Effect of Repetitive Bihemispheric Anodal Transcranial Direct Current Stimulation on Motor Function of Patients With Parkinson's Disease
Phase: PHASE3
Conditions: PARKINSON DISEASE (Disorder), Parkinson Disease
Sponsor: Dr. Ram Manohar Lohia Hospital

1 
 
EFFECT OF REPETITIVE BIHEMISPHERIC ANODAL TRANSCRANIAL 
DIRECT CURRENT STIMULATION ON MOTOR FUNCTION OF PATIENTS 
WITH PARKINSON’S DISEASE. 
 
Protocol Number: IEC/ABVIMS/RMLH/1092  
National Clinical Trial (NCT) Identified Number: Pending  
Principal Investigator: Ashish Kumar Duggal  
Sponsor: Dr. Ram Manohar Lohia Hospital  
Version Number: v.1  
25 January 2026 

2 
 
                                                    INDEX 
 
 
 
Topic 
Page 
INTRODUCTION 
3-4 
REVIEW OF LITERATURE 
5-6 
LACUNAE IN EXISTING KNOWLEDGE 
7 
RESEARCH QUESTION 
8 
RESEARCH HYPOTHESIS 
9 
AIMS AND OBJECTIVES 
10 
MATERIAL AND METHODS 
11-15 
REFERENCES 
16-17 
ABBREVIATIONS 
18 

3 
 
INTRODUCTION 
 
 
Parkinson’s disease is the second most common neurodegenerative disease with a prevalence of around 0.5– 
1% in people aged between 65 and 69 years, increasing to 1–3% among individuals aged over 80 years [1]. It 
is a leading cause of Disability Adjusted Life Years (DALY) globally with 148% increase from 1960 to 2016 
being the most growing neurological disease according to Global Burden of Disease 2016.[2] 
 
It is a chronic, multisystemic, neurodegenerative disorder with various mechanisms underlying its 
neuropathology[3] including degeneration of substantia nigra pars compacta and dysfunction of striatal 
pathway with presence of Lewy bodies which are intracytoplasmic inclusion bodies containing protein alpha 
synuclein.[4] This leads to increased GABAergic signalling from output nuclei of basal ganglia to subcortical 
structures including thalamus. Clinically, cardinal features of the Parkinson’s disease include tremors, rigidity, 
bradykinesia and postural instability. Other Non-motor features include autonomic dysfunction, sensory and 
sleep abnormalities, cognitive/neurobehavioral symptoms, freezing of gait and fatigue.[4] 
 
Motor symptoms experienced by the patients are responsible for the increased number of falls and reduction 
in functional independence [5]. Motor symptoms also act as an independent predictor of mortality in patients 
with PD[6]. Locomotor function abnormalities in patients with PD include short stepping gait, shuffling, 
festination, stooping while walking with postural abnormality. These abnormalities are responsible for 
disability and impaired functional independence. 
 
Although best medical therapy for PD is pharmacotherapy (especially with levodopa), with long term 
treatment patients develop hallucinations, postural hypotension, motor fluctuation and dyskinesias which can 
become more debilitating than symptoms of PD[7]. Among the locomotor abnormalities postural instability 
and gait abnormalities respond poorly with pharmacotherapy with dopaminergic medications.[8] 
 
Surgical interventions, primarily deep brain stimulation (DBS) of various target nuclei, are therapeutic options 
when conventional therapy fails. Yet DBS is limited to a small well defined patient population and carries the 
risk of serious surgical complications and significant 

4 
 
neuropsychiatric side effects. Therapeutic alternatives are needed. Thereby, searching for alternative 
treatment option is essential and non invasive brain stimulation technique like transcranial direct current 
stimulation is an interesting potential alternative for management in PD. 
 
Transcranial Direct Current Stimulation(tDCS) is a noninvasive brain stimulation technique in which a weak 
electric current is applied through the scalp to specific areas of brain. It alters the cortical excitability by 
modulating the neuronal resting membrane potential toward 
excitability.[9] 
 
Many previous studies have focused on application of tDCS in patients with PD with few of them showing 
promising results of motor function improvement following tDCS application. However, there is scarcity of 
data regarding any specific protocol of tDCS which gives consistent good results. With this background, we 
hypothesize that with repetitive bihemispheric anodal transcranial Direct Current Stimulation, locomotor 
function improve in patients with PD. 

