Low frequency transcranial magnetic stimulation in subacute ischemic stroke: Number of sessions that altered cortical excitability

Abstract

BACKGROUND:

Cortical reorganization between both cerebral hemispheres plays an important role in regaining the affected upper extremity motor function post-stroke.

OBJECTIVES:

The purpose of the current study was to investigate the recommended number of contra-lesion low frequency repetitive transcranial magnetic stimulation (LF-rTMS) sessions that could enhance cortical reorganization post-stroke.

METHODS:

Forty patients with right hemiparetic subacute ischemic stroke with an age range between 50–65 yrs were randomly assigned into two equal groups: control (GA) and study (GB) groups. Both groups were treated with a selected physical therapy program for the upper limb. Sham and real contra-lesion LF-rTMS was conducted for both groups daily for two consecutive weeks. Sequential changes of cortical excitability were calculated by the end of each session.

RESULTS:

The significant enhancement in the cortical excitability was observed at the fourth session in favor of the study group (GB). Sequential rate of change in cortical excitability was significant for the first eight sessions. From the ninth session onwards, no difference could be detected between groups.

CONCLUSION:

The pattern of recovery after stroke is extensive and not all factors could be controlled. Application of LF-rTMS in conjugation with a selected physical therapy program for the upper limb from four to eight sessions seems to be efficient.

Keywords

Cortical excitability cortical reorganization sequential changes single pulse TMS transcranial magnetic stimulation upper limb motor performance.

1 Introduction

Stroke is considered as the third leading cause of death in the world. The Middle East and North Africa region face a double burden of the disease, with projections that deaths by stroke will nearly double by 2030 (EL Tallawy et al., 2015 and Tran et al., 2010). Stroke has high rates of long term disability; the concept of stroke rehabilitation is poorly understood in developing countries. Although physiotherapy and neurophysiological rehabilitation units exist in most hospitals, there is an obvious shortage of multidisciplinary progressive goal-oriented rehabilitation programs. Because of this, monetary load and costs of disability are placed on the patients, care givers and family members (Abd-allah and Moustafa, 2014).

Upper limb motor dysfunction after stroke is a very common and significant disability that affects daily living (Hatem etal., 2016). It is a direct consequence of the lack of signal transmission from the motor cortex, which generates the movement impulse, to the spinal cord that executes the movement via signals to muscles. This results in delayed initiation and termination of muscle contraction, and slowness in developing forces, manifested as an inability to move (quickly) with negative functional consequences (Lang et al., 2013 and Raghavan, 2015).

Conventional therapies for motor recovery after stroke are still not satisfactory. It was claimed that upper limb motor recovery after stroke is enabled by reorganization of neural circuits (Volz et al., 2016 and Kubis, 2016). Post-stroke there are substantial modulations that occur in the cortical reorganization, where the injured ischemic motor cortex has a reduced cortical excitability, while the contralateral motor cortex has an increased excitability. This abnormal cortical interhemispheric balance contributes to the worsening of the neurological deficit (Edwardson et al., 2013 and Auriat et al., 2015).

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation that induces electrical currents in the brain tissues aiming to promote cortical reorganization and subsequently enhances the functional recovery post-stroke (Ed-wardson et al., 2013 and Matheson et al., 2016). Modulation of the cortical excitability was discussed in many prior studies using low frequency repetitive transcranial magnetic stimulation (LF-rTMS) applied on the contra-lesion or the non-affected hemisphere aiming to down-regulate this hemisphere which subsequently can enhance the regain of upper limb motor function recovery in stroke patients (Sebas-tianelli et al., 2017; Zhang et al., 2017 and El Tamawy et al., 2019). However, studies that discussed the safe and effective application of the LF-rTMS in stroke patients only the parameters of magnetic stimulation took in consideration, including: intensity of application, number of pulses per train, frequency, coil shape and orientation, clinical trial design characteristics (Hiscock et al., 2008; Rossi et al., 2009 and Adeyemo et al., 2012). Others relied on comparing different rTMS protocols (Sankarasubramanian et al., 2017), while neglecting the exact number of inhibitory rTMS sessions that could elicit cortical excitability enhancements in subacute hemiparetic stroke patients.

