Efficacy of the Theta Burst Stimulation and Functional Electrical Stimulation in Stroke Rehabilitation
Condition: Strokes Thrombotic
MeSH terms: Stroke; Thrombotic Stroke
Study type: Interventional

Summary: 
      Approximately 50% of patients have persistent motor disability following stroke. Current
      treatment approaches with conventional physiotherapy have limited efficacy. Repetitive
      transcranial magnetic stimulation (rTMS) and Functional electrical stimulation (FES) have
      been shown to improve the neuronal plasticity and motor control in few preliminary studies.
      Their efficacy in human stroke subjects is unproven. We planned to study their efficacy in
      improving the motor functions of stroke patients in a randomized trial. Sixty consecutive
      haemodynamically stable adult patients with first ischemic stroke within last 7-30 days were
      randomized into three treatment groups to receive either physiotherapy alone, or
      physiotherapy combined with either FES or rTMS. Outcome was assessed using Fugl Meyer
      assessment for physical performance of upper limb. Three groups were compared for the outcome
      measures using intention to treat analysis.
    

Detailed description: 
      Background

      Present management strategies involving conventional physiotherapy (PT) have limited efficacy
      in facilitating the motor recovery following stroke. Finding an effective intervention to
      improve motor recovery in individuals with hemiplegia is very important for improving the
      functional outcome and enabling independent living.

      Following an injury, the brain undergoes significant reorganization of its functions
      resulting in functional recovery, which occurs over a period of weeks to months. This
      postlesional reorganization occurs mostly in the premotor cortex, dorsolateral prefrontal
      cortex and supplementary motor area which are thought to play the most important role in
      recovery following any type of brain injury. Treatment approaches which can facilitate this
      reorganization process by enhancing the cortical plasticity might have a very important role
      in improving the functional outcome following neuronal injury.

      Both central and peripheral stimulation has potential to improve the cortical reorganization
      and functional recovery following acute stroke. Previous studies have established that
      following an acute stroke, the depressed excitability of the ipsilesional hemisphere can be
      increased by stimulating the ipsilesional hemisphere or by inhibiting the contralesional
      hemisphere.This happens because of the fact that one hemisphere has inhibitory effect on the
      other hemisphere through transcallosal inhibition. In preliminary studies, application of
      high frequency repetitive transcranial magnetic stimulation (rTMS) to motor cortex has been
      shown to produce an increase in corticospinal excitability leading to enhancement of motor
      functions. Theta Burst Stimulation (TBS), which is a novel method of delivering rTMS at lower
      intensities without the risk of any major adverse effects, has been found to be safe in
      chronic and acute stroke patients. In this regard, intermittent TBS (iTBS) has a stimulatory
      effect on the brain and continuous TBS (cTBS) has inhibitory effect on the brain. In
      preliminary studies, intermittent TBS (iTBS) applied to the ipsilesional hemisphere and
      continuous TBS (cTBS) applied to the contralesional hemisphere have been shown to improve the
      motor functions and corticospinal output in the paretic hands during experimental settings.
      However, long term effects of this strategy on functional outcome have not been previously
      studied. Similarly, functional electrical stimulation (FES), a form of peripheral
      stimulation, when applied to the paretic upper limb muscles has been shown to improve the
      upper limb functional activity in patients with acute or subacute stroke.

      Thus both the TBS and FES has a potential of improving the motor functions and the functional
      outcome following ischemic stroke. However, these strategies have not been used in clinical
      setting and their usefulness in promoting motor recovery over and above that of conventional
      PT has not been proven. If proven to be useful, these techniques have a potential of
      improving the otherwise dismal functional outcome following stroke. The purpose of this study
      is to determine efficacy of TBS or FES as an adjunctive to physical therapy for the
      rehabilitation of stroke patients.