5 
 
REVIEW OF LITERATURE 
 
Progression of Parkinson’s disease (PD) is characterised by multiple motor as well as non motor deficits. 
Severity of these symptoms gradually increases with duration and eventually respond less to dopaminergic 
therapy and thus pose a therapeutic challenge.[10] Neurosurgical procedures involving deep brain stimulation 
are another option with proven efficacy, but this method presents high cost, surgical risk, and possibility of 
worsening of verbal fluency and axial motor symptoms (11,12). Appropriate interventions should present little 
or no adverse effects, improve functionality and well-being, and delay the progression of the disease. Thus, 
new therapeutic approaches are necessary to provide a better quality of life and to reduce the financial burden 
for society and health systems. Non-invasive brain stimulation techniques have shown promising results and 
may provide a therapeutic alternative which includes tDCS (Transcranial Direct Current Stimulation) and 
rTMS (Repetitive Transcranial Magnetic Stimulation). tDCS has some advantages over rTMS, including a 
favourable safety profile, tolerability, easier applicability and cost effectiveness. 
 
Transcranial direct current stimulation (tDCS) is a mode of non-invasive brain stimulation in which a direct 
current is applied via surface electrodes on the head for a fixed period of time which modulates the cortical 
excitability and promotes motor learning in healthy individuals. There are multiple studies showing improved 
motor recovery in chronic stroke patients which has raised interest of tDCS in motor recovery in PD. Because 
PD is first and foremost a motor disturbance phenomenon, most studies in PD used tDCS to target the primary 
motor cortex (M1), reporting improvements in motor function and gait, compared with sham stimulation. The 
previous tDCS studies either stimulated primary motor cortex (M1) and supplementary motor area (SMA) or 
dorsolateral prefrontal cortex (DLPFC) directing the motor functions or non-motor function respectively. 
However, both M1 and DLPFC are found to be involved in both motor and non-motor functions and are 
involved in balance and mobility function. In accordance, a functional MRI study has shown that the anodal 
tDCS over the primary motor cortex (M1) and DLPFC increases the functional connectivity between the left 
caudate nucleus and parietal association cortices and modulates the functional connectivity of cortico-striatal 
and thalamo-cortical circuits resposnsible for motor improvement.[16] 

6 
 
In one of the first studies of tDCS in PD, Fregni et al [13] evaluated the effects of tDCS on both motor function 
and motor-evoked potentials (MEPs) of the hand in patients with PD. They found that anodal stimulation of 
primary motor cortex (M1) was associated with a significant improvement of motor function and reaction 
times. This effect was however not observed for cathodal stimulation of M1 or anodal stimulation of DLPFC, 
although a small (non statistically significant) improvement in motor function was noted. 
 
Francesca Valentino et al [14] noted that anodal tDCS of primary motor cortex (M1) has a significant 
improvement of gait, as assessed by the Stand Walk Sit test, with reduction in number and duration of FOG 
episodes, along with a significant reduction in the Unified Parkinson’s Disease Rating Scale score. 
 
In Benninger et al [15] twenty-five PD patients were investigated with randomized, double blind, sham 
controlled study design with 13 patients receiving anodal tDCS over motor and pre frontal cotices 
alternatively over 8 sessions and 12 patients received sham stimulation. They noted tDCS improved gait by 
some measures for a short time and improved bradykinesia in both the on and off states for longer than 3 
months. 
 
Rosa maneti et al has also noted that significant motor improvement with improved TUG test score is seen 
after anodal tDCS of dorsolateral prefrontal cortex of right or left side depending on the particular side of 
onset of motor symptoms. 

7 
 
LACUNAE IN EXISTING KNOWLEDGE 
 
 
Dopaminergic medication and Deep Brain Stimulation (DBS) are current standard interventions for 
PD. Pharmacotherapy with dopaminergic drugs leads to partial improvement in the motor functions 
of patients. Invasive therapies like Deep Brain Stimulation have as yet limited availability and 
accessibility with risk of adverse events as well. Noninvasive therapies like tDCS are currently 
increasingly being probed for their therapeutic value in view of their safety, portability and 
convenience of administration. 
 
 
 
 
Improvement in motor function immediately after a single session of tDCS has been observed. The 
effect of single stimulation is not sustained beyond a few days. Only a few studies with varied sites of 
stimulation have evaluated the effect of repetitive tDCS on motor function improvement in patients 
with PD with conflicting results. There is unmet need to probe the utility of repetitive tDCS on motor 
function of patients with PD. 

8 
 
RESEARCH QUESTION 
 
Does repetitive bihemispheric anodal transcranial direct current stimulation of dorsolateral prefrontal cortex 
and M1 cortex lead to improvement in motor function of patients with PD? 

9 
 
RESEARCH HYPOTHESIS 
 
Repetitive bihemispheric anodal tDCS of dorsolateral prefrontal cortex and M1 cortex leads to sustained 
improvement in motor function of patients with PD (Hoehn and Yahr stage 2 to 4) beyond the immediate 
period of 4 days after the stimulation 

10 
 
AIMS AND OBJECTIVES 
 
 
 
Primary Objective: To determine change in motor function score as assessed by MDS-UPDRS Part – III scale 1 
week after the repetitive tDCS 
 
Secondary Objective: To determine the change in Timed Up and Go test score of patients with Parkinson’s 
Disease at 1 week after the repetitive tDCS 

11 
 
MATERIAL AND METHODS 
 
 
Place of Study: Department of Neurology, ABVIMS & Dr. RML Hospital, New Delhi. 
 
 
Study design: Randomized, double blind, sham-controlled study. 
 
 
Sample size: 
The study of David H Benninger, et al observed that UPDRS(III) at 1 month post-intervention in tDCS group 
was 22.7 ± 6.6 and in sham group was 18.6 ± 8.1. Taking these values as reference, the minimum required 
sample size with 80% power of study and 5% level of significance is 51 patients in each study group. Due to 
time constraints and non-availability of patients, finite population correction factor is used. Taking population 
as 30, total sample size calculated is 24. Taking lost to follow up as 15% and to reduce margin of error, total 
sample size taken is at least 30 (15 patients per group for sample size of 30). 
 
Formula used is: 
For comparing mean of two groups 
N>=2(standard deviation)2 X(Zα + Zβ)2 
(mean difference)2 
 
Where Zα is value of Z at two sided alpha error of 5% and Zβ is value of Z at power 
of 80% and mean difference is difference in mean values of two groups. 
Pooled standard deviation= 
√(𝑆12 + 𝑆 22)/2 
 
Where S1 is standard deviation of 1 group. 
and S2 is standard deviation of other group. 
Finite population correction factor:- 
 
 
Where Pop is population 
 
 
 
 
𝑛 − 1 
𝑆𝑆 ≥ 𝑛/(1 + [ 𝑃𝑜𝑝 ]) 

12 
 
Calculations: 
Pooled standard deviation= 
=7.39 
N>=2(7.39)2 X(1.96 + 0.84)2 
(4.1)2 
 
 
>=50.91=51(approx.) 
 
 
√(6.62 + 8.12)/2 
 
 
Total sample size to be taken is 102 
Finite population correction factor:- 
SS >=102/ (1 + [(102 − 1)/30])>=23.36=24(approx.) 
 
Taking lost to follow up as 155, n>=24/.85>=28.23=29(approx.) 
 
 
Study population: Patients with PD. 
 
Type of Study: - Prospective interventional randomized double blinded comparative study. 
Block Randomization 
Block Randomization with Sealed envelope system:- In this, one person, who is neither investigator nor 
personnel applying tDCS, will prepare ten sealed opaque envelopes assigning A and B in 5 envelopes each, 
where one label represents tDCS group and other label represents sham group. Once a patient will consent to 
enter a trial an envelope will be opened and the patient will then be offered the allocated group. In this 
technique, patients will be randomized in a series of blocks of ten. So basically, we are using 3 blocks and in 
each block, 10 patients will be taken and among those 10 patients, 5 patients will be allocated tDCS group 
and 5 patients will be allocated sham group. Neither the patient nor the investigator will know which label 
represents which group making the study double blinded. 
 
The data will be entered in MS EXCEL spreadsheet and analysis will be done using Statistical Package for 
Social Sciences (SPSS) version 21.0. 

13 
 
INCLUSION CRITERIA 
 
 
 
1. Patients fulfilling the Movement Disorder Society (MDS) clinical diagnostic criteria for Parkinson’s 
disease. 
2. Patients with Hoehn & Yahr stages 2–4 Parkinson’s disease. 
3. Patients maintained on stable medical regimen for at least 1 month before entering the study. 
 
