|Year : 2020 | Volume
| Issue : 6 | Page : 755-759
The role of repetitive transcranial magnetic stimulation for enhancing the quality of life in Parkinson's Disease: A systematic review
Ashima Nehra1, Priya S Sharma1, Avneesh Narain1, Amit Kumar2, Swati Bajpai3, Roopa Rajan2, Nand Kumar4, Vinay Goyal5, Achal K Srivastava2
1 Division of Neuropsychology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
2 Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences (AIIMS), New Delhi, India
3 Department of Geriatric Medicine, All India Institute of Medical Sciences (AIIMS), New Delhi, India
4 Department of Psychiatry, All India Institute of Medical Sciences (AIIMS), New Delhi, India
5 Department of Neurology, Medanta, Gurgaon, Haryana, India
|Date of Submission||01-Feb-2020|
|Date of Acceptance||21-Feb-2020|
|Date of Web Publication||21-May-2020|
Dr. Achal K Srivastava
Room No. 60, GF, Neurosciences Centre, All India Institute of Medical Sciences (AIIMS), New Delhi - 110029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Parkinson's disease (PD) is a neurodegenerative disorder which greatly affects patients' quality of life. Despite an exponential increase in PD cases, not much attention has been paid to enhancing their quality of life (QoL). Thus, this systematic review aims to summarize the available literature for the role of repetitive transcranial magnetic stimulation (rTMS) intervention to improve QoL of PD patients. Methods: Literature review was carried out using PubMed, Embase, Web of Science and Scopus databases. The key search words were, “rTMS AND Parkinson AND QoL”, “rTMS AND Parkinson AND Quality of Life”. Cochrane Collaboration software Revman 5.3 was used to assess the quality of studies. Results: Over 707 studies were identified out of which 5 studies were included which consisted of 160 subjects, 89 male and 71 female, with mean age of 65.04 years. PD type varied from idiopathic PD, rigid, akinetic, tremor dominant to mixed type. The overall risk of bias across the studies was low and unclear with high risk of bias in incomplete outcome data domain in one study. Conclusions: The efficacy of rTMS as an adjunct intervention to enhance QoL of PD patients is uncertain due to dire lack of research in this area. The findings of the present review would help researchers conduct a well-defined, randomized, controlled trial by overcoming the present limitations associated with rTMS intervention to improve QoL of PD patients.
Keywords: Behaviour, cognition, emotion, health, neuropsychology
|How to cite this article:|
Nehra A, Sharma PS, Narain A, Kumar A, Bajpai S, Rajan R, Kumar N, Goyal V, Srivastava AK. The role of repetitive transcranial magnetic stimulation for enhancing the quality of life in Parkinson's Disease: A systematic review. Ann Indian Acad Neurol 2020;23:755-9
|How to cite this URL:|
Nehra A, Sharma PS, Narain A, Kumar A, Bajpai S, Rajan R, Kumar N, Goyal V, Srivastava AK. The role of repetitive transcranial magnetic stimulation for enhancing the quality of life in Parkinson's Disease: A systematic review. Ann Indian Acad Neurol [serial online] 2020 [cited 2021 Jan 25];23:755-9. Available from: https://www.annalsofian.org/text.asp?2020/23/6/755/284681
| Introduction|| |
Parkinson's disease (PD) is a neurodegenerative disorder that hampers greatly with activities of daily living (ADL). In 2016, 6.1 million individuals had PD globally. This number is estimated to double by 2030. The underlying physiological mechanisms of the disease involves the degeneration of dopaminergic neurons in the substantia nigra region of the brain.,, It is characterized by tremors, rigidity, bradykinesia, and instability of posture.,,, Non-motor and motor symptoms adversely affect patients' quality of life (QoL).
Repetitive transcranial magnetic brain stimulation (rTMS) is effective, non-invasive, and alters the excitatory levels of different brain areas. The excitability produced by high-frequency stimulation may be associated with long-term potentiation. It is safe, painless, and inexpensive.
