Mental Representation Techniques for the Treatment of Parkinson´s Disease-related Pain

Mental Representation Techniques Targeting Pain in Parkinson´s Disease Patients: A Randomized Controlled Trial

Pain is an under-reported but prevalent symptom in Parkinson´s Disease (PD), impacting patients' quality of life. Both pain and PD conditions cause cortical excitability reduction, but mental representations techniques are thought to be able to counteract it, resulting also effective in chronic pain conditions. The investigators of the present project aim to evaluate the efficacy of a novel mental representation protocol in the management of pain in PD patients during the ON state. The investigators hypothesize that Action Observation (AO) and Motor Imagery (MI) training through a Brain-Computer Interface (BCI) using Virtual Reality (AO+MI-BCI) can improve clinical pain and its central processing features.

Parkinson´s Disease (PD) affects between 4.1 and 4.6 million people in the world. The diagnosis of PD is currently clinical and based on its motor manifestations (bradykinesia, rest tremor, and rigidity). However, non-motor symptoms such as pain, fatigue, and neuropsychiatric manifestations are present in more than 70% of subjects. Pain affects about 85% of patients but is paradoxically under-reported and consequently under-treated in PD patients with a great impact on their quality of life. Levodopa, which is the election treatment in PD, has shown controversial results regarding pain sensitivity and has been shown ineffective for enhancing the endogenous pain modulation system. Furthermore, there is a lack of management protocols and nonpharmacologic treatments for pain in PD. Several syndromes are hypothesized to be involved in PD pain generation. Generally, PD patients suffer from alterations in peripheral transmission, sensitive-discriminative processing, pain perception, and pain interpretation in multiple levels, due to neurodegenerative changes in dopaminergic pathways and non-dopaminergic pain-related structures. Therefore, central mechanisms are proposed to be crucial for the development and establishment of pain in PD patients. Regarding pain processing features, PD patients have reduced pain thresholds, an augmented Temporal Summation (TS) after repetitive nociceptive stimulus, and the impairment of their Conditioned Pain Modulation (CPM) is correlated with greater severity and premature onset of the disease. Cortical excitability reduction is common in patients with pain. Therefore, diverse therapies are being developed to counteract this cortical excitability reduction and obtaining, consequently, effective pain relief. In consonance with these findings, in PD condition, especially in off state, there is also evidence of cortical excitability decrease but, to the best of investigators´ knowledge, there are no studies targeting cortical excitability to treat pain in PD. Thus, the present study proposes mental representation techniques for the treatment of PD-related pain. The mental representation techniques included in the protocol will be Action Observation (AO) and Motor Imagery (MI). The combination of AO and MI has shown to synergically increase cortical excitability, influencing the activation of cortical areas such as M1 and DLPFC. Specifically in PD, AO and MI have also demonstrated to produce corticomotor facilitation. In addition, mental representation training can produce neurophysiological activity similar to actual exercise training, which has shown to decrease the intensity and severity of pain in PD patients. The main aim of this study is to conduct an independent parallel randomized controlled trials based on AO+MI-BCI targeting changes in 1. validated general and specific PD related pain scales and 2. psychophysical measurements of pain modulation mechanisms. The investigators´ main hypothesis is that AO+MI-BCI will be superior to their respective control placebo intervention.

This study will be a double-blinded experimental longitudinal prospective randomized controlled trial with a parallel design. The randomization will be realized through randomization software. All the participants who fulfill the inclusion criteria and have none of the exclusion ones will be randomly allocated into two groups: AO+MI through a Brain-Computer Interface (BCI) training paradigm in Virtual Reality (VR) (AO+MI-BCI) or AO of non-related with movement illustrations (AO-control). Allocation concealment will be ensured by the inclusion of the assigned group in closed opaque envelopes that will be opened at the time of the intervention.

