Analysis of MEP parameters in patients with post stroke spasticity in relation with rTMS therapy

doi:10.21203/rs.3.rs-4991711/v1

BACKGORUND: Spasticity is a common complication of stroke limiting patient’s daily activities. Management of spasticity in chronic stroke patients may be necessary to improve their quality of life. Transcranial magnetic stimulation is a painless and non-invasive method that can potentially reduce post-stroke spasticity. In this study we evaluated the effectiveness of 3 sessions of low Hz rTMS therapy by analysing the changes in MEP parameters.

METHODS: Patients with upper limb spasticity after stroke of 3 months duration were randomised into active and sham groups. In the active group three sessions of 1000 pulses, 1 Hz rTMS at an intensity of 90% of resting motor threshold were applied to the primary motor area of the contra-lesional hemisphere over three consecutive days. Sham rTMS intensity was 0% but with a similar sound and scalp sensation. MEP was measured pre and post therapy in each group.

RESULTS: 106 patients were screened of which 50 patients were selected. 25 patients allotted to active group and 25 to sham group. Mean amplitude of MEP on stimulation of normal side was 1.98±1.70 mV before versus 1.53±1.16 mV after therapy showing significant reduction p=0.001 (95% CI-.135 - -.630). Similarly, there was significant increase in latency after therapy [22.92±2.25 ms vs 24.26±2.62 ms, p=0.001 (95% CI-2.0 - -.96)]. There was no significant change in amplitude (1.05±.69 mV vs 1.17±1.01 mV) or latency (23.66±2.45 ms vs 24.05±2.58 ms) after therapy in sham group.

CONCLUSION: MEP parameters revealed even three sessions of therapy can be helpful in supressing normal hemisphere. We found reduction in amplitude and increase in latency of MEP after low Hz rTMS therapy in contra-lesional hemisphere suggesting its suppression after therapy. Spasticity across each joint reduced after the therapy in active group.

modified-modified Ashworth scale

spasticity

stroke

transcranial magnetic stimulation

motor evoked potential

Stroke is a common acute cerebrovascular disorder which causes many disabilities leading to long term limitations of daily living activities.(1,2) Until date no validated treatment can restore the impaired functions by completely recovering the damaged tissue. Stroke, causes shift in the balance between the affected and non-affected hemisphere, consisting of increased excitability in unhurt hemisphere and increased inhibition in involved hemisphere.(3) The role of the uninjured hemisphere seems to be of utmost significance in post-stroke clinical and functional recovery. Unaffected hemisphere may contribute to the functional recovery after a stroke through the replacement of the lost functions of the affected areas.

Spasticity involves exaggerated stretch reflexes, and increased resistance to passive movement across a joint with associated loss of motion and functional control.(4) It is a common complication of stroke that affects quality of life of patients. Available treatments for the post-stroke spasticity includes physiotherapy, medications, and sometimes surgery. Each of these has its own limitations like feasibility, affordability and compliance, so exploration of alternative modes of treatment is necessary. Repetitive Transcranial Magnetic Stimulation (rTMS) can play potential role in reducing post-stroke spasticity.(5)

Repetitive Transcranial magnetic stimulation (rTMS) is a feasible and painless neurophysiological technique widely used for therapeutic purposes.(6,7) It generates sub or suprathreshold currents in the human cortex by electromagnetic induction.(8) Two types of rTMS modalities are available. First one is high-frequency (HF-rTMS) stimulation (>3 Hz), which increases motor cortex excitability of the stimulated area and the second is low-frequency (LF-rTMS) stimulation (⩽1 Hz) which usually produces a decrease in excitability. (9,10) The mechanisms by which rTMS modulates the brain is related to the phenomenon of long-term potentiation (LTP) and long-term depression (LTD).(11) Role of rTMS has already been proven in other disease like depression, migraine prophylaxis with minimal side effects. (12)

MEP latency has been used to demonstrate increased or decreased cortical excitability in normal and affected hemisphere of stroke patients respectively.(13) Previous studies have also shown changes in MEP parameter in response to rTMS therapy among stroke patients.(14) There are previous studies demonstrating the efficacy of low Hz and high Hz rTMS therapy in post-stroke spasticity, but most of studies are observational and have used long session of therapy.(15) None of studies have clearly demonstrated the changes in MEP parameter with rTMS therapy in affected and unaffected hemisphere. With this randomised trial we evaluated the changes in MEP parameters (latency and amplitude) in both hemispheres in relation to 3 session of low Hz rTMS therapy.

STUDY DESIGN: It is a hospital-based, single centre, open-label randomized control trial. The study was conducted in the Department of Neurology, AIIMS Bhubaneswar over a period of 18 months, from July 2021 to February 2023. Patients were recruited from Neurology OPD and the inpatient ward after obtaining written informed consent. Patients or their legal representatives provided the consent according to national and local regulations. The study was approved by Institute Ethics Committee (Ref Number: IEC/AIIMS BBSR/2021-22/31) and registered in Clinical Trials Registry of India (CTRI/2021/08/036026)

STUDY POPULATION: Inclusion criteria were first-time stroke at least three months prior to onset of study with spasticity in upper limb [modified modified Ashworth scale (mMAS) ≥1] irrespective of degree of motor weakness of upper limb. mMAS ranges from 0-5, with 0 being normal and 5 being maximum spasticity.(16) Patients should be 18 years or older, with any kind of stroke in any single hemisphere, with sufficient ambulation and ability to follow three-step commands.

Those on anti-spasticity medication, history of seizure within the past two years, inability to follow three-step directions, anosognosia, moderate to severe receptive aphasia, premorbid spasticity or neurologic impairment prior to stroke, co-morbidities impairing upper extremity function such as fracture or deformity, indwelling metal or medical devices incompatible with TMS, pregnancy, bi-hemispheric or multifocal stroke, severe dementia, neurolytic injection within the 3 months prior to onset of study or planned neurolytic injection during study period were excluded.

PROCEDURES: Patients were randomly assigned (1:1) to either active or sham rTMS therapy using computer-generated numbers. Each treatment arm consists of 3 daily treatment sessions, which was given over three consecutive days with gap of 24 hrs between each session, using Magstim Rapid-2 (Whiteland, Walsh, UK) with an air-cooled figure-eight coil of 7 cm diameter. One treatment session consisted of 1000 pulses of 1 Hz rTMS at an intensity of 90% of resting motor threshold (duration 15 minutes) applied to the primary motor area of the contra-lesional hemisphere. Coil position during rTMS session was defined by the place where motor threshold (MT) is recorded.(11) MT is lowest transcranial magnetic stimulation intensity required to produce a motor evoke potential (MEP) of amplitude >50µv in at least 5 of 10 trials. Before the start of rTMS, the first dorsal interossei resting motor threshold was determined, and area of stimulation decided accordingly. Sham rTMS intensity was 0% but with a similar sound and scalp sensation. MEP study were done before and after completion of treatment sessions through stimulation of both hemisphere one by one and parameters were recorded. Amplitude was measured from baseline to peak or any baseline EMG to peak (figure 1). Assessments for spasticity (mMAS) and hand grip strength (hand dynamometer) were made at pre and post therapy.

OUTCOME MEASURES: Primary outcome was to see for change in amplitude of MEP before and after therapy in unaffected hemisphere. Secondary outcomes were change in latency in normal hemisphere, change in latency and amplitude in affected hemisphere, improvement in spasticity (1 grade decrease in mMAS) and safety of therapy.

STATISTICAL ANALYSIS: Sample size was calculated using nMaster2.0 software with reference to a study evaluating the efficacy of rTMS in spasticity.(15) A sample size of 25 per group is powered at 80% to detect a mean difference of 1 in mMAS between the 2 groups assuming the SD of the mean difference to be 1. The alpha error allowed was 5%. The data collected were entered and analysed using SPSS version 26. Interpretation and analysis of obtained data were carried out with tests of significance. Categorical data were expressed in terms of numbers and percentages and the association between categorical data was determined by the chi-square test/Fischer exact test. Numerical data were expressed in terms of mean, median, range, and comparisons between groups were performed using Independent T-test or Mann Whitney U test. P-value <0.05 was considered statistically significant.

106 patients were screened and after exclusion 50 patients were enrolled, of which 38 were male and 12 females. 25 patients randomised to active (rTMS) group and rest 25 to sham group (Figure 2).

Patients in active group were comparatively younger, also active group had more male and less female patients. Other baseline parameters such as risk factors, duration of illness, type of stroke, size of stroke, spasticity across each joint and strength of handgrip were similar in both groups (Table 1).

