The Sequential Rate of Change in Cortical Excitability in Response to Transcranial Magnetic Stimulation in Stroke Patients
Phase: NA
Conditions: Stroke, Cardiovascular
Sponsor: Cairo University

 

 
INTRODUCTION 
       Stroke is the leading cause of acquired adult disability worldwide and the 
fourth most common cause of death in developed countries. It is the third leading 
cause of death after heart disease and cancer, and it is a leading cause of disability 
in the eastern world. Of those who survive a stroke, 90% have a neurological 
deficits which are disabling than fatal. Stroke is usually considered a disease of the 
elderly, but nowadays it can occur at any age and their consequences in terms of 
lost productivity and poor quality of life are even greater in younger patients than 
in older ones. Despite the abundance of numerous neurorehabilitative treatments, 
approximately 80% of stroke survivors still suffer from persistent motor 
dysfunction after stroke (Du et al, 2016). 
    
      Stroke survivors usually show significant residual neurological deficits that 
impair function. Upper limb dysfunction hemiparesis specifically, is a very 
common and significant disability that affects daily living and increases the burden 
on these patients and their families.  Restoring functional use of the upper 
extremity is a key goal and a priority for stroke patients. Proper outcome 
assessments at the activity and participation levels are necessary to determine the 
appropriate selected rehabilitation intervention that could result in changes that are 
important to the daily life of individuals living with stroke (Hatem et al, 2016). 
 
     Recovery of motor function after stroke depends mainly on the sustained 
capacity of the adult brain for plastic changes. This cortical excitability or cortical 
plasticity based on the concept of functional interhemispheric balance between the 
two motor cortices (Kubis , 2016). Various motor-related regions contribute to 

motor recovery after a stroke.  One of these motor-related regions, is the 
contralesional primary motor cortex (M1) contributes to the motor recovery of the 
upper extremity after a stroke (Favre  et al, 2014). 
 
     The substantial changes that occur in the cortical reorganization of the brain 
ischemic areas and of more remote areas play an integral role in the recovery of 
motor dysfunction post stroke. The injured ischemic motor cortex has a reduced 
cortical excitability at the acute phase and a suspension of the topographic 
representation of affected muscles, while the contralateral motor cortex has an 
increased excitability and an enlarged somatomotor representation. The 
contralateral cortex exerts a transcallosal interhemispheric inhibition on the 
ischemic cortex. This results from the imbalance of the physiological reciprocal 
interhemispheric inhibition of each hemisphere on the other, contributing to 
worsening of neurological deficit (Zhang et al , 2017).   .  
 
       Series of repetitive transcranial magnetic stimulation studies on stroke have 
been trying to understand the relationship between hemiparetic upper limb motor 
recovery and cortical reorganization post stroke (Tang et al , 2015) . Repetitive 
transcranial magnetic stimulation (rTMS) is a noninvasive stimulation to induce 
electrical currents in the brain tissues which can  modulate cortical excitability of 
motor areas and enhance recovery. (Du et al., 2018).  The application of repetitive 
transcranial magnetic stimulation depend on multiple parameters, such as stimulus-
train length, stimulation frequency, number of pulses delivered,  their temporal 
pattern and the targeted region . All of these parameters may differentially affect 
the responses of the intended target neurons to rTMS (Matheson et al., 2016). 
 

        Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) of the 
contralesional hemisphere is a safe procedure that suppresses local cortical activity 
of the non-affected cerebral cortex  (Li et al, 2016) .The  primary motor cortex 
(M1) forms a main part of the motor cortices and contributes to the high order 
control of motor recovery of the  hemiparetic upper limbs in stroke patients . It was 
assumed that the induced inhibitory effect of LF-rTMS on the non-lesional 
hemisphere  can cause direct  increase in the  neural activation of the lesional 
hemisphere which can consequently regain the cortical interhemispheric balance 
and  eventually can produce functional improvement in post-stroke patients with 
upper limb hemiparesis (Blesneag et al,2015, Du et al, 2018). 
 
 
Statement of the Problem: 
 Is there a significant effect of the contralesional low frequency repetitive 
transcranial magnetic stimulation (LF-rTMS) on cortical excitability 
modulation and consequently on the upper limb motor performance in stroke 
patients? 
 The recommended minimum number of contralesional low frequency 
repetitive transcranial magnetic stimulation (LF-rTMS) sessions that can 
induce significant cortical excitability changes in relation to the conventional 
therapeutic physical therapy interventions in stroke patients? 
 The recommended maximum number of contralesional low frequency 
repetitive transcranial magnetic stimulation (LF-rTMS) sessions that can 
induce significant cortical excitability changes before reaching a plateau in 
relation to the conventional therapeutic physical therapy interventions in 
stroke patients? 

