Academic Editor: Pietro Caliandro
Background: The bimodal balance-recovery model predicts that corticospinal tract (CST) integrity in the affected hemisphere influences the partterns of brain recovery after stroke. Repetitive transcranial magnetic stimulation (rTMS) has been used to promote functional recovery of stroke patients by modulating motor cortical excitability and inducing reorganization of neural networks. This study aimed to explore how to optimize the efficiency of repetitive transcranial magnetic stimulation to promote upper limb functional recovery after stroke according to bimodal balance-recovery model. Methods: 60 patients who met the inclusion criteria were enrolled to high CST integrity group (n = 30) or low CST integrity group (n = 30), and further assigned randomly to receive high-frequency rTMS (HF-rTMS), low-frequency rTMS (LF-rTMS) or sham rTMS in addition to routine rehabilitation, with 10 patients in each group. Outcome measures included Fugl-Meyer scale for upper extremity (FMA-UE), Wolf Motor Function (WMFT) scale and Modified Barthel Index (MBI) scale which were evaluated at baseline and after 21 days of treatment. Results: For patients with high CST integrity, the LF group achieved higher FMA-UE, WMFT and MBI scores improvements after treatment when compared to the HF group and sham group. For patients with low CST integrity, after 21 days treatment, only the HF group showed significant improvements in FMA-UE and WMFT scores. For MBI assessment, the HF group revealed significantly better improvements than the LF group and sham group. Conclusions: For stroke patients with high CST integrity, low-frequency rTMS is superior to high-frequency rTMS in promoting upper limb motor function recovery. However, only high-frequency rTMS can improve upper limb motor function of stroke patients with low CST integrity.
Motor deficits is one of the most common and serious disabling sequelae of stroke [1]. Approximately 80% of stroke survivors suffer from upper limb dyskinesias, with particular influences on manual dexterity and coordination [2]. These restrictions can reduce patients self-care capability and result in decreased living ability and quality of life [3].
In recent years, there have been many new intervention methods in upper limb motor function recovery of patients with stroke [4]. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive neurostimulation technique, can alter the plasticity of cortex and modify synaptic excitability through magnetic field [5]. It causes an motor-evoked potential generated to peripheral neurons and target muscles through the corticospinal tract (CST), which is a new direction for the motor functional recovery of stroke patients [6].
The classic stimulation scheme of rTMS in clinical practice is based on the theory of interhemispheric competition model, which through applying low frequency stimulation to suppress the motor cortex of the unaffected hemisphere or high frequency stimulation to improve the cortical excitability of the affected hemisphere to promote motor recovery of stroke patients [7]. However, this theory is not applicable to all patients, especially for those with severe motor deficits. Theilig et al. [8] reported that low-frequency rTMS stimulation over M1 of the contralesional hemisphere could not improve patients’ severely impaired motor function, while another study applied high-frequency rTMS on contralesional M1 of patients with severe hemiplegia and found noteworthy motor function recovery, which was explained through improving contralesional cortical function to achieve compensatory effect [9].
At present, the scholars proposed bimodal balance-recovery model which considered the integrity of corticospinal tract determined interhemispheric imbalance or contralateral compensation was more dominant [10]. This suggested that the selection of rTMS protocol for motor dysfunction after stroke could be made according to the integrity of CST. The CST is a major neural pathway regulating voluntary movement, its structural integrity affects the prognosis of limb motor function and the hemispheric activation pattern of stroke patients [11]. Diffusion tensor imaging (DTI) is a MRI modelling technique used to evaluate integrity of the white matter tracts [12], and intuitively show the spatial relationship between the lesions and corticospinal tract [13]. The magnitude and directionality of anisotropic diffusion yields DTI metrics of tract integrity such as fractional anisotropy (FA). In this study, we firstly compared the mean FA of the CST within the ipsilesional and the contralesional hemisphere, termed relative FA (rFA), to divided the patients into high CST integrity group or low CST integrity group. Different rTMS intervention were then peformed over the unaffected motor cortex of the stroke patients. The aim of current study was to investigate the influence of corticospinal tract integrity on upper limb motor function recovery of stroke patients, which would provide guidance for clinical application of repetitive transcranial magnetic stimulation.