 
 
 
 
EXCLUSION CRITERIA 
 
 
1. Patients with other confounding neurological and psychiatric disorders. 
 
2. The presence of metal objects or stimulators in the head. 
 
3. Patients with a history of deep brain stimulation. 
 
4. Patients with history of seizures. 
 
5. Patients with skull defect due to surgery e.g. craniectomy 
 
6. Patients with scalp condition likely to obstruct application of electrodes. 

14 
 
PROCEDURAL DETAILS 
 
Patients with PD will be included irrespective of treatment duration, age, gender and duration of illness. The 
demographic data of all the included patients will be collected and detailed clinical history and examination 
including neurological assessment will be done in all the patients. The diagnosis of Parkinson’s disease will 
be made by the MDS clinical diagnostic criteria for Parkinson’s disease. The severity of motor dysfunction 
will be assessed according to Movement Disorder Society (MDS)- Unified Parkinson’s Disease Rating Scale 
(UPDRS) revision (MDS-UPDRS) part III. Hoehn and Yahr staging will be done for each subject. Patients 
will be assessed by Timed up and go (TUG) test. 
The study will be double-blind, sham-controlled study wherein whether the patients will recieve sham or real 
stimulation will be decided by randomization. The patient will be serially given an envelope containing the 
modality of treatment to be given in coded numbers during sessions. He/she will take the envelope to the 
personel involved in the stimulation only. The person who will perform tDCS will open the envelope and 
stimulation will be given as per coded protocol for the sham or the real stimulation. The stimulation record 
will be stored in the machine or storage device. The patient will be given the appropriate stimulation on next 
visit based on the type of stimulation given during the previous visit. The envelopes containing the treatment 
modality will be prepared by another person not connected with the study using randomization software. The 
patients and the investigators making the pre-stimulation and the post-stimulation assessments will be blinded 
to the type of stimulation given. The participants will be made to learn the TUG test beforehand to minimize 
learning effects on the outcome measures from pre to post tDCS. 
Transcranial direct current stimulation (tDCS) procedure: 
Anodal tDCS will be administered at the beginning of the on period after the participant had taken the levo- 
dopa dosage (around 1 hour after medication). The stimulation will be delivered by a battery-driven, direct 
current stimulator (Startism 32, Neuroelectrics, Barcelona S.L., Spain) through an array of electrodes. A direct 
current of 2 mA will be applied for 20 minutes (with a ramping period of 10 sec at the beginning and end of 
the stimulation).The current density of ≤ 0.057 mA/cm2 will be maintained as per the safety guidelines. Thee 
electrodes will be secured, and an electroconductive gel will be applied under the electrodes before the 
montage to reduce contact impedance. The international 10–10 system of electrode placement will be used to 
place the tDCS electrodes. The active anodal electrodes will be placed on left FC1 and right FC2 in order to 
stimulate the M1 and DLPFC of both the brain hemispheres simultaneously and the one cathode electrodes 
will be placed over the left or right supra-orbital area. In the sham stimulation, the tDCS montage will be the 

15 
 
same, but the current will be turned off10 s after the stimulation begins and will be turned on for the last 10 s 
of the stimulation period (the duration of the fade-in and fade-out periods is 10 s), making this condition 
indistinguishable from the experimental stimulation. The sham or the active stimulation will be done 2-3 times 
a week for a total of 10 sessions. Assessment with TUG test and MDS-UPDRS part 3 will be done at the end 
of last session of stimulation and 1 week after the last session. 
The Timed Up and Go (TUG) test: 
In the TUG test, the patients will be instructed to stand up from the sitting position while seated on a chair on 
the examiner’s signal, and then they will be asked to walk on the floor upto a distance of 3 meters (which will 
be pre-marked), then they will be asked to turn around and walk back to the chair and sit down. Patients will 
be instructed to walk at their regular pace. 
The TUG test will be measured using a stop watch. The TUG test will be performed before and at the end of 
4 weeks and one week after last session of tDCS and recordings will be made by the examiner who is blind 
to the stimulation condition received by the patient. Video recording of the test will also be done. 
 
 
 
 
 
 
 
 
 
 
Patients with Parkinson’s Disease presenting at 
Neurology department. 
Clinical diagnosis of PD with MDS-PD criteria and 
assessment for inclusion and exclusion criteria; 
If fulfilling criteria, patient consent to be taken. 
Assessment of severity with UPDRS part 3 and TUG test 
Randomization into 1 of 2 groups for tDCS stimulation; 
2-3 sessions per week for total 10 sessions. 
Repeat UPDRS part 3 and TUG test at last session and 
7-10 days after last session. 

16 
 
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18 
 
ABBREVIATIONS 
 
 
PD 
Parkinson’s Disease 
 
tDCS 
transcranial Direct Current Stimulation 
M1 
primary motor cortex 
DLPFC 
Dorsolateral Prefrontal Cortex 
 
TUG 
Timed Up and GO 
 
FOG 
Freezing of Gait 
 
rTMS 
repetitive Transcranial Magnetic Stimulation 
DBS 
Deep Brain Stimulation 
H and Y 
Hoehn and Yahr