 
Purpose of the study: 
 To assess and analyze the effect of contralesional low frequency repetitive 
transcranial magnetic stimulation (LF-rTMS)  on cortical excitability and 
consequently its impact on the  upper limb motor performance in stroke 
patients. 
 To determine the recommended  minimum and maximum number of 
contralesional low frequency repetitive transcranial magnetic stimulation 
sessions (LF-rTMS)  in conjunction with the conventional physical therapy 
rehabilitation program that can induce significant impact on cortical 
excitability  by  analyzing  the sequential rate of change in cortical 
excitability in response to  contralesional  (Lf-rTMS) stimulation in stroke 
patients. 
 
Significance of the study 
       Stroke is a global disease with high rates of long-term disability. It is estimated 
that 25% to 74% of the 50 million stroke survivors worldwide require some 
assistance or are fully dependent on caregivers for activities of daily living (ADL) 
post stroke. (Veerbeek et al, 2011). It affects aspects of a person’s physical, 
emotional, and social life. Although stroke is a lesser cause of disability than heart 
disease, the population of stroke survivors continues to increase, in part because of 
a fall in mortality rates. This consequently increases the societal burden because of 
the monetary load and costs of care applied upon the care givers, in-patient 
hospitals and family members. Upper limb motor rehabilitation is a priority that 
can be achieved by   adopting a cohesive and multidisciplinary approach toward 

clinical management and rehabilitation   to minimize long-term stroke-related 
disability ( Santisteban et al, 2016). 
 
     Upper limb  motor impairments post stroke result in reduced functional 
mobility, motor or sensory dysfunctions as well as problems with balance, 
coordination, postural control, and walking mechanics  resulting in increased 
financial and social burden of stroke patients and their families. These  long-term 
sensorimotor impairments, is usually due to  the patients’ incapability to  execute 
movements of the affected arm or hand independentlyImpairments of the upper 
extremity post stroke   are usually due to  direct damage to the primary motor 
cortex, the primary somatosensory cortex, secondary sensorimotor cortical areas, 
subcortical structures, and/or the corticospinal tract (Raghavan , 2015). 
 
      Research in cortical excitability or cortical plasticity modulations highlighted 
the significance of such processes in the  potential enhancement of motor recovery 
after cerebrovascular stroke.  The modules involved in cortical reorganization post 
stroke can potentiate the results of clinical rehabilitation of various motor 
impairments in stroke patients. Non-invasive brain stimulation with inhibitory 
repetitive transcranial magnetic stimulation (rTMS) of the contralesional 
hemisphere may aid in relieving a post-stroke interhemispheric excitability 
imbalance, which could improve functional recovery ( Van et al, 2017) Abnormal 
cortical excitability and interhemispheric imbalance in stroke patients assumes 
that, the  increased excitability of the contralesional hemisphere applies  excessive 
interhemispheric inhibition onto ipsilesional cortical hemisphere . This excessive 
imbalanced inhibition impede the neuroplasticity in these areas and limit the gains 
in motor recovery that can be achieved through rehabilitation (Boddington &  
Reynolds 2017). 

        
Null Hypothesis: 
- There is no significant effect of using contralesional low frequency repetitive 
transcranial magnetic stimulation (LF-rTMS) on cortical excitability and 
consequently on the motor performance of the affected upper limb in stroke 
patients. 
 
-  There is no change in the sessional values of cortical excitability in response to 
contralesional low frequency repetitive transcranial magnetic stimulation (LF-
rTMS) thus the recommended minimum and maximum number of LF-rTMS 
sessions that can show significant changes in cortical excitability cannot be 
determined in stroke patients. 
 
Delimitations: 
This study was delaminated to:- 
 Forty hemiparetic stroke patients of both genders  who met all the 
inclusion criteria were recruited in this study from outpatient clinic, 
Faculty of Physical Therapy and outpatient clinic  in the Neurology 
department, Faculty of Medicine, Cairo University. 
  Their age ranged from 50  and 65 years  
 All patients experienced single ischemic stroke for at least three months 
but not exceeded for six months. 