Patients were recruited for the study between January 2020 to January 2021 from the inpatients of Department of Rehabilitation Medicine, the Affiliated Hospital of Qingdao University. Inclusion criteria included: (1) First-ever unilateral ischemic or hemorrhagic stroke documented by computed tomography (CT) or magnetic resonance imaging (MRI) within 2 weeks to 3 months; (2) Patients in a stable condition with clear consciousness, who can complete all examinations and treatments; (3) Age 30–80 years; (4) unilateral upper limb motor deficits. Exclusion criteria included: (1) metal implants in the brain or use of a pacemaker; (2) history of seizures; (3) severe aphasia or cognitive impairment; (4) apply drugs that alter cortical excitability; (5) associated severe medical complication.
DTI was obtained before grouping using a
TRIO 3.0T magnetic resonance imaging system (Siemens, Germany). A total of 60
contiguous slices (slice thickness = 2.3 mm) was acquired through applying the 32
noncollinear diffusion sensitizing gradients (matrix = 256
Example of patient with high CST integrity: A 47-year-old female. (A) DWI showed an infarct in the right corona-radiating. (B) FA map, arrow showing compression and thinning of CST on the right. (C) DTT diagram, arrow showing a reduction in the number of CST fibers at the right (rFA = 0.73).
Example of patient with low CST integrity: A 61-year-old female. (A) DWI showed an infarct in the right basal ganglia. (B) FA map, arrow showing the thinning of CST on the right. (C) DTT diagram, arrow showing sparse and interrupted CST fibers at the right (rFA = 0.15).
DTI examination was performed before treatment for all enrolled subjects.
According
to corticospinal tract integrity, the
patients were allocated into either the high CST integrity group (rFA
The following outcomes of enrolled patients were evaluated at baseline and post-interventions. All assessments were performed by the same therapist blinded to the randomization.
Upper-limb motor functions were evaluated with FMA-UE, which included 33 items such as shoulder, elbow, wrist and finger coordination and separation movement, with 0~2 points for each item and a maximum of 66 points. A higher score indicated a better motor function of upper-limb [19].
WMFT consisted of 17 items, which included 15 function-based tasks and 2 strength-based tasks with 0~5 points for each item and a total of 85 points. A higher score implied a better functioning level [20].
MBI was mainly used to evaluate the ability of daily life activities based on the patient’s actual daily performance. This scale includes 11 items, such as eating, bathing, grooming and dressing, etc., and each item is scored at 5 levels with a full score of 100. A higher score indicated a better ability of daily life activities [21].
The patients in all the 6 groups received routine rehabilitation treatment aimed at restoring upper limb motor functions. All treatment sessions were individually designed according to patients’ moter function of the affected upper limb and performed based on Bobath principles. The exercise protocols included shoulder flexion-extension, abduction-adduction, internal-external rotation, elbow flexion-extension, forearm pronation-supination, hand-digit motion. The treatment was performed by experienced therapists 25 mins twice a day, for 21 days.
Transcranial magnetic stimulation (TMS) was conducted using a 7-cm Magnetic
Stimulator (figure-8 circular coil,
Yiruide, Wuhan, China) positioned tangentially to the surface of patient’s skull.
The rTMS was conducted to stimulate the area over the primary motor cortex (M1)
of the unaffected hemisphere [22]. The resting motor threshold (RMT) was defined
as the minimum stimulus intensity that produced a motor evoked potential (MEP)
response of at least 50
Each patient received rTMS daily for 21 days. Patients in the
HF group were treated as follows: 5 Hz stimulation for 2 s per
session, intertrain interval 8 s, with pulses at
90% RMT over M1 of the unaffect hemisphere
for a total of 18 mins. For the LF group, patients receiced rTMS as follows: 1 Hz
stimulation for 15 s, intertrain interval 2 s, with pulses at 90% RMT over M1 of
the unaffect hemisphere for a total of 18 mins. The sham group received rTMS with
the same parameters (noise, time, and frequency) as the 1 Hz rTMS group
over the unaffected hemisphere but with the
coil rotated 90
At the baseline assessment,
the mean values among the three groups were compared by either a one-way ANOVA
for continuous data or chi-squared test for categorical data. Paired
t-tests were used for intra-group comparisons before and after
treatment. Inter-group comparisons after treatment were conducted using one-way
ANOVA, Bonferroni correction was applied for post hoc tests. A value of p
60 patients who met the inclusion criteria were enrolled to high CST intergerity group (n = 30) or low CST integrity group (n = 30), and further divided randomly into the high frequency group (HF group), the low frequency group (LF group), and the sham group with 10 patients in each group. 2 patients were unable to tolerate the pain caused by rTMS and requested to withdraw, The remaining 58 patients completed this study and were included in the final analyses. The patients flowchart was shown in Fig. 3. There were no significant differences among the groups in their baseline demographic and clinical characteristics (Tables 1,2).