Table 1. Baseline characteristics of patients in both groups

VARIABLE

rTMS group (n=25)

Sham group (n=25)

P value

Age (years)

52.84±11.53

58±11.47

.14

Sex

Male

Female

22

3

16

9

.06

Risk factors

DM

HTN

Smoker

13

7

2

11

8

3

.96

Duration of stroke (months)

21.36±29.22

20.36±17.50

.88

Type of stroke

Ischaemic

Haemorrhagic

13

12

14

11

1.00

Location of stroke

Cortical

Subcortical

8

17

4

21

.32

Size of stroke

Small

Medium

Large

7

10

8

10

8

7

.66

Degree of spasticity (mMAS)

Shoulder

Elbow

Wrist

Fingers

2.83±1.16

3.33±.96

3.08±1.06

2.54±1.25

2.30±.92

2.91±.94

2.70±.87

2.09±.90

.093

.13

.17

.16

Hang grip (kg)

3.03±3.30

3.38±3.29

.71

HTN: hypertension, DM: diabetes mellitus, mMAS: modified-modified Ashworth score

Outcomes: Mean amplitude of MEP on stimulation of normal side showed significant reduction [1.98±1.70 mV before therapy and 1.53±1.16 mV after therapy, p value of .001 (95% CI .135 - .630)]. There was significant increase in latency after therapy [22.92±2.25 ms vs 24.26±2.62 ms with p value 0.001 (95% CI -2.0 - -.96)]. No significant change in amplitude (1.05±.69 mV vs 1.17±1.01 mV) or increase in latency (23.66±2.45 ms vs 24.05±2.58 ms) after therapy in was found in sham group (Table 2, Figure 3)

Table 2: Changes in MEP parameters in both hemispheres among both groups and spasticity across each joint, before and after therapy in each group

		rTMS group (n=24)			Sham group (n=23)
		Before (mean±SD)	After (mean±SD)	P value	Before (mean±SD)	After (mean±SD)	P value
Normal hemisphere	Amp (mV)	1.98±1.70	1.53±1.16	.001	1.05±.69	1.17±1.01	.45
Normal hemisphere	L1 (ms)	22.92±2.25	24.26±2.62	.001	23.66±2.45	24.05±2.58	.31
Abnormal hemisphere	Amp (mV)	.94±1.67	.77±.70	.74	.61±.76	.84±.78	.23
Abnormal hemisphere	L1 (ms)	26.69±3.87	24.99±3.42	.005	27.05±4.65	26.45±5.05	.55
Spasticity (mMAS)	Shoulder	2.83±1.16	2.13±1.03	.001	2.30±.92	2.22±.99	.16
	Elbow	3.33±.96	2.58±1.06	.001	2.91±.94	2.83±.93	.16
	Wrist	3.08±1.06	2.0±.88	.001	2.70±.87	2.65±.98	.57
	Fingers	2.54±1.25	1.71±1.16	.001	2.09±.90	2.04±.92	.57

Amp-Amplitude, L1- latency, mMAS: modified-modified Ashworth score

On abnormal side there was significant decrease in latency after rTMS therapy (26.69±3.87 ms vs 24.99±3.42 ms, p=0.005). Decrement in latency in sham group was not significant (27.05±4.65 ms vs 26.45±.05 ms, p=0.55). However, no significant increase in amplitude was found after rTMS therapy (.94±1.67 mV vs.77±.70 mV) (Figure 3,4).

We also calculated the percentage change in MEP latency and amplitude and found similar results. There was increase in latency (-5.85±4.87) and decrease in amplitude (18.22±29.32) in non-affected hemisphere. In affected hemisphere there was decrease in latency (6.09±5.15) and increase in amplitude (-101±178.47) (Figure 5).

There was significant reduction in spasticity across each joint after rTMS therapy [(shoulder 2.83±1.16 vs 2.13±1.03, p=0.001), (elbow 3.33±.96 vs 2.58±1.06, p=0.001), (wrist 3.08±1.06 vs 2.0±.88, p=0.001), (fingers 2.54±1.25 vs 1.71±1.16, p=0.001)]. No difference in spasticity was seen in sham group (Table 2, Figure 6).

In active group we could not find any relationship between improvement in spasticity and MEP values. None of the patients experienced any adverse events like seizure, headache, hearing loss or tingling sensation in face.

In this trial of rTMS therapy among patients with post stroke spasticity, the primary outcome was achieved i.e., three session of low Hz rTMS therapy was able to suppress the unaffected hemisphere. Most of previous studies have shown a decrease in amplitude of MEP after low Hz rTMS therapy in non-affected hemisphere suggesting suppression of normal side after therapy.(14) Previous studies have incompletely demonstrated similar changes in MEP using single and long sessions of therapy, also MEP parameters has been used in prognosticating the outcome among stroke patients. (17) In our study we showed the changes in both latency and amplitude along both hemispheres.