The aim of this study was to determine the recommended number of contra-lesion low frequency repetitive transcranial magnetic stimulation (LF-rTMS) sessions that could enhance cortical reorganization post-stroke as an adjuvant to a selected physical therapy program.

2 Materials and methods

2.1 Design of the study

This single-blind, randomized controlled study was performed in the Transcranial Magnetic Lab of the Clinical Neurophysiology Unit and in the Outpatient Physical Therapy Clinic, Faculty of Medicine, Cairo University, between October 2018 and August 2019. All procedures were in accordance with the Declaration of Helsinki and were approved by the Faculty of Physical Therapy Research Ethics Committee, Cairo University (P.T.REC/012/001647) and registered at the ClinicalTrials.gov Protocol Registration and Results System (NCT03845595).

2.2 Subjects

Forty first-ever ischemic right hemiparetic stroke patients from both sexes were recruited for the study and signed an institutionally approved informed consent form prior to data collection. Their age ranged between 50 to 65 years and they had mild to moderate motor impairments according to the National Institutes of Health Stroke Scale (NIHSS), which is available in Arabic with cultural adaptation and validation (Hussein et al., 2015). Modified Ashwarth Scale was used to assess the muscle tone (Kaya et al., 2011). All patients were diagnosed and referred by a neurologist. Diagnosis was confirmed by magnetic resonance imaging (MRI) or non-contrast computed tomography (NCCT) to be within the domain of the left middle cerebral artery. During the initial assessment for eligibility a list of exclusion criteria was applied including severe aphasia or apparent cognitive deficits, other neurological or chronic disease, any contraindications for rTMS, head injury or loss of consciousness, uncontrolled diabetes mellitus or hypertension, use of any drugs that could influence cortical excitability.

Patients were randomly allocated by sealed envelope randomization into two groups: Group A (GA =control) was treated with a selected physical therapy program for the upper limb, daily for two consecutive weeks and sham rTMS. Group B (GB = study) was treated with contra-lesion LF-rTMS over the primary motor area “hotspot” five days a week for two consecutive weeks in addition to the same physical therapy program as in GA.

2.3 Methods

LF-rTMS intervention procedures: the Magstim Rapid2 magnetic stimulator system (Model P/N 3576-23-09; Magstim, USA) was used to deliver 1-Hz stimulation at 90% of the resting motor threshold (RMT) to the “hotspot” of the primary cerebral cortex (M1) in the contra-lesion hemisphere via a 70-mm figure- 8 coil. Each rTMS session lasted 20 minutes and consisted of 10 trains for 10 seconds and five seconds wait time with a total of 1200 pulses. Observational resting motor threshold (o-RMT) was the lowest intensity that produced five out of ten visible contractions in the contralateral first dorsal interosseous (FDI) muscle, while the patient performed a voluntary isotonic contraction (Westin et al., 2014; Badran et al., 2019). We used the observational method in detecting the motor hotspot as MRI-directed and EMG-TMS devices were not available. Skin areas of the targeted “motor hotspot” were marked using an inerasable marker to assure accurate application of rTMS each session. Sham rTMS session was applied by tilting the coil 45° over the M1 area.

Sequential assessment of active motor threshold: five to ten minutes after the end of each rTMS treatment session the contra-lesion and ipsi-lesion active motor threshold (cAMT and iAMT) was assessed. The sessional rate of change was calculated manually by subtracting the reading of each two consecutive sessions (i.e cAMT rate of change per seventh session = cAMT of eighth session - cAMT of seventh session). Sequential curves of cortical excitability were plotted after the accomplishment of the whole treatment protocol for each patient in both groups, to track the rate of change in cortical excitability measures per session.

