Electroencephalography, Musculoskeletal Pain, Neuromodulation, Parkinson's Disease, Primary Motor Cortex, Repetitive Transcranial Magnetic Stimulation
Conditions
Brief summary
Pain is an increasingly recognized non-motor symptom of Parkinson's disease (PD), with significant prevalence and negative impact on the quality of life of patients. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex（M1）has been proposed to provide definite analgesic effect for pain syndromes. However, very few placebo-controlled studies have been performed specifically to relieve pain in PD. What's more, based on behavioral measures alone, it is impossible to reveal the full network dynamics reflecting the impact of TMS. Electroencephalography (EEG), with high temporal resolution, records signal that its origin in electrical neural activity, which makes it suitable for measuring TMS-evoked activation. By recording the TMS induced neuronal activation directly from the cortex, TMS-EEG provides information on the excitability, effective connectivity of cortical area, thus exploring cortical network properties in different functional brain states. In addition, the use of EEG offers great prospects as a tool to select the right patients in order to achieve adequate, long-term pain relief. Besides assessing the efficacy and safety of high-frequency neuronavigated M1-rTMS in PD patients with musculoskeletal pain, the objective of this study additionally aimed to characterize cortical activation behind pain relief. Influence on motor and other non-motor symptoms after rTMS were also investigated.
Detailed description
Pain can appear as a pre-motor symptom, and its intensity could be severe enough to be the dominant non-motor symptom in the course of PD patients. It estimated the prevalence of painful phenomena in PD to be 30 to 85% (mean 66%), which is significantly greater than the age-matched general population. Painful experiences in PD are highly heterogeneous and complex, which is difficult to describe for patients but also diagnose for neurologists. In addition, this common and disabling symptom receives inadequate analgesic treatment. The distinction between these pain subtypes is required so that different therapeutic strategies can be established for each type of pain. The King's Parkinson's Pain scale (KPPS) was validated to identify and rate the various types of pain in PD. Fourteen items cover seven main domains, including musculoskeletal pain, chronic body pain (central or visceral), fluctuation-related pain, dyskinetic-dystonic pain, nocturnal pain, oro-facial pain, discolouration/oedema/swelling, and radicular pain. Of these subtypes, musculoskeletal pain is common. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that may be useful for the treatment of various psychiatric and neurological disorders. The mechanisms underlying rTMS effects remain to be elucidated. rTMS is postulated to induce neuronal excitability changes in a set of cortical and subcortical areas involved in pain processing and modulation. Interestingly, M1 stimulation had a positive effect on brain structures that are related to the affective-emotional components of pain, such as the insular cortex and cingulate cortex. The best efficacy for chronic pain has been achieved when primary motor cortex (M1) is stimulated at high frequency (5 to 20 Hz, 80% of the resting motor threshold (RMT)), as in previous rTMS studies in analgesia. In TMS, time-varying magnetic fields generates electrical currents in the cortex. TMS pulses can either directly or trans-synaptically depolarize neurons, and these neural activities can be recorded through the skull by EEG electrodes placed on the scalp. The combination of TMS with simultaneous EEG can be used to assess excitability, inhibition, plasticity and connectivity across almost all areas of the cortical mantle. The characterization of potential TMS-EEG predictors and markers could be the theoretical basis for verifying the response to neuromodulation protocols. In this randomised, double-blind, placebo-controlled study, the efficacy and safety of 7 sessions of 20 Hz-rTMS delivered to M1 will be assessed in PD patients with chronic musculoskeletal pain. A single-pulse TMS-EEG and resting-state EEG directly provide information on the cortical mechanisms before and after rTMS of M1.