Tang Z et al(18) in their meta-analysis showed that only 3 study reported change in MEP amplitude and all of these studies used HF-rTMS over the affected hemisphere. In a study among 8 patient, Hanafi et al (14), found decrease in amplitude in non-affected hemisphere and increase in amplitude in affected hemisphere with both types of therapies (inhibitory and facilitatory), but the differences were not significant. In our study we found significant reduction in amplitude and increase in latency with inhibitory therapy in non-affected hemisphere, but we didn’t find significant increase in amplitude in affected hemisphere. It suggests that the therapy was able to suppress the non-affected hemisphere which are over-excitable in stroke patients. Bashir et al(19) in their study among normal cohort of young and old patients with one session of 1 Hz therapy demonstrated, inhibition of ipsilateral hemisphere and facilitation of contralateral hemisphere in young group, while only facilitation of contralateral hemisphere in older group. Our cohort included mostly older patients and in affected hemisphere we found increased excitability, in the form of significant reduction in latency but no amplitude increase. This could be probably because in our study many patients had significant motor weakness at baseline on affected side. Thickbroom et al(20) had shown that MEP amplitude are significantly related to hand grip strength.

Nojima K et al(21) found inverse correlation between MEP amplitude and rTMS effect. They also demonstrated that amplitude and latency at baseline strongly affects the effect of rTMS therapy. Subjects with higher amplitude have more significant effect with therapy. We could not find relation between amplitude of MEP on affected limb and improvement in spasticity probably because many patients had non recordable MEP in affected limb. Most of patients have amplitude above 250µv on non-affected limb, which could explain the significant decrease in amplitude with therapy in non-affected side. In our study latency along normal hemisphere increased and decreased along affected hemisphere, showing the significant changes in excitability in both hemispheres. These findings are similar as shown by Wang C et al (22), in which latency reduced with both HF-rTMS and LF-rTMS. In this study changes along both hemispheres have not been evaluated.

In our study we stimulated the unaffected hemisphere with low Hz rTMS therapy. We choose the area of stimulation based on principle of altered relationship between two hemispheres after stroke. It has been proposed that after the stroke affected hemisphere get become suppressed by the unaffected hemisphere.(3) So, application of LF-rTMS to unaffected hemisphere will suppress it and will reduce its dominance over the affected hemisphere and this will help in maintaining the inhibition of spinal reflex on affected side. The mechanism of suppression is through the phenomenon of long-term depression (LTD).(11) Affected hemisphere are stimulated with high frequency rTMS, which activates the affected hemisphere.(23)

Similar to other previous studies our 3-session therapy was also able to improve the spasticity of shoulder, elbow, wrist and fingers on affected upper limb.(24) For persistence of the effect of therapy follow up study is needed. None of the patients experienced any adverse events like seizure, headache, hearing loss or tingling sensation in face which were reported in some of previous studies.

Our study has few limitations like at baseline active group had more younger patients. Previous studies have not shown the effects of age on rTMS therapy, rather the baseline MEP amplitude can affect the outcome. In our study neuro-navigation technique was not used, rather we used motor threshold to localise the area of stimulation. It was an open label study which can cause some observational bias in spasticity calculation among both groups, but the measurement of MEP physiological parameter has not been affected.

CONCLUSION: In conclusion we showed in detail the changes in amplitude and latency along both hemispheres with rTMS therapy. LF-rTMS has inhibitory effect on normal hemisphere and facilitatory effect on affected hemisphere. With rTMS therapy MEP latency increases and amplitude decreases on non-affected side while reverse occur in affected side. Even three sessions of therapy can be helpful in supressing normal hemisphere and is useful in improving spasticity without any significant side effects.

Ethical clearance has been obtained from Institute Ethics committee, AIIMS Bhubaneswar.

Informed consent: Written Informed consent was obtained from all the participants of this study

Source of supports/grants: Nil

Conflict of interest: All the authors declare that they have no conflict of interest.

Study has been presented in Indian National Stroke Conference (INSC 2023), at Chennai on April 2023.

Author contribution:

Dr Yuvraj Lahre - Data acquisition, data analysis, literature search, manuscript preparation.

Dr Sanjeev Kumar Bhoi- Concept, design, literature search, data acquisition, data analysis, manuscript preparation.

Dr Menka Jha- data analysis, manuscript editing and review.

Dr Priyanka Samal- manuscript editing, manuscript review.

Suprava Naik - manuscript editing, manuscript review.

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No competing interests reported.

Analysis of MEP parameters in patients with post stroke spasticity in relation with rTMS therapy

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Abstract

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INTRODUCTION

METHODOLOGY

RESULTS

DISCUSSION

Declarations

REFERENCES

Additional Declarations

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