Brain Stimulation xxx (2015) 1e6
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Original Research
Enhancement of Cortical Excitability and Lower Limb Motor Function in Patients With Stroke by Transcranial Direct Current Stimulation Min Cheol Chang, Dae Yul Kim*, Dae Hwan Park Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul 138-736, Republic of Korea
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Article history: Received 12 September 2014 Received in revised form 25 November 2014 Accepted 23 January 2015 Available online xxx
Background: Motor dysfunction in the lower limbs is a common sequela in stroke patients. Objective: We used transcranial magnetic stimulation (TMS) to determine if applying transcranial direct current stimulation (tDCS) to the primary motor cortex helps enhance cortical excitability. Furthermore, we evaluate if combination anodal tDCS and conventional physical therapy improves motor function in the lower limbs. Methods: Twenty-four patients with early-stage stroke were randomly assigned to 2 groups: 1) the tDCS group, in which patients received 10 sessions of anodal tDCS and conventional physical therapy; and 2) the sham group, in which patients received 10 sessions of sham stimulation and conventional physical therapy. One day before and after intervention, the motor-evoked potential (MEP) of the affected tibialis anterior muscle was evaluated and motor function was assessed using the lower limb subscale of the Fugl-Meyer Assessment (FMA-LE), lower limb Motricity Index (MI-LE), Functional Ambulatory Category (FAC), Berg Balance Scale (BBS), and gait analysis. Results: The MEPs in the tDCS group became shorter in latency and higher in amplitude after intervention in comparison with the sham group. Improvements in FMA-LE and MI-LE were greater in the tDCS group, but no significant differences in FAC or BBS scores were found. Also, the changes observed on the gait analyses did not significantly differ between the tDCS and sham groups. Conclusion: Combination anodal tDCS and conservative physical therapy appears to be a beneficial therapeutic modality for improving motor function in the lower limbs in patients with subacute stroke. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: Transcranial direct current stimulation Stroke Cortical excitability Transcranial magnetic stimulation Motor function Lower limb
Introduction Stroke can cause many types of neurological deficits [1]. Motor dysfunction in the lower limbs is one of the most common disabling sequela that affects stroke patients [2]. Conventional physical Abbreviations: ANCOVA, one-way analysis of covariance; BBS, Berg Balance Scale; CST, corticospinal tract; ET, excitatory threshold; FAC, Functional Ambulatory Category; FMA-LE, Fugl-Meyer Assessment; MEP, motor-evoked potential; MI-LE, lower extremity Motricity Index; TA, tibialis anterior; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation. Authorship: Each author made a substantial contribution to the intellectual content of the manuscript and participated in the work to an extent sufficient to allow that author to assume public responsibility for the content of the manuscript. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (grant no. 2010-0004373). * Corresponding author. Tel.: þ82 2 3010 3800; fax: þ82 2 3010 6964. E-mail address: [email protected] (D.Y. Kim). http://dx.doi.org/10.1016/j.brs.2015.01.411 1935-861X/Ó 2015 Elsevier Inc. All rights reserved.
therapy is applied to rehabilitate most patients with motor dysfunction, including neurodevelopment techniques and taskoriented gait training [3]. Recently, invasive and noninvasive neurostimulation approaches have been developed to modulate the human brain [4e7]. These neurostimulations influence cortical excitability in the brain [8,9] and enhance motor function in stroke patients [10e15]. Therefore, along with conventional rehabilitation, many clinicians have applied various forms of neurostimulation to treat motor dysfunction. Several invasive and noninvasive neurostimulation studies have attempted to modulate cortical excitability in the human brain. Enhanced cortical excitability could induce functional improvements in stroke patients [16e21]. Transcranial direct current stimulation (tDCS) is one recently described noninvasive technique. tDCS continuously applies a low-intensity electrical current between 2 electrodes placed over the scalp [22,23]. Anodal stimulation increases cortical excitability, whereas cathodal stimulation
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decreases it. Functional neuroimaging and transcranial magnetic stimulation (TMS) studies report that tDCS can modulate motor cortex excitability in normal patients [16,18,19]. However, little is known about this topic in stroke patients, and knowledge regarding the mechanisms of motor recovery following tDCS remains limited in stroke patients. In our current TMS study, we report enhanced cortical excitability after applying anodal tDCS over the lower limb primary motor cortex in patients with subacute stroke. We also investigated if this altered excitability is related to improvements in lower limb motor function. Patients and methods Patients We prospectively recruited 24 consecutive stroke patients who were admitted to the Department of Physical Medicine and Rehabilitation at a University Hospital. All patients provided signed informed consent, and the study protocol was approved by the institutional review board of Asan Medical Center. The inclusion criteria included the following: (1) first unilateral ischemic stroke in the cortical or subcortical area; (2) stroke diagnosed within 7e30 days of a cerebral infarct onset; (3) hemiparesis at the time of evaluation; (4) age between 21 and 80 years; and (5) walking without physical assistance. Exclusion criteria included the following: (1) severe somatosensory, apraxia, or cognitive impairments; (2) serious medical complications, such as pneumonia or cardiac problems, from onset to final evaluation; and (3) lesions in the cerebellum or brain stem. Experimental design This study was designed and performed as a prospective, randomized, controlled clinical trial. All patients were randomly assigned to 2 groups: 12 patients in the tDCS group and 12 patients in the sham group. Depending on the assigned group, patients underwent 2 different stimulations: either anodal tDCS or sham stimulation to the affected hemisphere. Both anodal tDCS and the sham stimulations were delivered through 2 saline-soaked sponge surface electrodes using a battery-driven constant current stimulator (Phoresor II Auto; Iomed, Inc., Salt Lake City, UT). Stimulations were delivered while the patient was receiving conventional physical therapy. All patients also received movement therapy for 6 days/week (MondayeFriday: 2.5 h/day; Saturday: 1 h/day), which was primarily administered to improve postural control, motor function, and movement patterns in the affected extremities. The center of the anodal electrode was placed above the tibialis anterior (TA) area of the precentral gyrus in the affected hemisphere. To confirm the exact location of this area, the optimal scalp site for the affected cortex was determined using TMS. TMS was performed using a Magstim 200 stimulator (Magstim Co., Dyfed, UK) with a 9-cm circular coil. A cloth marked with a 1 cm 1 cm grid and