Combining rTMS with existing interventions seems to be promising in neuromodulation. As compared to antiparkinsonian medications, rTMS has a long-term effect (up to 20 weeks from rTMS stimulation) on cognition, mood, motor symptoms, and QoL with minimal side effects. Longer duration rTMS sessions have long-lasting benefits.,
Health-related QoL refers to an individual's perception of the impact of an illness on his/her social, psychological, and physical domains of life. Issues such as gait,, dysphagia, sleep problems, and depression, impair QoL significantly and markedly restrict ADL. While QoL decreases with impaired motor symptoms, it is more severely affected by neuropsychological symptoms like cognition and mood. Thus, QoL is gradually becoming the focus of attention in research. There is a need for multidisciplinary interventions to enhance the well-being and QoL of patients with PD.,
Research on rTMS intervention as an adjunct therapy, for enhancing the QoL of patients with PD is required for holistic rehabilitation. No research has been undertaken in this topic for systematic review so far, to the best of our knowledge. Therefore, the primary objective is to carry out a review to assess the role of rTMS intervention on the QoL of patients with PD while the secondary objective is to observe whether other factors contribute towards increased QoL.
| Methods|| |
A literature search from inception to the mentioned date was carried out using the following sources – PubMed (27 studies; 17/06/19), Embase (37 studies; 27/05/19), Web of Science (16 studies; 21/06/19), and Scopus (626 studies; 16/09/19). The key search words were, “rTMS AND Parkinson AND QoL”, “rTMS AND Parkinson AND Quality of Life”. The details of the included studies are described in [Table 1]. Cochrane Collaboration software Revman 5.3 and the guidelines by Higgins and Altman were used to assess the risk of bias as described in [Table 3] (online only: supplementary material).vw
Studies with rTMS and sham intervention on humans with QoL assessment tools were included.
Studies were excluded if they were, reviews of previous studies (256), meta-analysis (13), without rTMS (69) or sham (4) intervention, not measuring QoL (16), editorials (6), articles (18), duplicates (74), case reports (2), chapters (53), books (36), not in English (16), not based on PD population (132), based on animal subjects (2), or was an on-going study (1), consensus (1), had multiple interventions (1) (online only: Supplementary material). Since the study design is a systematic review, no ethics committee approval was required.
Studies recruited patients with PD as classified by the UK PDS Brain Bank criteria,, for diagnosing PD by Calne et al. (1992) and the Queen Square Brain Bank Criteria by Lees et al. (2009).
Studies included determined the role of rTMS intervention on patients with PD.
Studies compared rTMS with sham group, which utilizes a sham coil that only generates sound instead of the magnetic field generated by the rTMS coil.
Included studies used QoL assessment tools to evaluate patients with PD post the rTMS intervention.
Two reviewers, PS and AN extracted the data individually [see [Table 1]]. Any disagreements between the reviewers were resolved through discussions and mutual consensus amongst all authors. The papers were read thoroughly to critically analyze the studies.
| Results|| |
Electronic search in PubMed, Embase, Web of Science, and Scopus databases identified over 707 studies out of which, five were included. A total number of 160 subjects were present with, 47 in sham group, 88 in experimental group, and 25 subjects belonged to both groups. The included studies consisted of, open-label, two pilots,, crossover, and multicenter study. No significant demographic difference across groups and baseline clinical characteristics was observed in two studies., However, it differed in other studies due to the low sample size., A summary of included and excluded studies is provided in [Table 1] and [Table 2] (online only: supplementary information), respectively. The study flow diagram is illustrated in [Figure 1].
As mentioned above, Revman 5.3 software was used to assess the risk of bias across seven domains (Refer to [Figure 2] and [Figure 3]). Within the trails - the studies by Dias, Makkos, Yokoe, and Randver et al., had low or unclear risk of bias for all key domains. However, Brys et al. demonstrated high risk of bias in the domain of 'incomplete outcome data'. Across the trails, there was low to uncertain risk of bias in all domains, in all studies except one study, which had high risk of bias in incomplete outcome data domain.
|Figure 2: Risk of bias summary: review authorsæ judgement about each risk of bias item for included studies|
Click here to view
A total number of 89 male and 71 female subjects participated in the studies with an average age of 65.04 years. PD type consisted of idiopathic, or rigid, akinetic, tremor dominant, mixed type. Several patients with PD had comorbid depression.,,
Studies provided no information regarding sample size calculation,,,, except one study, which had an initial sample size of 160 (81.7% power) subjects. However, this sample size was halved and the study was terminated prematurely, which reduced the statistical power and effect size and thus, resulted in inconclusive results.
Most of the studies focused on stimulating the dorsolateral prefrontal cortex (DLPFC),,, followed by the primary motor area (M1),, and supplementary motor area (SMA). The frequency of rTMS sessions ranged from 5 Hz to 15 Hz with 10 Hz, being the most common. The pulses ranged from 600 to 6000. All studies used figure- eight coil except one study, which used a circular coil. Most of the rTMS sessions lasted for 10 days,, however, one study gave the intervention for 6 consecutive weeks. Parkinson's disease questionnaire (PDQ-39) was the most common tool,,, and voice-related QoL (V-RQOL) was also used. No adverse side effects of rTMS were reported,,, apart from mild, transient head and neck ache.
Factors affecting QoL
Only one study recognized speech issues as significantly affecting the QoL of patients with PD and addressed V-RQOL as the primary objective. Whereas, in other studies,, QoL was a secondary outcome measure and not the primary concern. Additionally, a study noted that, along with the motor symptoms, neuropsychological issues may adversely affect the QoL of patients with PD.
As compared to sham, the following changes were observed in rTMS group: mean scores of V-RQOL increased from 26.67 (male) and 27.50 (female) to 51.25 (male) and 51.50 (female). A significant subjective improvement was observed in the emotional domain of V-RQOL. Another study established improvement in mobility, emotional well-being, and ADL domains of PDQ-39. The scores improved from a median of 25.4 [interquartile range (IQR): 18.5–35.4) to 16.9 (IQR: 4.5–20.0). Its efficacy was maintained in the 30-days follow-up (16.9 vs. 24.2 points). Another study measured PDQ-39 at baseline (1 week before) and then after 3 weeks and 6 weeks. In a study of 6 patients, following changes in the PDQ-39 subscales were noticed: an improvement in mobility subscale was observed in subject 3 after 3rd week and in subject 5 after 6th week. However, after the 6th week, the scores of the subjects returned to the previous level and became worse in some cases. In ADL subscale, subject 5 reported a beneficial effect after 6th week and subject 6 after 3rd week. However, the scores of subject 6 decreased. The total score demonstrated a decrease from the baseline, up to 3rd week. After 6th week, the total score returned to baseline or stayed the same for most of the subjects, however, subject 5 showed steady improvements in scores. Conversely, two studies, could not establish any difference in PDQ-39 scores between sham and rTMS groups.
The study by Dias et al. established a correlation between subjective improvement of speech and improvement in depression. A correlation between voice intensity and motor improvement as assessed by Unified Parkinson's Disease Rating Scale (UPDRS) was also established. It is probable that the increased scores of V-RQOL resulted indirectly due to enhanced voice intensity and motor symptoms. Additionally, in a study, significant improvement in QoL was observed in 'mobility', 'emotional well-being', and 'ADL' domains. Furthermore, four studies had to be excluded since, they were without sham intervention, which could have provided greater insight into the present research question.
Quality assessment of included studies
[Figure 3]: Risk of bias graph: review of authors' judgment about each risk of bias item presented as percentages across all included studies.
| Discussion|| |
Research in rTMS interventions to enhance QoL of patients with PD is required since the disease is drastically rising. Overall, the risk of biases across the studies ranged from low to unclear suggesting that, the present biases are unlikely to alter the results seriously. However, a study demonstrated a high risk of bias in the domain of incomplete outcome data.
Several limitations as outlined in the aforementioned studies should be addressed to improve future research.
There is a lack of sham group to negate the placebo effect. The placebo effect in rTMS intervention is particularly pronounced for mood symptoms that create confusion in determining the efficacy of rTMS intervention. The fact that placebo induced improvement can be observed in one domain but not the other gives us insight into the selectivity of placebo effect.
The issue of low sample size persists due to low confidence in the safety of the procedure, lack of rTMS professionals, alterations in PD course, overall disease burden, high patient drop-outs, non-consenting patients, and strict contraindications for rTMS. Reduced sample size leads to poor generalization and decreased effect size, which results in inconclusive results and large discrepancy between individual differences.
Mood and voice improvement via rTMS may be confounded with antidepressants since enhanced mood due to anti-depressants can also result in voice improvements. Moreover, decreased scores on measures assessing the efficacy of rTMS intervention, may be attributed to - 'regression to mean', spontaneous recovery, placebo effect, better palliative care, healthier lifestyle, illness duration, and medical adherence. There is also a lack of systematic data collection clearly outlining the medical regimen of the patients, their symptoms of fluctuation and consistency of pre and post-assessment during off/on periods. Since patients with PD are prone to motor fluctuations during the daytime, based on the timing of their medications, motor symptoms should be assessed at fixed intervals.
The efficacy of rTMS varies due to its heterogeneous stimulation protocols. The studies suggest that its effectiveness is dependent on patients' age, illness duration and severity, rTMS pulses, frequency, sessions, coil type, and intensity. Furthermore, the stimulation parameters are restricted to existing literature. While this is mandatory for patients' safety, it limits the exploration of other efficient parameters. For instance, a study mentioned that, in elderly, the stimulation intensity required to produce a significant effect may be higher than the existing guidelines.
Moreover, there is a lack of standardized reporting guidelines that may be followed to collate results of multiple studies. This is required to perform systematic reviews and meta-analysis easily and provide clearer results that can be generalized.
Data could not be extracted for meta-analysis because of insufficient information to pool the data. The corresponding authors of relevant studies were contacted, however, no reply, except one, was received (till second follow-up). Additionally, the email address of one author was non-existent. Publication bias could not be assessed since it requires at least 10 studies. Lastly, studies in non-English languages were not accessed.
| Conclusions|| |
The role of rTMS intervention in PD population, for enhancing QoL is unclear and controversial. This review provides insight to conduct well-defined, randomized, controlled, multicenter trials and highlights present limitations that need to be addressed while designing future neuro-psychological rTMS interventions to enhance QoL of patients with PD.
Research protocols that address the aforementioned limitations should be prepared. The discrepancy between female to male subjects ratio should be reduced and the various PD symptoms should be addressed. A consensus in the standardized classification protocol for PD is also required to ensure that the clinical characteristics of patients do not vary largely to impact the outcome of the interventions. Different rTMS protocols should be observed to assess their efficacy and standardization for safety. Precautions like earbuds and sturdy neck support should be taken to avoid head and neck aches. Cognitive, mood, speech, and motor symptoms should be focused upon to enhance QoL. Symptom-specific QoL measures are required and should be used as primary assessment tools in rTMS studies.
Additional research is required to observe the effectiveness of focalized vs. multifocal stimulation (for assessing the extent of synergic effect) and unilateral vs. bilateral stimulation. The duration of sessions along with the wash-out period and durability of rTMS effects also needs clarity. A deeper understanding of the underlying neurophysiological mechanisms, in the case of multifocal stimulations is also required. Multicenter studies should be designed to overcome low sample size issues and thus increase the power of the study. Lastly, it is speculated that providing neuropsychological interventions along with rTMS intervention, would greatly enhance the QoL of patients with PD.
Financial support and sponsorship
This study was financially supported by the Department of Biotechnology (DBT), Government of India.
Conflicts of interest
There are no conflicts of interest.
| Supplementary Information|| |
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[Figure 1], [Figure 2]