2.4 Statistical analysis

Data analysis was performed using the SPSS statistical software version 23.0 for Windows. At the beginning, the normality of data distribution was tested through the Shapiro-Wilk test. Descriptive data for participants, characteristics and dependent variables was calculated as mean±SD. Chi-square (χ²) test was performed to compare the categorical data of the patients’ main characteristics and clinical features within and between groups. Fisher’s Exact Test was used instead when the expected frequency was less than five. Paired and unpaired t tests were used to compare different numerical variables represented in mean values and standard deviations for chronological features, cortical excitability. The alpha point of 0.05 was used as a level of statistical significance

3 Results

Patients of both groups were matched considering age, duration of illness, gender and smoking habit (Table 1). Test of normality revealed that the data are normally distributed, where probabilities were > 0.05 (Table 2).

Table 1
Demographics and clinical characteristics of the participants

GA n = 20 GB n = 20 P-Value

Age (years) 57.45±3.649 57.15±4.380 0.815

Duration since stroke onset (months) 4.35±1.268 4.45±0.999 0.783

Gender (%) 65% M 75% M 0.490

35% F 25% F

Smoking (%) 50% S 65% S 0.337

50% NS 35% NS

NIHSS

Mild impairment 20% 25% 0.705

Moderate impairment 80 % 75%

	GA n = 20	GB n = 20	P-Value
Age (years)	57.45±3.649	57.15±4.380	0.815
Duration since stroke onset (months)	4.35±1.268	4.45±0.999	0.783
Gender (%)	65% M	75% M	0.490
	35% F	25% F
Smoking (%)	50% S	65% S	0.337
	50% NS	35% NS
NIHSS
Mild impairment	20%	25%	0.705
Moderate impairment	80 %	75%

^*P values≤0.05 was considered statistically significant. Age and duration of illness are represented in mean and standard deviation. Gender, smoking history and National Institutes of Health Stroke Scale (NIHSS) are represented in percentage (%). M: male, F: Female, S: smoking, NS: non-smoking.

Table 2

Test of normality for the data distribution

	Tests of normality
	Group	Shapiro-Wilk test
		Statistic	df	Sig
cRMT pre	GA	0.961	20	0.568
	GB	0.953	20	0.417
cRMT post	GA	0.957	20	0.482
	GB	0.915	20	0.080
iRMT pre	GA	0.963	20	0.609
	GB	0.948	20	0.334
iRMT post	GA	0.871	20	0.012
	GB	0.891	20	0.028

cRMT: contra-lesion resting motor threshold, iRMT: ipsi lesion resting motor threshold for upper extremity.

There was no difference in the pre-treatment RMT of either hemispheres (cRMT and iRMT) between groups (Table 3).

Table 3

The mean values of cortical excitability pre- and post-treatment

Cortical excitability seasures		Mean±SD		t-value	P-value
		Pre-treatment	Post-treatment
cRMT	GA	51.75±4.435	60.5±4.310	–40.486	≤0.001^*
	GB	53.3±5.440	72.65±4.771	–36.204	≤0.001^*
	t-value	–0.988	–8.450
	P -value	0.330	≤0.001^*
iRMT	GA	87.95±6.825	81.80±4.797	7.930	≤0.001^*
	GB	86.55±7.466	76.35±2.390	6.354	≤0.001^*
	t-value	0.619	4.548
	P -value	0.540	≤0.001^*

Significance^*: P value≤0.05. cRMT: contra-lesion resting motor threshold, iRMT: ipsi lesion resting motor threshold.

Both groups showed significant improvement in cortical excitability after treatment manifested by increased cRMT & decreased iRMT compared to the pre-treatment values as P≤0.05. However, comparisons between groups was in favor of GB (P≤0.05) (Table 2).

The sequential curve of cortical excitability chan-ges revealed that by the third session of treatment significant difference in favor of GB was observed at the contralateral side, while that of the ipsilateral hemisphere was noticed from the first session (Fig. 1 & 2). Starting from the ninth session no significant difference could be detected between both groups.

Fig. 1

The mean values of contra-lesion active motor threshold (cAMT) through the 10 therapeutic sessions for both groups.

Fig. 2

The mean values of ipsi lesion active motor threshold (iAMT) through the 10 therapeutic sessions for both groups.

The largest difference in the sequential rate of change for GA was that between the eighth and seventh session (4.51±0.924, –3.79±0.671 for contra- and ipsilateral hemisphere respectively), while for GB it was the difference between the fourth and third session (7.14±0.688, –2.55±0.803 respectively) (Table 4).

Table 4

The mean rate of cortical excitability changes over the 10 treatment sessions

Sessional rate of change	(GA)	(GB)	t-value	P-value
	Mean±SD	Mean±SD
cAMT 1–0	0.10±0.447	2.00±0.485	–0.826	0.414
iAMT 1–0	0.00±0.000	–1.05±0.530	8.875	≤0.001^*
cAMT 2–1	0.10±0.447	2.55±0.699	–0.977	0.318
iAMT 2–1	0.00±0.000	–1.48±0.562	8.921	≤0.001^*
cAMT 3–2	0.99±1.031	3.08±0.953	–1.519	0.137
iAMT 3–2	–0.22±0.455	–1.95±0.588	8.433	≤0.001^*
cAMT 4–3	1.13±0.948	7.14 ± 0.688	–2.319	0.026^*
iAMT 4–3	–0.56±0.576	–3.79 ± 0.671	16.347	≤0.001^*
cAMT 5–4	0.89±1.013	3.18±1.029	–4.521	≤0.001^*
iAMT 5–4	–0.51±0.584	–1.42±0.852	3.911	≤0.001^*
cAMT 6–5	1.04±1.142	3.16±0.952	–6.381	≤0.001^*
iAMT 6–5	–0.45±0.566	–1.57±0.873	4.807	≤0.001^*
cAMT 7–6	1.15±1.146	3.65±0.931	–7.581	≤0.001^*
iAMT 7–6	–0.91±0.770	–1.20±1.013	1.036	0.307
cAMT 8–7	4.51 ± 0.924	3.32±1.027	3.835	≤0.001^*
iAMT 8–7	–2.55 ± 0.803	–1.79±1.058	–2.546	0.015^*
cAMT 9–8	3.19±0.812	3.51±0.914	–1.146	0.259
iAMT 9–8	–1.23±0.420	–1.15±1.189	–0.292	0.772
cAMT 10–9	3.00±0.822	3.45±0.832	–1.698	0.098
iAMT 10–9	–1.95±0.938	–1.59±1.036	–1.157	0.255

Significance^*: P value≤0.05. cAMT: contra-lesion active motor threshold, iAMT: ipsi lesion active motor threshold.

4 Discussion

Ischemic stroke is a heterogeneous neurologic disorder characterized by sudden onset and multiple environmental risk factors. It develops as a result of complex patho-mechanisms induced by a critical reduction in cerebral blood flow caused by either sudden or gradual occlusion of cerebral arteries (Khoshnam et al., 2017). The patients’ age ranged from 50 to 65, attributed to the increased co-existence of cardiovascular risk factors, in addition to low rates of self-awareness and lack of knowledge for stroke risk factors, awareness, causes, and symptoms (El-Hajj et al., 2016 and Turk-Adawi et al., 2018). The duration of illness represents the sub-acute stage of stroke. Usually, the responsiveness to rehabilitation programs is the maximum during acute stage and typically reaches a plateau by six months after stroke onset (Teasell et al., 2018).