Cz-referenced to the intersection of the midsagittal and interaural lines was placed on the scalp. The excitatory threshold (ET) was defined as the minimum stimulus required to elicit a motor-evoked potential (MEP) with a 50 mV peak-to-peak amplitude in 2 of 4 attempts. The stimulation intensity was set to ET plus 20% when the ET was 80%. In all patients, magnetic stimulation was applied at 100% of the maximum output. MEPs were obtained from the hemiparetic TA muscle. Each site was stimulated 4 times at 1-cm intervals with a minimum of 10 s between stimulations, and the location that demonstrated the shortest latency and largest peak-to-peak amplitude was chosen as the optimal scalp site. We obtained MEPs from the hemiparetic TA muscle in all evaluated patients. The cathode electrode was then placed on the forehead above the contralateral supraorbital area, and the current was run through the brain and other tissues of the head from the anodal to cathodal electrode. The diameter of the anodal electrode was 3 cm (7.07 cm2), and that of the cathodal electrode was 6 cm (28.26 cm2). We used the small anodal electrode to give focal stimulation to underlying cortex. In the tDCS group (conventional therapy þ anodal tDCS), the current was delivered for 10 min at 2 mA, which has been proven as safe by prior studies. The same procedure was used for the sham group, but the current was only delivered for the initial 15 s. For the sham group (conventional therapy þ sham stimulation), the electrodes were maintained so that no participants knew which stimulation they were receiving. Anodal tDCS or sham stimulation was administered once-daily for 2 weeks (MondayeFriday for a total of 10 sessions) to each group (Fig. 1). The experimenters who applied the anodal tDCS or sham stimulations were different from the experimenters who measured the outcomes. The experimenters who determined the results of the MEP data and those who measured physical function were blind to each other’s results. The experiments for assessing MEP were blind to patient information, such as the group assignment and the outcomes of any functional evaluations. Also, the therapists who performed conventional therapy were blind to the group assignment. After completing each stimulation session, the experimenter who applied the interventions asked the patient if they could differentiate the interventions they had received. MEP and functional evaluation The MEP results of the TA and gait analyses, as well as the lower limb subscale of the Fugl-Meyer Assessment (FMA-LE) [24], lower limb Motricity Index (MI-LE) [25], Functional Ambulatory Category (FAC) [26], and Berg Balance Scale (BBS scores) [27], were used to evaluate motor function in the lower limb on the day before the tDCS or sham stimulations were administered (Pre) and 1 day (approximately 24 h) after administering the 10 stimulations (Post) (Fig. 1). MEPs were measured from the site where the center of the anodal tDCS electrode was placed. The site was stimulated 4 times at 10-s intervals, and the MEPs with the shortest latency and largest
Figure 1. Experimental design. Motor-evoked potential in the tibialis anterior, the lower limb subscale of the Fugl-Meyer Assessment, lower limb Motricity Index, Functional Ambulatory Category, Berg Balance Scale scores, and the results of gait analyses were assessed at baseline (Pre) and 1 day after intervention (Post). Patients were randomly assigned to receive anodal transcranial stimulation or sham stimulation. Ten sessions (five 10-min sessions/week for 2 weeks) of anodal transcranial direct current stimulation or sham stimulation were applied during conventional physical therapy.
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peak-to-peak amplitude were used. To measure the latency and amplitude of the MEPs, we identified the hot spot twice (1 day before initiating tDCS sessions and 1 day after finishing the 10 stimulations). The coordinates of the hotspot did not change in any patients. FMA-LE, which is used to evaluate motor function in the affected lower limb, consists of 17 items scored using a 3-point ordinal scale (0e2; maximum score ¼ 34). MI-LE was also used to measure motor function in the lower limbs (maximum score ¼ 100). Walking ability was assessed using FAC, which is based on the level of assistance required during a 15-min walk. The following 6 categories were used in the FAC assessment: 0, nonambulatory; 1, need for continuous support from 1 person; 2, need for intermittent support from 1 person; 3, need for only verbal supervision; 4, help required on stairs and uneven surfaces; and 5, able to walk independently anywhere. BBS was also used, which consists of 14 items that evaluate the patient’s ability to maintain positions of varying difficulty and perform specific tasks such as transferring between positions, reaching forward, and altering stance. Each item is scored from 0 to 4, yielding a total possible score of 56. The reliability and validity of all evaluations are well established. Gait analysis was performed using a motion analysis system (Eagle Digital System; Motion Analysis, Santa Rosa, CA), which consists of 6 Eagle infrared cameras, 2 force plates (Advanced Mechanical Technology Inc., Watertown, MA), an Eagle hub (100 Mbps), and a computer for analysis. Spatiotemporal parameters (e.g., cadence, walking speed, stride length, step time, step length) were obtained by the infrared camera, which recognizes the markers attached to each patient’s body. A total of 19 markers were attached to the patient’s lower body segment, including the pelvis, mid-thighs, knee joint, mid-point of the lower leg, ankle, and foot. Foot markers were placed at the medial and lateral malleolus, midpoint of the heel, and between the second and third metatarsal head. Motion capture, model constructing, and all trials were processed using VICON Nexus 1.4 software (Oxford. Metrics Group, oxford, UK). Data analysis All statistical analyses were performed using SPSS 20.0. The independent t test was used to compare demographic data and the initial results of the MEP and motor function evaluations (FMA-LE, MI-LE, FAC, BBS, and gait analysis) for both the tDCS and sham groups. Changes in motor function and MEP results from the initial evaluations through the follow-up assessment (i.e., after completing the stimulation program) were compared between all patients using the paired t test. Differences in improvement between the tDCS and sham groups were analyzed using one-way analysis of covariance (ANCOVA) with the corresponding baseline measurements as the covariate. We also assessed any significant correlation between changes in the MEP results and motor function in the tDCS group using Spearman’s correlation analysis. Statistical significance was defined as P < 0.05. In addition, the intraclass correlation coefficient (ICC) was used to evaluate the intra- and interobserver reliability of MEP latencies as measured by 2 assessors who were blind to each other’s data. Statistical significance was defined as P < 0.05. MEP latency demonstrated good intraobserver (ICC ¼ 0.96e0.99) and interobserver reliability (ICC ¼ 0.93e0.99). Results This study included 15 men and 9 women. The infarcts were located at the following locations: corona radiata (n ¼ 11), middle cerebral artery territory (n ¼ 7), middle cerebral artery borderzone (n ¼ 4), and internal capsule (n ¼ 2). Of the 24 analyzed patients, 13
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had infarcts in the right hemisphere, and the other 11 patients had infarcts in the left hemisphere. No patients had received physical or occupational therapy before initiating the experiment. As previously mentioned, patients were divided into 2 groups: 12 were allocated to the tDCS group, and 12 were allocated to the sham group. During the experimental sessions, none of the patients knew which type of stimulation they received. The age distribution (mean standard deviation ¼ 62.8 10.6 years; range ¼ 47e79 years) and number of days to the initial evaluation before starting intervention (16.3 5.6 days) were not significantly different between groups (P ¼ 0.180 and 0.807, respectively, according to the independent t test) (Table 1). Moreover, the modified Rankin Scale, National Institutes of Health Stroke Scale, and modified Barthel Index scores determined at the time of the initial evaluation were not significantly different between groups (P ¼ 0.231, 0.327, and 0.761, respectively, according to the independent t test) (Table 1). The initial MEP evaluations of the affected TA, FMA-LE, MI-LE, FAC, BBS, and gait analyses did not significantly differ between groups (P > 0.05 according to the independent t test) (Table 1). The MEPs and all evaluated data related to motor function in all patients significantly improved through the follow-up evaluations (P < 0.05 according to the paired t test) (Table 2). When comparing improvements from the initial evaluation through follow-up, we found that the MEPs became shorter in latency and higher in amplitude in the tDCS group in comparison with the sham group (P ¼ 0.000 for latency and P ¼ 0.048 for amplitude according to ANCOVA) (Table 2). As for improvements in FMA-LE and MI-LE, the improvements in the tDCS group were significantly higher than in the sham group (P ¼ 0.023 and 0.031, respectively, according to ANCOVA) (Table 2). In contrast, no significant differences between groups were found in terms of the FAC and BBS scores during the 2-week intervention period (P ¼ 0.077 and 0.759, respectively, according to ANCOVA) (Table 2). However, the changes in FAC in the tDCS group tended to be higher than in the sham group. The changes observed in the gait analyses were not significantly different between the tDCS and sham groups (P ¼ 0.905 for cadence; P ¼ 0.666 for speed; P ¼ 0.453 for stride length; P ¼ 0.881 for step time; P ¼ 0.492 for step length; all according to ANCOVA) (Table 2).