Double-blind criteria will be achieved by following the same protocol with the same instruments in both groups. The evaluator will not be able to stay in the same room during the intervention and patients will not know the instructions and specific hypotheses of each protocol. The statistician will be blinded through the assignment of neutral numbers to both groups. Patients recruited will not meet in waiting rooms to avoid them to comment on their experience during the protocol. Unblinding will be permissible when any event could suppose a risk for the patient's health.

Action Observation+Motor Imagery through a Brain-Computer Interface training paradigm in Virtual Reality using the "NeuRow" platform during 10 sessions of 20 minutes, divided in 4 series of 5 minutes.

Control Action Observation protocol of non-related with movement illustrations during 10 sessions of 20 minutes, divided in 4 series of 5 minutes.

Patients will undergo the treatment through the NeuRow platform. NeuRow is a gamified Brain-Computer Interface training paradigm in Virtual Reality (or neurogame) that allows patients to perform the same actions as they would do in real-life by imaging the movement. In NeuRow, patients will see a boat and two high fidelity virtual arms gripping two oars in the first-person view. Patients will have to imagine the movement of each corresponding hand to rotate each oar and progress, observing the movement imagined on screen. The goal of the task is to collect as many flags as possible in a fixed amount of time. In order to improve adherence, the number of flags collected will be recorded in each session. It will be able to adapt the boat speed, turn speed, and cut-off angle, to help patients not to deviate in excess from the target. The treatment itself will be performed for 20 minutes each session, divided into 4 series of 5 minutes to prevent fatigue.

The same configuration will be applied to simulate a BCI task, but playing a video about graphic illustrations, people's faces, and landscapes, never related to human movement. They will address interesting and changing topics to avoid patient's boredom. The control session will last 20 minutes, also divided into 4 series of 5 minutes and the therapist will give the instructions of observing and relax.

Parkinson´s Disease specific scale that evaluates the localization, frequency, and intensity of pain. It has 14 items distributed in 7 domains: 1. Musculoskeletal Pain; 2. Chronic Pain; 3. Fluctuation-related Pain; 4. Nocturnal Pain; 5. Oro-facial Pain; 6. Discoloration, Oedema/Swelling Pain; 7. Radicular Pain. Each item is scored by severity (0, none to 3, very severe) multiplied by frequency (0, never to 4, all the time) resulting in a subscore of 0 to 12, the sum of which gives the total score with a theoretical range from 0 to 168, with higher scores indicating more severity and frequency of pain.

Parkinson´s Disease specific scale that evaluates the localization, frequency, and intensity of pain. It has 14 items distributed in 7 domains: 1. Musculoskeletal Pain; 2. Chronic Pain; 3. Fluctuation-related Pain; 4. Nocturnal Pain; 5. Oro-facial Pain; 6. Discoloration, Oedema/Swelling Pain; 7. Radicular Pain. Each item is scored by severity (0, none to 3, very severe) multiplied by frequency (0, never to 4, all the time) resulting in a subscore of 0 to 12, the sum of which gives the total score with a theoretical range from 0 to 168, with higher scores indicating more severity and frequency of pain.

It contains 15 items, including 2 multi-item scales to measure the intensity of pain and its impact on the function and welfare of patients. It also presents open questions to assess the localization of pain and the treatment used for its management, just as its effectiveness. Scores oscillate from 0 to 110, with higher scores indicating more pain and more impact on function and welfare of patients.

It contains 15 items, including 2 multi-item scales to measure the intensity of pain and its impact on the function and welfare of patients. It also presents open questions to assess the localization of pain and the treatment used for its management, just as its effectiveness. Scores oscillate from 0 to 110, with higher scores indicating more pain and more impact on function and welfare of patients.

Assesses the descending pain modulatory system. The Pain Pressure Threshold will be assessed in the middle of the distal phalanx of the thumb with ta handheld algometer, corresponding to the first test stimulus. Afterward, the patient will immerse the contrary hand up to the wrist into stirred ice-cold water (0-4º) maintaining it for 3 minutes, corresponding to the conditioning stimulus. If the pain is unbearable before the 3 minutes, the patient will be able to remove his/her hand. Immediately after removing the hand, a second Pain Pressure Threshold measure will be performed in the same place as the first one, corresponding to the second test stimulus. After 1-minute rest, a third Pain Pressure Threshold will be measured to assess the Conditioned Pain Modulation residual functioning.

Assesses the descending pain modulatory system. The Pain Pressure Threshold will be assessed in the middle of the distal phalanx of the thumb with ta handheld algometer, corresponding to the first test stimulus. Afterward, the patient will immerse the contrary hand up to the wrist into stirred ice-cold water (0-4º) maintaining it for 3 minutes, corresponding to the conditioning stimulus. If the pain is unbearable before the 3 minutes, the patient will be able to remove his/her hand. Immediately after removing the hand, a second Pain Pressure Threshold measure will be performed in the same place as the first one, corresponding to the second test stimulus. After 1-minute rest, a third Pain Pressure Threshold will be measured to assess the Conditioned Pain Modulation residual functioning.

Represents excitatory modulation processes. It will be generated through the application of 10 pulses of the handheld pressure algometer over the middle of the distal phalanx of the thumb with the intensity of the Pain Pressure Threshold, previously calculated. In each pulse, pressure intensity will be increasing at a rate of 2 kg/s over the previously determined Pain Pressure Threshold intensity, leaving an interstimulus interval of one second according to the optimal method reported for inducing Temporal Summation with pressure pain. Before the first pressure pulse, subjects were taught to use a verbal numeric pain rating scale to rate the pain intensity of the first, fifth, and 10th pressure pulses. The verbal numeric pain rating scale ranged from 0 ("no pain") to 10 ("the worst possible pain").

Represents excitatory modulation processes. It will be generated through the application of 10 pulses of the handheld pressure algometer over the middle of the distal phalanx of the thumb with the intensity of the Pain Pressure Threshold, previously calculated. In each pulse, pressure intensity will be increasing at a rate of 2 kg/s over the previously determined Pain Pressure Threshold intensity, leaving an interstimulus interval of one second according to the optimal method reported for inducing Temporal Summation with pressure pain. Before the first pressure pulse, subjects were taught to use a verbal numeric pain rating scale to rate the pain intensity of the first, fifth, and 10th pressure pulses. The verbal numeric pain rating scale ranged from 0 ("no pain") to 10 ("the worst possible pain").

Two Pain Pressure Thresholds will be measured by a handheld algometer, one over the most painful area (peripheric hyperalgesia) and the other one over the middle of the distal phalanx of the thumb (central hyperalgesia). The Pain Pressure Threshold will be applied with the algometer perpendicular to the skin increasing at a rate of 1 kg/s until the first sensation of pain. 3 measures with 30-seconds rest between them will be performed, taking the average as Pain Pressure Threshold.

Two Pain Pressure Thresholds will be measured by a handheld algometer, one over the most painful area (peripheric hyperalgesia) and the other one over the middle of the distal phalanx of the thumb (central hyperalgesia). The Pain Pressure Threshold will be applied with the algometer perpendicular to the skin increasing at a rate of 1 kg/s until the first sensation of pain. 3 measures with 30-seconds rest between them will be performed, taking the average as Pain Pressure Threshold.

Measures depressive symptoms. Scores range from 0 to 63 leading to 6 groups: 0-10, normal; 11-16, mild mood disturbance; 17-20, borderline clinical depression; 21-30, moderate depression; 31-40, severe depression; and over 40, extreme depression.

Measures depressive symptoms. Scores range from 0 to 63 leading to 6 groups: 0-10, normal; 11-16, mild mood disturbance; 17-20, borderline clinical depression; 21-30, moderate depression; 31-40, severe depression; and over 40, extreme depression.

Measures depressive symptoms. Scores range from 0 to 63 leading to 6 groups: 0-10, normal; 11-16, mild mood disturbance; 17-20, borderline clinical depression; 21-30, moderate depression; 31-40, severe depression; and over 40, extreme depression.