  All patients were referred from a neurologist and the diagnosis was 
confirmed with non-contrast computed tomographic (CT) or magnetic 
resonance imaging (MRI) scans of the brain. 
 The selected patients were randomly assigned into two equal groups 
(control group (GA) and study group (GB)), The randomization was 
done by random generator using permuted blocks of different 
sizes(Randomized Controlled Trial). 
 All patients were selected with mild to moderate motor impairment 
verified according to the national istitutes of health stroke scale ( NIHSS 
) (score 1-15) and modified ashworth scale (MAS) (1 or 1+). 
 Fugl-Myer upper extremity assessment scale (FMA-UE)  and hand grip 
dynamometer  were used  to assess the upper limb motor function  for 
each patient in both groups (before and after treatment). 
 Single pulse TMS was used to assess cortical excitability represented in 
measuring the active motor threshold from the  contralesional  (CAMT) 
and the ipsilesional (IAMT) primary motor “hot spot” for each patient in 
both groups (before and after treatment). 
  Single pulse TMS was used to assess the sequential change in cortical 
excitability represented by the sessional measurement of  (CAMT) and 
(IAMT) for all patients in both groups. 
 Patients participated in the study were not informed whether they are in 
the Control group(GA) or in the Study group(GB) (Single blind study). 
 The treatment sessions for all patients  in both groups was conducted 
daily, ﬁve times per week for two consecutive weeks. 
- The control group (GA) were treated by a  conventional physical 
therapy upper limb rehabilitation protocol (Lie etal,2015). 

- The study group (GB) were treated with the conventional physical 
therapy upper limb rehabilitation protocol in addition to the  
contralesional low frequency repetitive transcranial magnetic 
stimulation (LF-rTMS).  
Limitations: 
An Effort was made to minimize the effect of the possible limitations which 
are: 
1. The psycho-physiological status of the patients; all the patients were 
interested and motivated during all the sessions. 
2. The transportation of all patients from the Outpatient clinic, Faculty 
of Physical Therapy, Cairo University was comfortable and without 
any effort or extra load on the patient as much as possible. 
3. Each patient was assessed using single pulse TMS at the 
neurophysiology lab at Kasr El Aini, teaching Hospital, Cairo 
University, at a time suitable for each patient and without any list of 
waiting as much as possible. 
 
Basic assumption: 
It was assumed that: 
 
 The sample of this study were carefully selected to represent all the subacute 
stroke population. 
 Patient’s motivation & cooperation were the same throughout the assessment 
and treatment procedures for each patient. 

 All other factors which may influence the outcomes such as noise, 
distraction…..etc during the assessment and treatment sessions were 
controlled. 
 All risk factors of stroke would be controlled to avoid any recurrent stroke or 
instability of their medical state like blood pressure, glucose and cholesterol 
level that was achieved with their physicians. 
 
Data Analysis and Statistical Design:  
 
A- Descriptive statistics:  
         The  mean value and standard deviations for upper limb motor function   
findings represented in Fugl-Myer Upper Extremity Scale (FMA-UE), Hand 
grip dynamometer and Findings of cortical excitability represented in 
Contralesional Active Motor Threshold (cAMT) and Ipsilesional Active 
Motor Threshold (iAMT) obtained  from MagstimRapid2 stimulator system were 
compared for  both groups (Control group (GA) and Study group (GB)) . 
 
B- Inferential statistics: 
- Student t Test was used  to compare different numerical variables 
represented in  mean values  and standard deviations of the patients 
chronological features as Age (in years) and duration since onset of stroke 
(in months)  between both groups ((GA)  and (GB)). 
-  Student t Test  for independent samples test was also used  to compare  
different numerical variables represented in  mean values  and standard 
deviations that were  obtained from MagstimRapid2 stimulator system ( 

cAMT , iAMT) for cortical excitability and upper limb motor function 
findings  ( Fugl-Myer assessment- Upper Extremity  (FMA-UE), Hand grip 
dynamometer)  between  both groups  ((GA)  and (GB)) (Pre treatment 
findings). 
- Chi-square (2) Test was performed to compare the categorical data of the 
patients’ main features as gender, smoking history,within and between 
groups (control group (GA)  and study group  (GB)) . Fisher’s Exact Test 
was used instead when the expected frequency is less than 5. 
- Paired  t Test for independent samples test was used to compare the  post to 
pretreatment  change  between both groups, represented in the mean values  
and standard deviations obtained for the recorded post to pretreatment 
difference in  cortical excitability ( cAMT , iAMT ) and upper limb motor 
function findings  ( (FMA-UE), Hand grip dynamometer)  . 
- The mean values of the  Sequential rate of change in cAMT and iAMT  
findings over the 10 therapeutic sessions were assessed by comparing the 
CAMT and the IAMT  mean values of each session in relation to the 
previous session findings for each patient in both groups  
- Paired t Test for independent samples test was used to compare the mean   
sessional values (sequential change)  and the mean difference in the 
sessional rate of change of the cortical excitability findings represented by 
cAMT and iAMT between group control group  (GA)  and study group  
(GB). 
- The alpha point of 0.05 was used as a level of statistical significance (when 
P = 0.05 is usually classed as “significant”, P = 0.01 as “highly significant”, 
and P = 0.001 as “very highly significant”) (Betty and Jonathan, 2003). 

-  All statistical calculations were done using computer program IBM SPSS 
(Statistical Package for the Social Science; IBM Corp, Armonk, NY, USA) 
release 22 for Microsoft Windows.