Table 1 Demographic data according to the stimulation group.
Age, y Lesion side (Rt./Lt.) Mean number of days to the first evaluation mRS NIHSS MBI TMS findings Latency (ms) Amplitude (mV) FMA-LE MI-LE FAC BBS Gait analysis Cadence (steps/min) Speed (m/s) Stride length (m) Step time (s) Step length (m)
tDCS
Sham
P
59.9 10.2 6/6 16.0 6.2
65.8 10.6 7/5 16.6 5.2
0.180 e 0.807
3.08 1.44 6.83 3.53 69.5 15.4
3.66 0.77 8.66 5.26 67.75 12.21
0.231 0.327 0.761
28.90 246.7 30.9 76.8 3.58 44.0
2.66 135.9 2.7 9.7 0.51 7.0
29.88 203.3 28.7 73.9 3.50 39.6
2.19 102.8 3.2 8.6 0.52 7.4
0.335 0.388 0.092 0.448 0.698 0.157
83.9 0.55 0.74 0.766 0.37
20.2 0.31 0.28 0.182 0.13
82.0 0.52 0.73 0.775 0.36
18.8 0.18 0.21 0.237 0.09
0.819 0.819 0.977 0.924 0.850
tDCS, transcranial direct current stimulation; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; MBI, modified Barthel Index; TMS, transcranial magnetic stimulation; FMA-LE, lower limb subscale of Fugl-Meyer Assessment; MI-LE, lower limb Motricity Index; FAC, Functional Ambulatory Category; BBS, Berg Balance Scale. Values are shown as the mean standard deviation.
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Table 2 Changes in motor-evoked potential and motor function according to the stimulation group. Variables
Group
Pre
Post
Difference
TMS Latency (ms) tDCS Sham Total
28.9 2.6 29.8 2.1 29.3 2.4
26.7 1.8 29.0 1.6 27.9 2.0
tDCS Sham Total
246.7 135.9 203.3 102.8 225.0 119.9
933.3 652.4 462.5 238.0 697.9 537.1
591.7 624.5 349.2 344.7 470.4 508.6
tDCS Sham Total
30.9 2.7 28.7 3.2 29.8 3.1
33.5 0.7 31.4 2.1 32.4 1.8
2.5 2.7 2.6 2.5 2.6 2.6
tDCS Sham Total
76.8 9.7 73.9 8.6 75.3 9.1
86.5 6.8 80.5 4.6 83.5 6.4
10.3 11.3 5.9 7.0 8.1 9.5
tDCS Sham Total
3.58 0.51 3.50 0.52 3.54 0.50
4.33 0.49 3.91 0.66 4.12 0.61
0.75 0.45 0.41 0.51 0.58 0.50
tDCS Sham Total
44.0 7.0 39.6 7.4 41.8 7.4
50.1 4.6 48.3 4.6 49.2 4.6
6.1 4.7 8.6 4.2 7.4 4.6
tDCS Sham Total
83.9 20.2 82.0 18.8 82.9 19.1
94.0 17.1 94.0 16.9 94.0 16.6
10.1 18.0 12.0 20.4 11.0 18.9
tDCS Sham Total
0.55 0.31 0.52 0.18 0.53 0.25
0.70 0.25 0.65 0.24 0.68 0.24
0.15 0.26 0.13 0.24 0.14 0.25
tDCS Sham Total
0.74 0.28 0.73 0.21 0.74 0.24
0.88 0.20 0.82 0.21 0.85 0.20
0.14 0.25 0.08 0.20 0.11 0.22
tDCS Sham Total
0.766 0.182 0.775 0.237 0.770 0.207
0.658 0.124 0.666 0.107 0.662 0.113
tDCS Sham Total
0.26 0.01 0.36 0.09 0.36 0.11
0.44 0.10 0.41 0.11 0.42 0.10
Amplitude (mV)
2.1 1.2 0.8 0.9 1.4 1.2
FMA-LE
MI-LE
FAC
BBS
Gait analysis Cadence (steps/min)
Speed (m/s)
Stride length (m)
Step time (sec) 0.108 0.118 0.108 0.231 0.108 0.206
Step length (m) 0.06 0.12 0.04 0.10 0.05 0.11
P 0.000a e e 0.000b 0.048a e e 0.000b 0.023a e e 0.000b 0.031a e e 0.000b 0.077a e e 0.000b 0.759a e e 0.000b 0.905a e e 0.009b 0.666a e e 0.010b 0.453a e e 0.019b 0.881a e e 0.017b 0.492a e e 0.019b
tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation; FMA-LE, lower limb subscale of the Fugl-Meyer Assessment; MI-LE, lower limb Motricity Index; FAC, Functional Ambulatory Category; BBS, Berg Balance Scale. Values represent (mean standard deviation). Figures marked in bold indicate significant results (P < 0.05). a P values determined using ANCOVA and represent differences in the stimulation effects between the tDCS and sham groups. b P values determined using the paired t test and represent changes in data from the initial through the follow-up evaluations in all patients.
