical instruction. Furthermore, tDCS was well tolerated by patients in the present study, which is in line with previous reports on adverse effects [13]. All training sessions and performance tests were supervised by the primary investigator, which ensured a high degree of reliability and internal validity in administration. It could be argued that the therapist, who carried out the training, should not apply the performance tests, due to potential bias introduced by observing progress following the respective intervention. However, the main purpose was to investigate whether patients who receive active tDCS would improve more in ADL performance compared with patients who receive sham tDCS. Because performance tests were done blind to treatment allocation, the primary investigator was unbiased during assessments. Furthermore, JTT and assessment of grip strength with a dynamometer are very simple and standardized tests, ensuring that assessment can be made the exact same manner every time. The screening process of eligible patients included only patients who were registered in a clinical database at a specialized neurorehabilitation hospital. Thus, a potential selection bias could be present, as patients with mild impairments would not be referred to this neurorehabilitation hospital. However, patients who are not referred to this hospital are perhaps unlikely to have any noteworthy upper limb impairment 6 months from the primary ICH. Based on this, we consider the external validity of the study to be high.
Implications This study shows that five consecutive days of focused occupational therapy provides effects in ADL performance, which last at one-week follow-up. Furthermore, results support previous findings from studies on patients with ischemic stroke, which have shown tDCS as a promising add-on therapy for training of upper limb motor function. In the present study, anodal tDCS resulted in increased grip strength and a non-significant tendency for greater ADL improvement compared with sham tDCS. tDCS can easily be applied for home-based training by occupationaland physiotherapists in primary care. Also, tDCS is well tolerated by patients and is a suitable intervention for blinded clinical trials. Larger studies investigating the effect of tDCS on motor impairment following ICH are warranted. Additionally, longterm effects and adverse effects following tDCS should be investigated.
Declaration of interest This study was financially supported by the BEVICA foundation.
DOI: 10.3109/09638288.2015.1055379
Downloaded by [Stockholm University Library] at 11:24 22 September 2015
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