The patients flowchart.
Group | HF Group (n = 9) | LF Group (n = 10) | Sham Group (n = 10) |
Gender | |||
Male | 6 | 6 | 6 |
Female | 3 | 4 | 4 |
Age (years) ( |
55.89 |
55.00 |
55.40 |
Time from stroke to recruitment (weeks) ( |
8.11 |
8.80 |
8.00 |
Type of the stroke | |||
hemorrhagic | 3 | 3 | 4 |
ischemic | 6 | 7 | 6 |
Stroke location | |||
cortical | 2 | 3 | 2 |
subcortical | 5 | 5 | 6 |
brain stem | 2 | 2 | 2 |
rFA | 0.70 |
0.73 |
0.75 |
FMA-UE score | 29.33 |
29.10 |
30.10 |
WMFT score | 34.33 |
34.20 |
35.10 |
MBI score | 63.33 |
63.50 |
63.50 |
Group | HF Group (n = 10) | LF Group (n = 9) | Sham Group (n = 10) |
Gender | |||
Male | 6 | 6 | 5 |
Female | 4 | 3 | 5 |
Age (years) ( |
56.40 |
55.78 |
56.30 |
Time from stroke to recruitment (weeks) ( |
8.20 |
8.33 |
8.10 |
Type of the stroke | |||
hemorrhagic | 4 | 3 | 5 |
ischemic | 6 | 6 | 5 |
Stroke location | |||
cortical | 2 | 2 | 2 |
subcortical | 6 | 5 | 6 |
brain stem | 2 | 2 | 2 |
rFA | 0.33 |
0.30 |
0.29 |
FMA-UW | 8.70 |
8.56 |
8.72 |
WMFT | 11.70 |
11.33 |
11.70 |
MBI | 39.00 |
40.00 |
39.00 |
Changes in FMA-UE, WMFT, and MBI scores at baseline and post-treatment in each group of patients with high CST integrity and with low CST integrity were presented in Fig. 4 and Fig. 5 separately.
Changes in
FMA-UE, WMFT, and MBI scores at baseline and post-treatment in each group of
patients with high CST integrity. FMA-UE, Fugl-Meyer scale for Upper Extremity;
WMFT, Wolf Motor Function Test; MBI, Modified Barthel Index; HF group, high
frequency rTMS group; LF group, low frequency rTMS
group; *: p
Changes in FMA-UE, WMFT,
and MBI scores at baseline and post-treatment in each group of patients with low
CST integrity. FMA-UE, Fugl-Meyer scale for Upper Extremity; WMFT, Wolf Motor
Function Test; MBI, Modified Barthel Index; HF group, high frequency rTMS group;
LF group, low frequency rTMS group; *: p
For patients with high CST, all three groups
showed significant improvements in FMA-UE scores after 21 days treatments (all
p
With regard to patients
with high CST, the WMFT scores increased
significantly from baseline to post-treatment for
all three groups (all
p
Similar results were recorded in MBI scores of patients with high CST. After 21
days treatment, MBI scores in all three groups were significantly improved
compared with pre-treatment (all p
There were no severe adverse reactions such as seizures or recurrent stroke happened during all treatments. Only one patients in the HF-rTMS group experienced dizziness at the first few sessions of stimulation. No special treatment was performed, the symptom disappeared soon after intervention.
The recovery of motor function of patients with stroke is associated with cortical reorganization and synaptic plasticity. Both hemispheres participate in the recovery processes, which are highly active during the first few months after stroke [24]. The corticospinal tract is the most important voluntary motor conduction pathway, and its structural and functional integrity can predict the potential for motor recovery after stroke [25, 26]. Meanwhile, the reorganization of motor function after stroke is associated with the integrity of the imparied corticospinal tract. Therefore, this study took the integrity of the corticospinal tract as the target to explore its impact on the neural regulation mechanisms of rTMS.
Current studies suggested that rTMS could promote motor-function recovery in
stroke patients through regulation of cortical excitability and interhemispheric
interactions. Stimulation frequency
Our findings showed that, for patients with high CST integrity, LF-rTMS was superior to HF-rTMS and sham stimulation in upper limb motor rehabilitation after stroke. Inhibition of hyperexcitability of the contralesional hemisphere through performing low-frequency rTMS to restore the interhemispheric balance could promote the recovery of motor function. For patients with low CST integrity, the application of HF-rTMS to the contralesional hemisphere improved motor functionin patients with severe hemiplegia. It could be explained that when severe unliateral damage hemisphere happened, the residual neurons may insufficient to compensate for the lost function, in this condition the functional recovery was dominated by contralateral hemisphere. For thoses patients with severe unilateral injury, lost functions are partly relocalized in the unaffected side [28, 29]. The remodeling and reorganization of brain function involved all the surviving neurons of bilateral hemispheres. It was considered that in the case of unilateral brain is severely damaged, unlike the previous HF-rTMS excitation of the affected cortex or the LF-rTMS suppression of the intact side, the high frequency stimulation of contralateral brain could improve its compensation function to help restore the impairment. Suppressing the activity of the contralesional hemisphere with LF-rTMS may not beneficial for patients with low CST integrity. The role of the contralateral hemisphere in stroke recovery are double-sided. In addition to interhemispheric inhibition, the contralateral hemisphere also has compensatory potential. Based on the results of our study, we considered that the leading role in the process of recovery was associated with lateral corticospinal tract integrity. That is, for patients with high CST integrity, inhibition of hyperexcitability of the contralesional hemisphere with low-frequency rTMS to restore the interhemispholar balance could promote the recovery of motor function. For patients with low CST integrity, through exciting the affected cortex with HF-rTMS can promote hemiplegia recovery after stroke.
After the occurrence of stroke, different kinds of changes happened at cellular and neural network levels. Previous animal studies reported that axonal extension and sprouting in the CST play a significant role throughout the whole recovery process [30, 31]. The recrossing of the corticospinal axon projecting from the contralesional hemisphere to the ipsilesional spinal cord which innervate fore-limb or more caudal body part and corticospinal neurons originally innervating the ipsilesional body part acquire the output to the contralesional body part. These results suggested that axonal remodeling of the CST in the contralateral hemisphere could be an important mechanism for the recovery of upper limb motor function after stroke.
The connectivity of neural functional network is extensive and complex [32]. Post-stroke neurological recovery included cortical and subcortical functional reorganization, which was affected by a variety of factors. Studies have shown that the vestibular spinal tract and reticular spinal tract can replace the corticospinal tract in the recovery of lower limb motor function after stroke, but their roles in the recovery of upper limb motor function remain to be further explored. To our knowledge, this is the first first study that explore the influence of the CST integrity on the therapeutic effect of rTMS on upper limb moter function recovery. For future study, it is necessary to increase sample size and follow up period combined with functional MRI to provide more objective and reliable evidence.
For stroke patients with high CST integrity, low-frequency rTMS is superior to high-frequency rTMS in promoting upper limb motor function recovery. However, only high-frequency rTMS can improve upper limb motor function of stroke patients with low CST integrity.
CST, corticospinal tract; R-TMS, repetitive transcranial magnetic stimulation; DTI, Diffusion tensor imaging; DTT, Diffusion tensor tractography; CT, computed tomography; MRI, magnetic resonance imaging; ROI, region of interest; FA, fractional anisotropy; RFA, relative FA; FMA-UE, Fugl-Meyer Assessment-Upper Extremity; WMFT, Wolf Motor FunctionTest; MBI, Modified BarthelIndex; RMT, resting motor threshold; MEP, motor evoked potential.
These should be presented as follows: LW and QXZ designed the research study. LW, QXZ, MHZ, RZZ, XQL performed the research. NST, XCF provided help and advice on the study. CFG, MHZ analyzed the data. LW, CFG wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
All participants signed a written informed consent before-hand, which abided by Helsinki Declaration, and all research activities were authorized by the Affiliated Hospital of Qingdao University. The study was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University (QYFYWZLL26418) and registered in the Chinese Clinical Trial Registry (ChiCTR2100043590).
Thanks to the assistance of all the peer reviewers for their opinions and suggestions.
This research was funded by Youth Scientific Research Fund Project of the Affiliated Hospital of Qingdao University (NO.3471) and Shandong Provincial Natural Science Foundation (ZR2021QH062).
The authors declare no conflict of interest.