Finally, significant correlations were found between changes in motor function (FMA-LE and MI-LE) and MEP in the patients of the tDCS group (rho ¼ 0.672 and P ¼ 0.000 for FMA-LE vs latency; rho ¼ 0.502 and P ¼ 0.012 for FMA-LE vs amplitude; rho ¼ 0.629 and P ¼ 0.001 for MI-LE vs latency; rho ¼ 0.585 and P ¼ 0.003 for MI-LE vs amplitude; all according to Spearman correlation analysis). Discussion In the present study, our aim was to determine if cortical excitability and lower limb motor function improved after applying anodal tDCS to the lower limb primary motor cortex along with conservative therapy during the subacute infarction period. After completing the stimulation program, we observed a shorter latency and higher MEP amplitude in the TA muscle in the tDCS group in comparison with the sham group. These results indicate that cortical excitability was enhanced following anodal tDCS and
conventional physical therapy. Given that cortical excitability reflects neuronal activity, the enhanced excitability that we observed in our patients demonstrates that anodal tDCS stimulation induces neuronal changes in the motor cortex. According to Nitsche et al.’s study [28], increased motor cortical excitability following tDCS is sustained for as long as 90 min after stimulation. On the other hand, in our present study, increased cortical excitability was sustained for approximately 24 h. We believe these different results might have been caused by differences in the recruited patients and follow-up periods. Nitsche et al. enrolled healthy patients and assessed MEP immediately before and after 1 tDCS session, whereas we assessed MEP in subacute stroke patients at 2 weeks after the first MEP evaluation. Administering 10 tDCS sessions and conventional physical therapy for 2 weeks might induce relatively longer changes in cortical excitability. Also, recovery processes actively occur in the brain during the subacute stages of stroke, and thus cortical excitability in patients with subacute stroke can be enhanced during 2 weeks. To further clarify
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the duration that sustains cortical excitability in subacute stroke patients following tDCS, further evaluations using more detailed experimental methods are required. Although the neural mechanisms associated with these changes are not clearly understood, previous studies report that tDCS can either hyperpolarize or depolarize the resting membrane potential and recruit larger neuronal populations [29,30]. This effect is mediated by activating sodium- and calcium-dependent membrane channels and NMDA receptors [29,30]. Additionally, tDCS reportedly enhances brainderived neurotrophic factor secretion and tyrosine receptor kinase B activation, thereby augmenting synaptic plasticity [31]. Therefore, anodal tDCS could have activated these cellular mechanisms and induced neuronal changes in the lower limb primary motor cortices in our patients. TMS is useful for evaluating the state (i.e. fiber number, integrity, and excitability) of the corticospinal tract (CST), which is one of the most important neural tracts involved in motor function in the human brain [32]. Using the characteristics of MEPs, the TMS results can show the amount of CST [33]. We evaluated the MEPs of the CST obtained from the affected TA muscle because the CST is primarily involved in the motor control of the distal limbs (i.e., the ankle) [34]. Our results (i.e., shorter latency and high amplitude of the MEPs) indicate that the amount of CST that innervates the affected TA muscle increases following tDCS. Considering that our results specifically that changes in the latency and amplitude of MEPs after 10 sessions of anodal tDCS are positively correlated with improvements in FMA-LE and MI-LE and the neuronal changes observed following anodal tDCS and conventional physical therapy can be attributed to recovery from motor impairment. In addition, these neuronal changes were maintained for 24 h after finishing the stimulation program. These findings lend considerable support to the idea that tDCS helps promote brain plasticity after cerebral infarction, which aids motor recovery. After the 2-week stimulation program, FMA-LE and MI-LE significantly improved in the tDCS group in comparison with the sham group. However, the improvements in FMA were too small (0.1) to be considered significant. Also, we could not find any differences in the improvements in the FAC or BBS scores, although there was a tendency for these scores to improve more in the tDCS group. Additionally, we found that changes according to the gait analysis did not significantly differ between groups. MI-LE reflects general muscle strength, whereas FAC and BBS reflect gait function and standing balance, respectively. We also noted that the results of gait analysis reflect the patient’s actual gait function. Taken together, our findings suggest that applying anodal tDCS over the affected motor cortex helps recover lower limb motor weakness, but this recovery did not lead to functional recovery. We don’t believe improvement in lower limb motor weakness is enough to recover standing and gait function. So far, many previous studies have reported that tDCS can enhance upper limb motor function in stroke patients [35e38]. Likewise, several recent studies report that tDCS improves lower motor function in stroke patients. In 2011, Madhavan et al. [12] investigated the effectiveness of applying anodal tDCS (one 15-min session at 2 mA) to the lower limb primary motor cortex of the affected hemisphere in 9 patients with chronic stroke (18 months after onset). They found that anodal tDCS stimulation positively influences voluntary control in the paretic ankle. In 2013, Sohn et al. [14] reported that applying anodal tDCS (one 10-min session at 2 mA) to the affected lower limb primary motor cortex in 11 stroke patients enhanced the isometric strength of the affected quadriceps and postural stability. In 2014, Tahtis et al. [15] assessed the effect of bicephalic tDCS (one 15-min session at 2 mA) on gait performance in 14 patients during the subacute stage of stroke (2e8 weeks after onset). In their study,
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the anodal electrode was placed on the scalp over the ipsilesional lower limb primary motor cortex, and the cathode was placed over the contralesional lower limb motor cortex. Patients received either active (7 patients) or sham tDCS (7 patients), and patients who received active stimulation demonstrated better gait performance recovery. In addition, 2 previous studies investigated the relationship between applying tDCS over the leg area of the motor cortex and motor cortex excitability in stroke patients. In 2009, Jayaram et al. [39] reported that applying anodal tDCS (one 10-min session at 2 mA while walking on a treadmill) over the leg area of the motor cortex to 9 chronic stroke patients increased the excitability of CST projection to the TA and medial hamstrings muscles, which was reflected by the increase in the MEP amplitude on TMS. In 2011, Madhavan et al. [12] reported that MEP size increased in all 9 chronic stroke patients after applying tDCS to the primary motor cortex of the affected hemisphere (one 15-min session at 2 mA). However, none of the previous studies were performed during the subacute stage of stroke. Therefore, our current report is the first TMS study to describe enhanced excitability in the lower limb motor cortex after administering tDCS to patients during the subacute stage of stroke. In conclusion, applying anodal tDCS over the lower limb primary motor cortex and conventional physical therapy improves motor cortex excitability and function, but does not affect gait and balance control in patients with subacute stroke. We suggest that tDCS can be successfully used as an adjuvant therapeutic modality to improve motor function in the lower extremities of patients with subacute stroke. However, some limitations to our analyses must be mentioned. First, because we planned to investigate gait function and standing balance, only patients who could independently walk were enrolled in this study. Second, we did not evaluate the longterm effects of tDCS treatment. Lastly, statistical reliability might have been detrimentally affected because several intergroup comparisons were performed. Thus, further studies that address these limitations are required.
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[14] Sohn MK, Jee SJ, Kim YW. Effect of transcranial direct current stimulation on postural stability and lower extremity strength in hemiplegic stroke patients. Ann Rehabil Med 2013;37:759e65. [15] Tahtis V, Kaski D, Seemungal BM. The effect of single session bi-cephalic transcranial direct current stimulation on gait performance in sub-acute stroke: a pilot study. Restor Neurol Neurosci 2014;32:527e32. [16] Jeffery DT, Norton JA, Roy FD, Gorassini MA. Effects of transcranial direct current stimulation on the excitability of the leg motor cortex. Exp Brain Res 2007;182:281e7. [17] Kirton A, Deveber G, Gunraj C, Chen R. Cortical excitability and interhemispheric inhibition after subcortical pediatric stroke: plastic organization and effects of rTMS. Clin Neurophysiol 2010;121:1922e9. [18] Miyaguchi S, Onishi H, Kojima S, et al. Corticomotor excitability induced by anodal transcranial direct current stimulation with and without nonexhaustive movement. Brain Res 2013;1529:83e91. [19] Pellicciari MC, Brignani D, Miniussi C. Excitability modulation of the motor system induced by transcranial direct current stimulation: a multimodal approach. Neuroimage 2013;83:569e80. [20] Romero Lauro LJ, Rosanova M, Mattavelli G, et al. TDCS increases cortical excitability: direct evidence from TMS-EEG. Cortex 2014;58:99e111. [21] Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 2000;123:572e84. [22] Lefaucheur JP. Principles of therapeutic use of transcranial and epidural cortical stimulation. Clin Neurophysiol 2008;119:2179e84. [23] Paulus W. Transcranial direct current stimulation (tDCS). Suppl Clin Neurophysiol 2003;56:249e54. [24] Fugl-Meyer AR, Jääskö L, Leyman I, Olsson S, Steglind S. The post-stroke hemiplegic patient. 1. a method for evaluation of physical performance. Scand J Rehabil Med 1975;7:13e31. [25] Demeurisse G, Demol O, Robaye E. Motor evaluation in vascular hemiplegia. Eur Neurol 1980;19:382e9. [26] Cunha IT, Lim PA, Henson H, et al. Performance-based gait tests for acute stroke patients. Am J Phys Med Rehabil 2002;81:848e56.
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Original Research
Enhancement of Cortical Excitability and Lower Limb Motor Function in Patients With Stroke by Transcranial Direct Current Stimulation Min Cheol Chang, Dae Yul Kim*, Dae Hwan Park Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul 138-736, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 September 2014 Received in revised form 25 November 2014 Accepted 23 January 2015 Available online xxx
Background: Motor dysfunction in the lower limbs is a common sequela in stroke patients. Objective: We used transcranial magnetic stimulation (TMS) to determine if applying transcranial direct current stimulation (tDCS) to the primary motor cortex helps enhance cortical excitability. Furthermore, we evaluate if combination anodal tDCS and conventional physical therapy improves motor function in the lower limbs. Methods: Twenty-four patients with early-stage stroke were randomly assigned to 2 groups: 1) the tDCS group, in which patients received 10 sessions of anodal tDCS and conventional physical therapy; and 2) the sham group, in which patients received 10 sessions of sham stimulation and conventional physical therapy. One day before and after intervention, the motor-evoked potential (MEP) of the affected tibialis anterior muscle was evaluated and motor function was assessed using the lower limb subscale of the Fugl-Meyer Assessment (FMA-LE), lower limb Motricity Index (MI-LE), Functional Ambulatory Category (FAC), Berg Balance Scale (BBS), and gait analysis. Results: The MEPs in the tDCS group became shorter in latency and higher in amplitude after intervention in comparison with the sham group. Improvements in FMA-LE and MI-LE were greater in the tDCS group, but no significant differences in FAC or BBS scores were found. Also, the changes observed on the gait analyses did not significantly differ between the tDCS and sham groups. Conclusion: Combination anodal tDCS and conservative physical therapy appears to be a beneficial therapeutic modality for improving motor function in the lower limbs in patients with subacute stroke. Ó 2015 Elsevier Inc. All rights reserved.
Keywords: Transcranial direct current stimulation Stroke Cortical excitability Transcranial magnetic stimulation Motor function Lower limb
Introduction Stroke can cause many types of neurological deficits [1]. Motor dysfunction in the lower limbs is one of the most common disabling sequela that affects stroke patients [2]. Conventional physical Abbreviations: ANCOVA, one-way analysis of covariance; BBS, Berg Balance Scale; CST, corticospinal tract; ET, excitatory threshold; FAC, Functional Ambulatory Category; FMA-LE, Fugl-Meyer Assessment; MEP, motor-evoked potential; MI-LE, lower extremity Motricity Index; TA, tibialis anterior; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation. Authorship: Each author made a substantial contribution to the intellectual content of the manuscript and participated in the work to an extent sufficient to allow that author to assume public responsibility for the content of the manuscript. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (grant no. 2010-0004373). * Corresponding author. Tel.: þ82 2 3010 3800; fax: þ82 2 3010 6964. E-mail address: [email protected] (D.Y. Kim). http://dx.doi.org/10.1016/j.brs.2015.01.411 1935-861X/Ó 2015 Elsevier Inc. All rights reserved.
therapy is applied to rehabilitate most patients with motor dysfunction, including neurodevelopment techniques and taskoriented gait training [3]. Recently, invasive and noninvasive neurostimulation approaches have been developed to modulate the human brain [4e7]. These neurostimulations influence cortical excitability in the brain [8,9] and enhance motor function in stroke patients [10e15]. Therefore, along with conventional rehabilitation, many clinicians have applied various forms of neurostimulation to treat motor dysfunction. Several invasive and noninvasive neurostimulation studies have attempted to modulate cortical excitability in the human brain. Enhanced cortical excitability could induce functional improvements in stroke patients [16e21]. Transcranial direct current stimulation (tDCS) is one recently described noninvasive technique. tDCS continuously applies a low-intensity electrical current between 2 electrodes placed over the scalp [22,23]. Anodal stimulation increases cortical excitability, whereas cathodal stimulation
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decreases it. Functional neuroimaging and transcranial magnetic stimulation (TMS) studies report that tDCS can modulate motor cortex excitability in normal patients [16,18,19]. However, little is known about this topic in stroke patients, and knowledge regarding the mechanisms of motor recovery following tDCS remains limited in stroke patients. In our current TMS study, we report enhanced cortical excitability after applying anodal tDCS over the lower limb primary motor cortex in patients with subacute stroke. We also investigated if this altered excitability is related to improvements in lower limb motor function. Patients and methods Patients We prospectively recruited 24 consecutive stroke patients who were admitted to the Department of Physical Medicine and Rehabilitation at a University Hospital. All patients provided signed informed consent, and the study protocol was approved by the institutional review board of Asan Medical Center. The inclusion criteria included the following: (1) first unilateral ischemic stroke in the cortical or subcortical area; (2) stroke diagnosed within 7e30 days of a cerebral infarct onset; (3) hemiparesis at the time of evaluation; (4) age between 21 and 80 years; and (5) walking without physical assistance. Exclusion criteria included the following: (1) severe somatosensory, apraxia, or cognitive impairments; (2) serious medical complications, such as pneumonia or cardiac problems, from onset to final evaluation; and (3) lesions in the cerebellum or brain stem. Experimental design This study was designed and performed as a prospective, randomized, controlled clinical trial. All patients were randomly assigned to 2 groups: 12 patients in the tDCS group and 12 patients in the sham group. Depending on the assigned group, patients underwent 2 different stimulations: either anodal tDCS or sham stimulation to the affected hemisphere. Both anodal tDCS and the sham stimulations were delivered through 2 saline-soaked sponge surface electrodes using a battery-driven constant current stimulator (Phoresor II Auto; Iomed, Inc., Salt Lake City, UT). Stimulations were delivered while the patient was receiving conventional physical therapy. All patients also received movement therapy for 6 days/week (MondayeFriday: 2.5 h/day; Saturday: 1 h/day), which was primarily administered to improve postural control, motor function, and movement patterns in the affected extremities. The center of the anodal electrode was placed above the tibialis anterior (TA) area of the precentral gyrus in the affected hemisphere. To confirm the exact location of this area, the optimal scalp site for the affected cortex was determined using TMS. TMS was performed using a Magstim 200 stimulator (Magstim Co., Dyfed, UK) with a 9-cm circular coil. A cloth marked with a 1 cm 1 cm grid and