Interventions
PROCEDUREactive M1-rTMS
Magnetic stimulation will be carried out using a MagPro X100 machine with a MCF-B70 figure-of-eight coil (Magventure, Farum). All rTMS sessions will be assisted by a neuronavigation system (TMS Navigator，Localite GmbH), maintaining the M1 target and the orientation of coil stable during stimulation sessions. The M1 target was defined as the "hand knob" region, which corresponds to the motor cortical representation of the hand, regardless of the location of pain. Stimulation paradigm consists of 20 trains of pulses with an intra-train frequency of 20 Hz, resulting in 2000 pulses for a total duration of 20 minutes. The stimulation intensity will be 80% of RMT, defined as the lowest stimulation intensity necessary to induce a visible muscle twitch of the hand contralateral to the stimulated hemisphere. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
PROCEDUREsham rTMS
The sham protocol was similar to the rTMS protocol. Sham stimulations will be performed with a MCF-P-B65 figure-of-eight coil (Magventure) to M1, assisted by a neuronavigation system. The following stimulation parameters will be used: stimulus frequency 20 Hz; stimulus intensity 80 % of RMT; total stimulation pulses 2,000; total stimulation time 20 min. Participants will receive 7 sessions of treatment once a day in the same time continuously for 7 days, and keep antiparkinsonism drugs unchanged throughout the whole study.
Sponsors
Second Affiliated Hospital of Soochow University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Masking description
The figure-of-eight coils used for active or sham stimulation are similar, including the emitted sound and the scalp tapping sensation.
Intervention model description
Patients will be randomised to receive either active or sham-rTMS according to a 2:1 ratio.
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Idiopathic PD was diagnosed according to the 2015 Movement Disorder Society (MDS) clinical diagnostic criteria 2. Hoehn and Yahr stages of I to III 3. musculoskeletal pain was detected based on the Ford classification system for pain in PD. Pain duration of at least 3 months, with continuous moderate intensity pain (≥ 3/10 on a 0-10 numerical rating scale) occurring at least three days per week. 4. stable antiparkinsonian therapy for ≥4 weeks
Exclusion criteria
1. Contraindications to rTMS 2. unstable ongoing psychiatric disorder, history of substance abuse (alcohol, drugs) 3. histories of deep brain stimulation surgery 4. Mini-mental State Examination scores ≤24 5. Other pain conditions, such as apparent osteoarthritis, or rheumatoid arthritis depended on laboratory or imaging findings
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Over 2 Months (Group by Time Interaction) in Modified KING'S PD Pain Scale Domain 1 | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | Modified King's PD Pain Scale (MKPPS)，the modified version which is more suitable for Chinese people, combined with Ford's pain subtypes basing on the original. It covers five main domains, including 16 items, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a total possible score range from 0 to 192. Higher scores indicate greater symptom severities and more serious influence. |
| Change From Baseline Over 2 Months (Group by Time Interaction) in KING'S PD Pain Scale Domain 1 | before the first rTMS session (day 1), after rTMS therapy (day8、1month、2months) | KING'S PD Pain Scale (KPPS) Domain 1 focused on musculoskeletal pain, covering one item, which was scored by multiplying severity (from 0 \[no pain\] to 3 \[very severe pain\]) by frequency (from 0 \[never\] to 4 \[all the time\]), yielding sub-scores between 0 and 12. Higher scores indicate greater symptom severity. |
| Change in 0-10 Numeric Rating Scale | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | Pain intensity was assessed over the past 24 hours using a 0-10 number, where 0 indicating no pain and 10 indicating maximal pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Resting-state EEG Oscillations | before the first rTMS session (day 1), after rTMS therapy (day8) | For each EEG epoch, we computed the fast Fourier transform (FFT) algorithm to convert to frequency domain. The power values in following five frequency bands were obtained: delta (1-4Hz), theta (4-8Hz), alpha(8-13Hz), beta(13-30Hz), gamma(30-80Hz). |
| Changes in Movement Disorder Society-Unified PD Rating Scale Part I | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | The participants will be evaluated in their "ON" medication states. The scale was used to assess the impact of non-motor symptoms on daily life, ranging from 0 to 52, with higher scores indicating more severe symptoms. |
| Change in Movement Disorder Society-Unified PD Rating Scale Part II | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | The participants will be evaluated in their "ON" medication states. The scale was used to evaluate the patient's perspective on how motor symptoms impact their ability to perform daily activities, ranging from 0 to 52, with higher scores indicating more severe symptoms. |
| Change in Movement Disorder Society-Unified PD Rating Scale Part III | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | The participants will be evaluated in their "ON" medication states. The scale was used to provide a quantitative, objective measure of motor signs, ranging from 0 to 132, with higher scores indicating more severe symptoms. |
| Change in Movement Disorder Society-Unified PD Rating Scale Part IV | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | The participants will be evaluated in their "ON" medication states. The scale was used to document the presence and impact of motor fluctuations and dyskinesias, ranging from 0 to 24, with higher scores indicating more severe symptoms. |
| Changes in Hamilton Depression Scale | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | The depression score (ranging from 0 to 76 with higher scores indicating more severe depression) from the 24 items Hamilton Depression Scale (HAMD). |
| Changes in Hamilton Anxiety Scale | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | The anxiety score (ranging from 0 to 60 with higher scores indicating more severe anxiety) from the 14 items Hamilton Anxiety Scale (HAMA). |
| Changes in PD Sleep Scale-2 | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | The sleep problem index (from 0 to 68 with higher scores indicating more severe sleep problem) from the PD Sleep Scale-2 (PDSS-2). |
| Changes in Epworth Sleeping Scale | before the first rTMS session (day 1), after rTMS therapy at day8、1month、2months | The daytime sleepiness was assessed by the Epworth Sleeping Scale, which has a score range of 0-24, with higher scores indicating more severe symptoms. |
| Changes in PD for Autonomic Symptoms | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | The Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOUP-AUT), which has a score range of 0-67, with higher scores indicating higher autonomic nervous system dysfunction. |
| Changes in PD Questionnaire-39 | before the first rTMS session (baseline), after rTMS therapy (day8、1month、2months) | We will also assess change in quality of life from the Parkinson's Disease Questionnaire-39 (PDQ-39), ranging from 0 to 156 with higher scores indicating more serious influence. |
Countries
China
Participant flow
Pre-assignment details
After screened, 68 patients were included in the study, of which, 6 withdrew consent before randomization. 2 patients were exhausted to the journey, 3 patients were declined to participate, 1 patient was infected coronavirus.
Baseline characteristics
| Characteristic | — |
|---|---|
| 0-10 numeric rating scale | 5.0 units on a scale |
| Age, Continuous | 62.92 years STANDARD_DEVIATION 0.99 |
| Disease duration | 6 years |
| Education | 7.45 years STANDARD_DEVIATION 0.63 |
| Epworth Sleeping Scale | 8.23 units on a scale STANDARD_DEVIATION 0.94 |
| Hamilton Anxiety Scale | 10.5 units on a scale |
| Hamilton Depression Scale | 11.0 units on a scale |
| Hoehn and Yahr stage | 2.0 units on a scale |
| KING'S PD Pain Scale Domain 1 | 8.0 units on a scale |
| levodopa-equivalent daily dose (LEDD) | 586.72 mg/day STANDARD_DEVIATION 56.93 |
| Modified KING'S PD Pain Scale Domain 1 | 12.0 units on a scale |
| Movement Disorder Society-Unified PD Rating Scale Part I | 12.0 units on a scale |
| Movement Disorder Society-Unified PD Rating Scale Part II | 12.65 units on a scale STANDARD_DEVIATION 0.7 |
| Movement Disorder Society-Unified PD Rating Scale Part III | 30.82 units on a scale STANDARD_DEVIATION 3.24 |
| Movement Disorder Society-Unified PD Rating Scale Part IV | 3.0 units on a scale |
| PD Questionnaire-39 | 36.0 units on a scale |
| PD Sleep Scale-2 | 10.5 units on a scale |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment China | 40 participants |
| Resting motor threshold | 46.33 percentage of maximum stimulator output STANDARD_DEVIATION 1.68 |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 10 Participants |
| the Scales for Outcomes in PD-Autonomic Symptoms | 17.29 units on a scale STANDARD_DEVIATION 1.17 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 22 |
| other Total, other adverse events | 15 / 40 | 9 / 22 |
| serious Total, serious adverse events | 0 / 40 | 0 / 22 |
Outcome results
None listed