      METHODS Study Setting and Participants This study is a single blind randomized controlled
      trial to assess the efficacy of TBS and FES in improving motor functions over and above that
      of standard PT following acute stroke. This study was carried out at the Department of
      Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum,
      Kerala, India. We recruited consecutive patients over a 28 months period from the outpatient
      clinics and inpatient wards. Patients with first ever ischemic stroke in middle cerebral
      artery territory who presented within 10 days to 30 days of onset and had ability to give
      informed consent and comprehend instructions were included in this study. All the patients
      underwent 1.5 T MRI and had documented single infarct in MCA territory with no other lesion.
      All the patients received standard medical and rehabilitative care including passive and
      active PT. The study was approved by the institutional ethics committee (SCT/IEC/223). All
      the patients provided written informed consent to undergo the trial. Consecutive patients who
      fulfilled the inclusion and exclusion criteria were randomized to one of the three groups:
      (1) those who received TBS as per the predefined protocol along with standard PT (Group A);
      (2) those who received FES as per the predefined protocol along with standard PT (Group B);
      and (3) those who received PT (PT) alone (Group C).

      Random allocation and sequence generation The patients were randomly allocated into three
      groups by block randomization method. Concealed allocation was done by principle investigator
      who blindly allocated the subjects into different groups according to the block randomization
      table to receive the designated intervention

      Blinding After providing the informed consent, a subject fulfilling the inclusion and
      exclusion criteria was initially assessed by first co-investigator for all the outcome
      measures and neurophysiological parameters. Patients who were eligible for the study were
      allocated to different intervention groups by principle investigator. Interventions were done
      by second co-investigator for all the subjects. Follow-up assessments were done by the first
      co-investigator who was blinded to the allocation to intervention groups.

      Outcome measures As we mainly wanted to assess upper extremity functions, we used Fugl Meyer
      Assessment (FMA) scale as the primary outcome measure to assess the upper limb motor
      functions. This is a 66-point scale to evaluate upper limb functions, a standard tool for
      this purpose. In addition, we used Modified Rankin Scale (mRS) to assess global outcome,
      National Institute of Health Stroke Scale (NIHSS) to assess stroke severity and Barthel Index
      (BI) to assess activities of daily living. These three scales were used as secondary outcome
      measures.

      Outcome scales were applied at baseline (T1) and then subsequent assessments were done at one
      month (T2), three months (T3), six months (T4) and at one year (T5) after the enrollment.

      Sample size calculation Primary outcome measure for this study was the Fugl Meyer Assessment
      of upper limb functions at one year. Previous studies have shown that FMA score increases by
      16.5 ± 9.4 at one year in control subjects.21 We hypothesized that for a clinically
      meaningful outcome, the intervention should produce an increase of 10 points over and above
      the control group. To achieve this, a sample size of 14 patients in each arm was required for
      a power of 80% with alpha fixed at 5%. In a previous study conducted at our institute, the
      post stroke mortality was 27.2 % at one year, of these 72.1% died within 10 days after the
      stroke.2 As have planned to include patients between 10 to 30 days of stoke onset, to account
      for the mortality rate of 7.6% after 10 days, the required sample size was 16 in each group.
      Considering a dropout rate of 20 %, we calculated a sample size of 20 patients in each group
      as adequate.

      TMS Protocol We assessed resting motor threshold (RMT) for both the hemispheres at baseline
      using Magstim Rapid2 (Whitland, Wales, UK) stimulator with a figure-of-eight coil having an
      external loop diameter of 9 cm. After making the patient seated comfortably in an armchair,
      posterior-anterior orientation was used over the motor cortex (M1) to assume the optimal
      scalp position to elicit MEP in the contralateral first dorsal interosseous (FDI) muscle. RMT
      was assessed from ipsilesional hemisphere initially and followed by contralesional hemisphere
      as per the standard techniques. Surface electromyograms (EMGs) were recorded from the FDI
      muscles bilaterally using Ag-AgCl electrodes with a gain of 1-2 mv. Signals were filtered
      (10Hz-10 KHz), and then stored for off-line analysis. Audio-visual feedback of the EMG signal
      at high gain were given to assist subjects to maintain complete relaxation.