Cz-referenced to the intersection of the midsagittal and interaural lines was placed on the scalp. The excitatory threshold (ET) was defined as the minimum stimulus required to elicit a motor-evoked potential (MEP) with a 50 mV peak-to-peak amplitude in 2 of 4 attempts. The stimulation intensity was set to ET plus 20% when the ET was 80%. In all patients, magnetic stimulation was applied at 100% of the maximum output. MEPs were obtained from the hemiparetic TA muscle. Each site was stimulated 4 times at 1-cm intervals with a minimum of 10 s between stimulations, and the location that demonstrated the shortest latency and largest peak-to-peak amplitude was chosen as the optimal scalp site. We obtained MEPs from the hemiparetic TA muscle in all evaluated patients. The cathode electrode was then placed on the forehead above the contralateral supraorbital area, and the current was run through the brain and other tissues of the head from the anodal to cathodal electrode. The diameter of the anodal electrode was 3 cm (7.07 cm2), and that of the cathodal electrode was 6 cm (28.26 cm2). We used the small anodal electrode to give focal stimulation to underlying cortex. In the tDCS group (conventional therapy þ anodal tDCS), the current was delivered for 10 min at 2 mA, which has been proven as safe by prior studies. The same procedure was used for the sham group, but the current was only delivered for the initial 15 s. For the sham group (conventional therapy þ sham stimulation), the electrodes were maintained so that no participants knew which stimulation they were receiving. Anodal tDCS or sham stimulation was administered once-daily for 2 weeks (MondayeFriday for a total of 10 sessions) to each group (Fig. 1). The experimenters who applied the anodal tDCS or sham stimulations were different from the experimenters who measured the outcomes. The experimenters who determined the results of the MEP data and those who measured physical function were blind to each other’s results. The experiments for assessing MEP were blind to patient information, such as the group assignment and the outcomes of any functional evaluations. Also, the therapists who performed conventional therapy were blind to the group assignment. After completing each stimulation session, the experimenter who applied the interventions asked the patient if they could differentiate the interventions they had received. MEP and functional evaluation The MEP results of the TA and gait analyses, as well as the lower limb subscale of the Fugl-Meyer Assessment (FMA-LE) [24], lower limb Motricity Index (MI-LE) [25], Functional Ambulatory Category (FAC) [26], and Berg Balance Scale (BBS scores) [27], were used to evaluate motor function in the lower limb on the day before the tDCS or sham stimulations were administered (Pre) and 1 day (approximately 24 h) after administering the 10 stimulations (Post) (Fig. 1). MEPs were measured from the site where the center of the anodal tDCS electrode was placed. The site was stimulated 4 times at 10-s intervals, and the MEPs with the shortest latency and largest
Figure 1. Experimental design. Motor-evoked potential in the tibialis anterior, the lower limb subscale of the Fugl-Meyer Assessment, lower limb Motricity Index, Functional Ambulatory Category, Berg Balance Scale scores, and the results of gait analyses were assessed at baseline (Pre) and 1 day after intervention (Post). Patients were randomly assigned to receive anodal transcranial stimulation or sham stimulation. Ten sessions (five 10-min sessions/week for 2 weeks) of anodal transcranial direct current stimulation or sham stimulation were applied during conventional physical therapy.
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peak-to-peak amplitude were used. To measure the latency and amplitude of the MEPs, we identified the hot spot twice (1 day before initiating tDCS sessions and 1 day after finishing the 10 stimulations). The coordinates of the hotspot did not change in any patients. FMA-LE, which is used to evaluate motor function in the affected lower limb, consists of 17 items scored using a 3-point ordinal scale (0e2; maximum score ¼ 34). MI-LE was also used to measure motor function in the lower limbs (maximum score ¼ 100). Walking ability was assessed using FAC, which is based on the level of assistance required during a 15-min walk. The following 6 categories were used in the FAC assessment: 0, nonambulatory; 1, need for continuous support from 1 person; 2, need for intermittent support from 1 person; 3, need for only verbal supervision; 4, help required on stairs and uneven surfaces; and 5, able to walk independently anywhere. BBS was also used, which consists of 14 items that evaluate the patient’s ability to maintain positions of varying difficulty and perform specific tasks such as transferring between positions, reaching forward, and altering stance. Each item is scored from 0 to 4, yielding a total possible score of 56. The reliability and validity of all evaluations are well established. Gait analysis was performed using a motion analysis system (Eagle Digital System; Motion Analysis, Santa Rosa, CA), which consists of 6 Eagle infrared cameras, 2 force plates (Advanced Mechanical Technology Inc., Watertown, MA), an Eagle hub (100 Mbps), and a computer for analysis. Spatiotemporal parameters (e.g., cadence, walking speed, stride length, step time, step length) were obtained by the infrared camera, which recognizes the markers attached to each patient’s body. A total of 19 markers were attached to the patient’s lower body segment, including the pelvis, mid-thighs, knee joint, mid-point of the lower leg, ankle, and foot. Foot markers were placed at the medial and lateral malleolus, midpoint of the heel, and between the second and third metatarsal head. Motion capture, model constructing, and all trials were processed using VICON Nexus 1.4 software (Oxford. Metrics Group, oxford, UK). Data analysis All statistical analyses were performed using SPSS 20.0. The independent t test was used to compare demographic data and the initial results of the MEP and motor function evaluations (FMA-LE, MI-LE, FAC, BBS, and gait analysis) for both the tDCS and sham groups. Changes in motor function and MEP results from the initial evaluations through the follow-up assessment (i.e., after completing the stimulation program) were compared between all patients using the paired t test. Differences in improvement between the tDCS and sham groups were analyzed using one-way analysis of covariance (ANCOVA) with the corresponding baseline measurements as the covariate. We also assessed any significant correlation between changes in the MEP results and motor function in the tDCS group using Spearman’s correlation analysis. Statistical significance was defined as P < 0.05. In addition, the intraclass correlation coefficient (ICC) was used to evaluate the intra- and interobserver reliability of MEP latencies as measured by 2 assessors who were blind to each other’s data. Statistical significance was defined as P < 0.05. MEP latency demonstrated good intraobserver (ICC ¼ 0.96e0.99) and interobserver reliability (ICC ¼ 0.93e0.99). Results This study included 15 men and 9 women. The infarcts were located at the following locations: corona radiata (n ¼ 11), middle cerebral artery territory (n ¼ 7), middle cerebral artery borderzone (n ¼ 4), and internal capsule (n ¼ 2). Of the 24 analyzed patients, 13
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had infarcts in the right hemisphere, and the other 11 patients had infarcts in the left hemisphere. No patients had received physical or occupational therapy before initiating the experiment. As previously mentioned, patients were divided into 2 groups: 12 were allocated to the tDCS group, and 12 were allocated to the sham group. During the experimental sessions, none of the patients knew which type of stimulation they received. The age distribution (mean standard deviation ¼ 62.8 10.6 years; range ¼ 47e79 years) and number of days to the initial evaluation before starting intervention (16.3 5.6 days) were not significantly different between groups (P ¼ 0.180 and 0.807, respectively, according to the independent t test) (Table 1). Moreover, the modified Rankin Scale, National Institutes of Health Stroke Scale, and modified Barthel Index scores determined at the time of the initial evaluation were not significantly different between groups (P ¼ 0.231, 0.327, and 0.761, respectively, according to the independent t test) (Table 1). The initial MEP evaluations of the affected TA, FMA-LE, MI-LE, FAC, BBS, and gait analyses did not significantly differ between groups (P > 0.05 according to the independent t test) (Table 1). The MEPs and all evaluated data related to motor function in all patients significantly improved through the follow-up evaluations (P < 0.05 according to the paired t test) (Table 2). When comparing improvements from the initial evaluation through follow-up, we found that the MEPs became shorter in latency and higher in amplitude in the tDCS group in comparison with the sham group (P ¼ 0.000 for latency and P ¼ 0.048 for amplitude according to ANCOVA) (Table 2). As for improvements in FMA-LE and MI-LE, the improvements in the tDCS group were significantly higher than in the sham group (P ¼ 0.023 and 0.031, respectively, according to ANCOVA) (Table 2). In contrast, no significant differences between groups were found in terms of the FAC and BBS scores during the 2-week intervention period (P ¼ 0.077 and 0.759, respectively, according to ANCOVA) (Table 2). However, the changes in FAC in the tDCS group tended to be higher than in the sham group. The changes observed in the gait analyses were not significantly different between the tDCS and sham groups (P ¼ 0.905 for cadence; P ¼ 0.666 for speed; P ¼ 0.453 for stride length; P ¼ 0.881 for step time; P ¼ 0.492 for step length; all according to ANCOVA) (Table 2).
Table 1 Demographic data according to the stimulation group.
Age, y Lesion side (Rt./Lt.) Mean number of days to the first evaluation mRS NIHSS MBI TMS findings Latency (ms) Amplitude (mV) FMA-LE MI-LE FAC BBS Gait analysis Cadence (steps/min) Speed (m/s) Stride length (m) Step time (s) Step length (m)
tDCS
Sham
P
59.9 10.2 6/6 16.0 6.2
65.8 10.6 7/5 16.6 5.2
0.180 e 0.807
3.08 1.44 6.83 3.53 69.5 15.4
3.66 0.77 8.66 5.26 67.75 12.21
0.231 0.327 0.761
28.90 246.7 30.9 76.8 3.58 44.0
2.66 135.9 2.7 9.7 0.51 7.0
29.88 203.3 28.7 73.9 3.50 39.6
2.19 102.8 3.2 8.6 0.52 7.4
0.335 0.388 0.092 0.448 0.698 0.157
83.9 0.55 0.74 0.766 0.37
20.2 0.31 0.28 0.182 0.13
82.0 0.52 0.73 0.775 0.36
18.8 0.18 0.21 0.237 0.09
0.819 0.819 0.977 0.924 0.850
tDCS, transcranial direct current stimulation; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; MBI, modified Barthel Index; TMS, transcranial magnetic stimulation; FMA-LE, lower limb subscale of Fugl-Meyer Assessment; MI-LE, lower limb Motricity Index; FAC, Functional Ambulatory Category; BBS, Berg Balance Scale. Values are shown as the mean standard deviation.
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Table 2 Changes in motor-evoked potential and motor function according to the stimulation group. Variables
Group
Pre
Post
Difference
TMS Latency (ms) tDCS Sham Total
28.9 2.6 29.8 2.1 29.3 2.4
26.7 1.8 29.0 1.6 27.9 2.0
tDCS Sham Total
246.7 135.9 203.3 102.8 225.0 119.9
933.3 652.4 462.5 238.0 697.9 537.1
591.7 624.5 349.2 344.7 470.4 508.6
tDCS Sham Total
30.9 2.7 28.7 3.2 29.8 3.1
33.5 0.7 31.4 2.1 32.4 1.8
2.5 2.7 2.6 2.5 2.6 2.6
tDCS Sham Total
76.8 9.7 73.9 8.6 75.3 9.1
86.5 6.8 80.5 4.6 83.5 6.4
10.3 11.3 5.9 7.0 8.1 9.5
tDCS Sham Total
3.58 0.51 3.50 0.52 3.54 0.50
4.33 0.49 3.91 0.66 4.12 0.61
0.75 0.45 0.41 0.51 0.58 0.50
tDCS Sham Total
44.0 7.0 39.6 7.4 41.8 7.4
50.1 4.6 48.3 4.6 49.2 4.6
6.1 4.7 8.6 4.2 7.4 4.6
tDCS Sham Total
83.9 20.2 82.0 18.8 82.9 19.1
94.0 17.1 94.0 16.9 94.0 16.6
10.1 18.0 12.0 20.4 11.0 18.9
tDCS Sham Total
0.55 0.31 0.52 0.18 0.53 0.25
0.70 0.25 0.65 0.24 0.68 0.24
0.15 0.26 0.13 0.24 0.14 0.25
tDCS Sham Total
0.74 0.28 0.73 0.21 0.74 0.24
0.88 0.20 0.82 0.21 0.85 0.20
0.14 0.25 0.08 0.20 0.11 0.22
tDCS Sham Total
0.766 0.182 0.775 0.237 0.770 0.207
0.658 0.124 0.666 0.107 0.662 0.113
tDCS Sham Total
0.26 0.01 0.36 0.09 0.36 0.11
0.44 0.10 0.41 0.11 0.42 0.10
Amplitude (mV)
2.1 1.2 0.8 0.9 1.4 1.2
FMA-LE
MI-LE
FAC
BBS
Gait analysis Cadence (steps/min)
Speed (m/s)
Stride length (m)
Step time (sec) 0.108 0.118 0.108 0.231 0.108 0.206
Step length (m) 0.06 0.12 0.04 0.10 0.05 0.11
P 0.000a e e 0.000b 0.048a e e 0.000b 0.023a e e 0.000b 0.031a e e 0.000b 0.077a e e 0.000b 0.759a e e 0.000b 0.905a e e 0.009b 0.666a e e 0.010b 0.453a e e 0.019b 0.881a e e 0.017b 0.492a e e 0.019b
tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation; FMA-LE, lower limb subscale of the Fugl-Meyer Assessment; MI-LE, lower limb Motricity Index; FAC, Functional Ambulatory Category; BBS, Berg Balance Scale. Values represent (mean standard deviation). Figures marked in bold indicate significant results (P < 0.05). a P values determined using ANCOVA and represent differences in the stimulation effects between the tDCS and sham groups. b P values determined using the paired t test and represent changes in data from the initial through the follow-up evaluations in all patients.
Finally, significant correlations were found between changes in motor function (FMA-LE and MI-LE) and MEP in the patients of the tDCS group (rho ¼ 0.672 and P ¼ 0.000 for FMA-LE vs latency; rho ¼ 0.502 and P ¼ 0.012 for FMA-LE vs amplitude; rho ¼ 0.629 and P ¼ 0.001 for MI-LE vs latency; rho ¼ 0.585 and P ¼ 0.003 for MI-LE vs amplitude; all according to Spearman correlation analysis). Discussion In the present study, our aim was to determine if cortical excitability and lower limb motor function improved after applying anodal tDCS to the lower limb primary motor cortex along with conservative therapy during the subacute infarction period. After completing the stimulation program, we observed a shorter latency and higher MEP amplitude in the TA muscle in the tDCS group in comparison with the sham group. These results indicate that cortical excitability was enhanced following anodal tDCS and
conventional physical therapy. Given that cortical excitability reflects neuronal activity, the enhanced excitability that we observed in our patients demonstrates that anodal tDCS stimulation induces neuronal changes in the motor cortex. According to Nitsche et al.’s study [28], increased motor cortical excitability following tDCS is sustained for as long as 90 min after stimulation. On the other hand, in our present study, increased cortical excitability was sustained for approximately 24 h. We believe these different results might have been caused by differences in the recruited patients and follow-up periods. Nitsche et al. enrolled healthy patients and assessed MEP immediately before and after 1 tDCS session, whereas we assessed MEP in subacute stroke patients at 2 weeks after the first MEP evaluation. Administering 10 tDCS sessions and conventional physical therapy for 2 weeks might induce relatively longer changes in cortical excitability. Also, recovery processes actively occur in the brain during the subacute stages of stroke, and thus cortical excitability in patients with subacute stroke can be enhanced during 2 weeks. To further clarify
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the duration that sustains cortical excitability in subacute stroke patients following tDCS, further evaluations using more detailed experimental methods are required. Although the neural mechanisms associated with these changes are not clearly understood, previous studies report that tDCS can either hyperpolarize or depolarize the resting membrane potential and recruit larger neuronal populations [29,30]. This effect is mediated by activating sodium- and calcium-dependent membrane channels and NMDA receptors [29,30]. Additionally, tDCS reportedly enhances brainderived neurotrophic factor secretion and tyrosine receptor kinase B activation, thereby augmenting synaptic plasticity [31]. Therefore, anodal tDCS could have activated these cellular mechanisms and induced neuronal changes in the lower limb primary motor cortices in our patients. TMS is useful for evaluating the state (i.e. fiber number, integrity, and excitability) of the corticospinal tract (CST), which is one of the most important neural tracts involved in motor function in the human brain [32]. Using the characteristics of MEPs, the TMS results can show the amount of CST [33]. We evaluated the MEPs of the CST obtained from the affected TA muscle because the CST is primarily involved in the motor control of the distal limbs (i.e., the ankle) [34]. Our results (i.e., shorter latency and high amplitude of the MEPs) indicate that the amount of CST that innervates the affected TA muscle increases following tDCS. Considering that our results specifically that changes in the latency and amplitude of MEPs after 10 sessions of anodal tDCS are positively correlated with improvements in FMA-LE and MI-LE and the neuronal changes observed following anodal tDCS and conventional physical therapy can be attributed to recovery from motor impairment. In addition, these neuronal changes were maintained for 24 h after finishing the stimulation program. These findings lend considerable support to the idea that tDCS helps promote brain plasticity after cerebral infarction, which aids motor recovery. After the 2-week stimulation program, FMA-LE and MI-LE significantly improved in the tDCS group in comparison with the sham group. However, the improvements in FMA were too small (0.1) to be considered significant. Also, we could not find any differences in the improvements in the FAC or BBS scores, although there was a tendency for these scores to improve more in the tDCS group. Additionally, we found that changes according to the gait analysis did not significantly differ between groups. MI-LE reflects general muscle strength, whereas FAC and BBS reflect gait function and standing balance, respectively. We also noted that the results of gait analysis reflect the patient’s actual gait function. Taken together, our findings suggest that applying anodal tDCS over the affected motor cortex helps recover lower limb motor weakness, but this recovery did not lead to functional recovery. We don’t believe improvement in lower limb motor weakness is enough to recover standing and gait function. So far, many previous studies have reported that tDCS can enhance upper limb motor function in stroke patients [35e38]. Likewise, several recent studies report that tDCS improves lower motor function in stroke patients. In 2011, Madhavan et al. [12] investigated the effectiveness of applying anodal tDCS (one 15-min session at 2 mA) to the lower limb primary motor cortex of the affected hemisphere in 9 patients with chronic stroke (18 months after onset). They found that anodal tDCS stimulation positively influences voluntary control in the paretic ankle. In 2013, Sohn et al. [14] reported that applying anodal tDCS (one 10-min session at 2 mA) to the affected lower limb primary motor cortex in 11 stroke patients enhanced the isometric strength of the affected quadriceps and postural stability. In 2014, Tahtis et al. [15] assessed the effect of bicephalic tDCS (one 15-min session at 2 mA) on gait performance in 14 patients during the subacute stage of stroke (2e8 weeks after onset). In their study,
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the anodal electrode was placed on the scalp over the ipsilesional lower limb primary motor cortex, and the cathode was placed over the contralesional lower limb motor cortex. Patients received either active (7 patients) or sham tDCS (7 patients), and patients who received active stimulation demonstrated better gait performance recovery. In addition, 2 previous studies investigated the relationship between applying tDCS over the leg area of the motor cortex and motor cortex excitability in stroke patients. In 2009, Jayaram et al. [39] reported that applying anodal tDCS (one 10-min session at 2 mA while walking on a treadmill) over the leg area of the motor cortex to 9 chronic stroke patients increased the excitability of CST projection to the TA and medial hamstrings muscles, which was reflected by the increase in the MEP amplitude on TMS. In 2011, Madhavan et al. [12] reported that MEP size increased in all 9 chronic stroke patients after applying tDCS to the primary motor cortex of the affected hemisphere (one 15-min session at 2 mA). However, none of the previous studies were performed during the subacute stage of stroke. Therefore, our current report is the first TMS study to describe enhanced excitability in the lower limb motor cortex after administering tDCS to patients during the subacute stage of stroke. In conclusion, applying anodal tDCS over the lower limb primary motor cortex and conventional physical therapy improves motor cortex excitability and function, but does not affect gait and balance control in patients with subacute stroke. We suggest that tDCS can be successfully used as an adjuvant therapeutic modality to improve motor function in the lower extremities of patients with subacute stroke. However, some limitations to our analyses must be mentioned. First, because we planned to investigate gait function and standing balance, only patients who could independently walk were enrolled in this study. Second, we did not evaluate the longterm effects of tDCS treatment. Lastly, statistical reliability might have been detrimentally affected because several intergroup comparisons were performed. Thus, further studies that address these limitations are required.
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