The patients’ biological sex is one of the main variables to be considered. It was claimed that female patients showed enhanced inhibition of motor ev-oked potentials with more recovery progress than male patients in response to brain stimulation therapy (Sohrabji et al., 2017). Despite the expected impact of sex difference on the intervention outcomes, the randomization process in the current study did not affect the equity of allocation of both sexes in both groups. The distribution of the enrolled smoker and non-smoker patients was statistically matched in both groups. Chronic smoking is thought to influence neuronal excitability, and nicotine has a negative effect on the primary motor cortex (M1), thalamus, medial frontal gyrus, insula, angular gyrus and the inferior parietal lobule function which reduces the facilitatory mechanism of specific neuronal circuits in the motor cortex (Lang et al., 2008; Wang et al., 2014 and Sutherland et al., 2016). Mizrahi et al. (2015) reported a significant difference in the functional gains to rehabilitation between patients with recurrent strokes or previous transient ischemic attacks (TIAs) versus first-ever reported ones, due to the plasticity accumulative consequences of recurrent stroke that consequently affects the recovery progress of the motor function (Ng et al., 2016). Left-handed patients were excluded to avoid the effect of hemispheric dominance on the motor control of different tasks between right- and left-handed patients. (Mutha et al., 2013 and Sainburg, 2014). As the contra-lesion deficits differ depending on the hemisphere of damage, left cerebral ischemic strokes (LCIS) were selected for this study, where predictive control of movement is disturbed only from damage to the left hemisphere, while damage to right hemisphere regions causes deficits in controlling movement distance (Kongsawasdi et al., 2018).

Varnava et al. (2011) assumed that the observational measurement of resting motor threshold is a safe and feasible method in detecting motor threshold, whereas Westin et al. (2014) had subtle limitations regarding the safety and accuracy of such technique in measuring the active motor threshold compared to the EMG-determined motor threshold.

The response of cortico-muscular interaction in the early stages of stroke (acute and subacute) to the long term depression (LTD) induced by LF-rTMS is assumed to be more obvious and effective than the long term potentiation (LTP) induced by HF-rTMS (Zhang et al., 2017 and Xiang et al., 2019), the reverse was also claimed (Du et al., 2019). However, sometimes the effects of rTMS are quite fragile and variable, which can potentially flaw therapeutic applications (Ziemann and Siebner, 2015). Such variability may be attributed to age, gender, genetic polymorphisms and effect of some thrombolytic drugs (Terranova et al., 2019).

Recently, attention was drawn to the suitable number of TMS sessions. Zhang et al. (2017) found a peak of efficacy on post-stroke motor function after five rTMS sessions, whereas Xiang et al. (2019) described the best effects after seven sessions. The number of stimulation sessions and the total length of treatment significantly varied among the studies and, to date, there is no conclusive statement about this feature (Fisicaro et al., 2019). Schulze et al. (2017) found that twice a day is better than once a day dorsomedial rTMS session in major depression. They claimed that the therapeutic gains tracked the accumulative number of sessions, not pulses.

This study assumed that the recommended minimum and maximum number of (LF-rTMS) sessions that revealed significant modulation in cortical excitability was four and eight sessions respectively. Before, no differences were detected between sham and real stimulation and after, there was a plateau in the findings and no significant difference was detected between groups. This is a relatively more applicable and more explicit way to track cortical excitability sessional response not only to LF-rTMS but also to diverse treatment interventions.

LF-rTMS induces macroscopic changes dependent on synaptogenesis, angiogenesis, gliogenesis, neurogenesis at site of stimulation that increases cell size, and cerebral blood flow to primary motor areas which subsequently enhance motor recovery (May, 2011 and Chervyakov et al., 2015). Tracking the sessional neuroplastic and cortical response in (GA) patients, who received sham rTMS and a selected physical therapy program, is another preliminary and intriguing finding. This group also showed modulation of cortical excitability which could be related to both metabolic activity, neurophysiological and anatomical connections alternation (Dimyan and Cohen, 2011). A physical therapy program could enhance cortical reorganization in subacute stroke patients due to increased peripheral levels of brain-derived neurotrophic factor, enhancing the long term depression (LTP) in both the hippocampus and motor system, which consequently increased the ipsi lesion motor cortical excitability after exercise (Li et al., 2019).

5 Conclusion

The inter-individual variability in the pattern of recovery after stroke is certainly extensive and not all factors contributing to such variability could be controlled. Moreover, the application of LF-rTMS was conjugated with a selected physical therapy program for the upper limb. The results in the interventional group did not solely rely on the effect of rTMS. Follow up after a certain period is an important recommendation to assess the sustained effect of rTMS on cortical excitability.

Conflict of interest

None to report.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Footnotes

Acknowledgments

The authors thank all participants that took part in the study for their cooperation.

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