Measures anxious states and anxious traits. It has 20 items for assessing trait anxiety and 20 for state anxiety. All items are rated on a 4-point scale (e.g., from "Almost Never" to "Almost Always"). Higher scores indicate greater anxiety.

Measures anxious states and anxious traits. It has 20 items for assessing trait anxiety and 20 for state anxiety. All items are rated on a 4-point scale (e.g., from "Almost Never" to "Almost Always"). Higher scores indicate greater anxiety.

Measures anxious states and anxious traits. It has 20 items for assessing trait anxiety and 20 for state anxiety. All items are rated on a 4-point scale (e.g., from "Almost Never" to "Almost Always"). Higher scores indicate greater anxiety.

Measures fear of movement-related pain. Its scores range from 11-44 points with higher scores indicating greater fear of pain, movement, and injury.

Measures fear of movement-related pain. Its scores range from 11-44 points with higher scores indicating greater fear of pain, movement, and injury.

Measures fear of movement-related pain. Its scores range from 11-44 points with higher scores indicating greater fear of pain, movement, and injury.

Measures catastrophizing thinking. Its total score range from 0-52, along with three subscale scores assessing rumination, magnification and helplessness, with higher scores indicating higher level of catastrophizing.

Measures catastrophizing thinking. Its total score range from 0-52, along with three subscale scores assessing rumination, magnification and helplessness, with higher scores indicating higher level of catastrophizing.

Measures catastrophizing thinking. Its total score range from 0-52, along with three subscale scores assessing rumination, magnification and helplessness, with higher scores indicating higher level of catastrophizing.

Measures disability in Parkinson´s Disease patients. The scale itself has four components: Part I, Mentation, Behavior and Mood; Part II, Activities of Daily Living; Part III, Motor aspects; Part IV, Associated Complications. Scores range from 0 to 159 with higher scores indicating more severity.

Measures disability in Parkinson´s Disease patients. The scale itself has four components: Part I, Mentation, Behavior and Mood; Part II, Activities of Daily Living; Part III, Motor aspects; Part IV, Associated Complications. Scores range from 0 to 159 with higher scores indicating more severity.

Measures disability in Parkinson´s Disease patients. The scale itself has four components: Part I, Mentation, Behavior and Mood; Part II, Activities of Daily Living; Part III, Motor aspects; Part IV, Associated Complications. Scores range from 0 to 159 with higher scores indicating more severity.

Performed through 2 related subtasks. Finger Taping task, where the participants will be instructed to press the space bar on the keyboard as fast as possible and repeatedly with the index finger, to measure motor function. And Simple Reaction Time task, where participants will be instructed to press the left mouse button as fast as possible when the stimulus "+" appears in the center of the screen at a size of 2 cm x 2 cm, to measure simple perception and sustained alertness.

Performed through 2 related subtasks. Finger Taping task, where the participants will be instructed to press the space bar on the keyboard as fast as possible and repeatedly with the index finger, to measure motor function. And Simple Reaction Time task, where participants will be instructed to press the left mouse button as fast as possible when the stimulus "+" appears in the center of the screen at a size of 2 cm x 2 cm, to measure simple perception and sustained alertness.

Performed through 2 related subtasks. Finger Taping task, where the participants will be instructed to press the space bar on the keyboard as fast as possible and repeatedly with the index finger, to measure motor function. And Simple Reaction Time task, where participants will be instructed to press the left mouse button as fast as possible when the stimulus "+" appears in the center of the screen at a size of 2 cm x 2 cm, to measure simple perception and sustained alertness.

Inclusion Criteria: Neuroimaging study without previous pathologies. Score > 5 in transfers (bed to chair and back) item in Barthel Index. Score = or > 24 in Mini-Mental State Examination. Able to provide informed consent to participate in the study. Exclusion Criteria: History of neurologic disease different from PD. Presence of non-related to PD pain. Dermatologic problems, wounds, or ulcers in the electrode's application area. Significative difficulties in language. History of alcohol or drugs abuse. Non-controlled medical problems. Pregnancy.

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