      Patients in group A were subjected to TBS in addition to standard PT as described below.
      Intermittent TBS (iTBS), which is facilitatory, was given to the ipsilesional hemisphere and
      continuous TBS (cTBS), which is inhibitory, was given to contralesional hemisphere. The
      stimulation was given at an intensity of 60% of RMT. The iTBS protocol of 10 bursts of
      high-frequency stimulation (3 pulses at 50 Hz) was applied at 5 Hz every 10 s for a total of
      600 pulses. When no MEP was elicited from the ipsilesional motor area (<0.05mV), 100%
      stimulator intensity as that of contralesional hemisphere was applied at the mirror location
      of the contralesional motor area.14 Continuous TBS was given with an intensity of 60% of RMT,
      3 pulses at 50 Hz, repeated every 200 ms for a total of 600 pluses. Both iTBS and cTBS were
      delivered for three times in a week for four weeks.

      Functional Electrical Stimulation. Electrical stimulation was given with Mega XP (Cybermedic
      Corporation, South korea). The patient received the electrical stimulation in sitting
      position with affected arm positioned over the pillow and electrodes were positioned
      according to pattern 3 [Grasp/Flexion/Extension, PATT (pattern movement)] of the FES (F) mode
      of the instrument. The stimulator controller unit of the machine could deliver alternating
      current at a frequency of 35 Hz, pulse width of 200 µs and intensity of 10~50 mA. The
      stimulator was set to deliver interrupted trains of pulses with the contraction and
      relaxation so as to simulate the lifting of upper limb in a functional position. The FES
      group stimulation session was given for 30 minutes for each day, 3 times in a week (alternate
      days) for 4 weeks and it was concurrently synchronized with the physical therapy.

      Physical therapy treatment protocol The following physical therapy regimens were followed for
      all the patients in the study: Passive/Active Range of Motion (ROM) at all joints; weight
      bearing and supportive reaction; reaching activities; grasping, holding and release; and
      upper extremity activities of daily living (ADL). Physical therapy intervention was given to
      all the patients five days per week for one month. Modifications in the physical therapy was
      made by second co-investigator for each patient so that he or she was able to practice
      independently or with assistance from a family member after the intervention and was
      instructed to practice one hour per day. In addition, all patients continued to receive
      in-home physical therapy 1-2 times per week by a home care physical therapist who was guided
      by second co-investigator. The investigators used a logbook to monitor the actual amount of
      time that each patient exercised at home.

      Statistical Methods We used descriptive statistics to summarize the data. Baseline
      comparability of groups, in terms of demographic data and baseline measurements were assessed
      with chi-square test and ANOVA. Non-normal data was subjected to reciprocal, logarithmic and
      exponential transformation and Komogrov-Smirnov and Shapiro-Wilks tests were done to assess
      normality. Parametric measures were analyzed with ANOVA followed by post-hoc analysis with
      bonferroni correction. Repeated measure ANOVA was used to find out between group and within
      group variability. Non parametric measures were analyzed with Kruskal Wallis test followed by
      post hoc analysis with Mann Whitney U test. Friedmans test and Kendalls W test was done to
      find the changes in three groups over a period of one year. All analyses were done using SPSS
      version 17.0 and p value of less than 0.05 was considered significant.
    

Intervention name(s): Theta burst stimulation; Functional Electrical Stimulation; Physiotherapy
Intervention type(s): Procedure; Procedure; Procedure
Intervention description(s): Patients were given intermittent TBS to the affected hemisphere and continuous TBS to the unaffected hemisphere for 4 weeks along with physiotherapy.; Patients were given functional electrical stimulation of affected upper extremity for four weeks along with physiotherapy.; Patients received active and passive physiotherapy of the affected extremity for four weeks.
Other intervention name(s): TBS; FES; PT
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Single blind randomized controlled trial
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment