Transcranial Direct Current Stimulation Effect on Pain Threshold and Working Memory: Impact of Age and Protocol Type

Study Overview
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Brief Summary
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Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation method which has great potential as an aid in the therapeutic management of neuropsychiatric disorders and chronic pain syndromes. However, despite promising results, the response to stimulation presents great variability among subjects. Age is a factor that is known to influence the tDCS effect forging the inconsistency of clinical effect.The purpose of this study is to evaluate the effect of tDCS on pain perception and working memory in healthy women from 3 different age groups: adolescents, young adults and elderly. This is a randomized, single-blinded, cross-over study of 2 different active interventions and sham.

Detailed Description
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Transcranial direct current stimulation (tDCS) is a neuromodulation method that has great potential as an aid in the therapeutic management of neuropsychiatric disorders and chronic pain syndromes. tDCS modulates the neuronal membrane potential , facilitating neuronal depolarization or hyperpolarization, hence modifying the cortical excitability of the stimulated area. However, despite promising results the response to stimulation presents great variability among subjects. Chronological age is an important factor in the variation of brain plasticity. The dorsolateral prefrontal cortex (DLPFC) is associated with cognitive and emotional aspects of pain, in addition to being related to executive components of working memory. Anodal tDCS on DLPFC modulates pain level in patients with chronic pain and modifies working memory performance in healthy subjects and patients with memory impairment. The prefrontal cortex presents a great structural difference throughout lifespan: it is under maturational process in the adolescence, reaching peak of maturation in the adult life, and initiating process of cerebral senescence in elderly subjects. Therefore, the use of tDCS on DLPFC in these three age groups presents potential for a large variation in response. Faced with the potential of tDCS for adjuvant use in the treatment of several diseases, it is imperative to understand the variability of this intervention between different age groups. This knowledge may allow the optimization of neuromodulation protocols, allowing more careful and refined use in the clinic. The study primary outcomes is the difference between and within age groups on the variation of pre and post tDCS on pain threshold evaluated by Heath pain threshold on a Quantitative sensory testing paradigm and working memory performance evaluated by n-back test in healthy subjects of three age groups: adolescents, young adults, elderly. This is a randomized, single blinded, cross-over, sham-controlled clinical trial. The study will be conducted at the Clinical Research Center of the Hospital de Clínicas of Porto Alegre (HCPA). It will include 30 women, 10 women by age group: adolescents between 15 and 16 years,young adults between 30 and 40 years old and elderly women between 60 and 70 years. Participants will be randomized for a cross-over of three sessions: anodal stimulation in DLPFC, anodal stimulation in primary motor cortex (M1) as active control and sham stimulation.

Official Title
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Transcranial Direct Current Stimulation Effect on Pain Threshold and Working Memory in Healthy Adolescents, Young Adults and Elderly: a Randomized , Cross-over, Single Blind Trial

Conditions
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Transcranial Direct Current Stimulation, Working Memory, Pain

Intervention / Treatment
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* Device: Anodal tDCS on DLPFC
* Device: Anodal tDCS on M1
* Device: Sham tDCS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 15 to 16 years for the adolescent group Age between 30 to 40 years for the young adult group Age between 60 to 70 years for the elderly group From completed elementary school to incomplete superior education right handed Exclusion Criteria: Pregnancy Current smoker or previous smoker within 10 years Current Substance Use Disorder Neurological condition (e.g., traumatic brain injury, stroke, brain tumor, epilepsy, brain surgery, brain implant) Any diagnosed Psychiatric condition (e.g., Attention deficit/hyperactivity deficit (ADHD), bipolar disorder, major depressive disorder, schizophrenia, generalized anxiety disorder) Use of any antidepressive or psychoactive, psychostimulant medication Any chronic pain condition

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anodal tDCS on DLPFC<br>Participants will receive anodal tDCS on the left DLPFC for 30 mins duration, cathode will be placed over the right supra orbital area. The electrodes are 25cm², The stimulation current is 2 milliamperes (2mA). | Device: Anodal tDCS on DLPFC<br>* Participants will receive anodal tDCS on the left DLPFC for 30 min duration, cathode will be placed over the right supra orbital area. The electrodes are 25cm², The stimulation current is 2 milliamperes (2mA).<br>* Other names: DLPFC;|
| Active Comparator: Anodal tDCS on M1<br>Participants will receive anodal tDCS on the left M1 for 30 min duration, cathode will be placed over the right supra orbital area. The electrodes are 25cm², The stimulation current is 2 milliamperes (2mA). | Device: Anodal tDCS on M1<br>* Participants will receive anodal tDCS on the left M1 for 30 min duration, cathode will be placed over the right supra orbital area. The electrodes are 25cm², The stimulation current is 2 milliamperes (2mA).<br>* Other names: M1;|
| Sham Comparator: Sham tDCS<br>Participants will receive sham tDCS. The anode will be placed on the left DLPFC and the cathode on the over the right supra orbital area. The electrodes are 25cm², There will be a ram up and down of 30 seconds each, after the ramp up the current will be turned off. | Device: Sham tDCS<br>* Participants will receive sham tDCS. The anode will be placed on the left DLPFC and the cathode on the over the right supra orbital area. The electrodes are 25cm², There will be a ram up and down of 30 seconds each, after the ramp up the current will be turned off.<br>* Other names: Sham;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heat pain Threshold | Using the Quantitative sensory testing, this measure consists of the average temperature of 3 stimulus with increasing magnitude of heat where the participant presses a button to indicate when he/she first perceives pain. | percentual change from before the tDCS onset, to immediately after the end of tDCS application for each cross-over session | 
| Working memory performance | Working memory performance will be evaluated by a computerized n-back test associated with flankers at baseline and after each session of active tDCS (DLPFC or M1) or sham. The measure of performance is the D' discrimination index (calculated based on hit rate and false alarm rate). | up to 60 minutes after tDCS onset | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inhibitory control performance | A computerized stop-signal task associated with flankers will evaluate inhibitory control. Performance index are calculated with the D' discrimination index (based on hits and false alarms for go and stop trials). The task will be performed at baseline and after the stimulation on each cross-over session. | up to 60 minutes after tDCS onset | 
| Area under the curve of the ERP during inhibitory control task | Area under the curve of the signal of event-related potential (ERP) evoked during the stop signal task with flankers (inhibitory control performance). The signal will be assessed using an 8 channel EEG device at baseline and after each cross-over session. | up to 60 minutes after tDCS onset | 
| Heat thermal threshold | Using the Quantitative sensory testing, this measure consists of the average temperature of 3 stimulus with increasing magnitude of heat where the participant presses a button to indicate when he/she first perceives heat. | percentual change from before the tDCS onset, to immediately after the end of tDCS application for each cross-over session | 
| Heat pain tolerance | Using the Quantitative sensory testing, this measure consists of the temperature for a stimulus with increasing magnitude of heat where the participant presses a button to indicate the maximum heat tolerated. | percentual change from before the tDCS onset, to immediately after the end of tDCS application for each cross-over session | 
| Moderate pain | Using the Quantitative sensory testing, this measure consists of the average temperature of 3 stimulus with increasing magnitude of heat where the participant presses a button to indicate pain perceived at a moderate level, i.e. level of 6 in a numeric pain scale (0 to 10). | percentual change from before the tDCS onset, to immediately after the end of tDCS application for each cross-over session | 
| Unpleasantness sensation | This measure will be assessed using a numeric pain scale (0 to 10 in which 0 represents no unpleasant sensation and 10 extremely unpleasant sensation) with which participant will indicate how unpleasant was the temperature of the quantitative sensory testing stimulus for the heat pain threshold. | percentual change from before the tDCS onset, to immediately after the end of tDCS application for each cross-over session | 
| Alpha wave power | Assessment of alpha wave power (8Hz to 12Hz) will be done using an 8 channel EEG device during an eyes-open and eyes-closed paradigm where participant is in a resting state at baseline and after each cross-over session. | up to 60 minutes after tDCS onset | 
| Beta wave power | Assessment of beta wave power (12Hz to 25Hz) will be done using an 8 channel EEG device during an eyes-open and eyes-closed paradigm where participant is in a resting state at baseline and after each cross-over session. | up to 60 minutes after tDCS onset | 
| Theta wave power | Assessment of theta wave power (4Hz to 8Hz) will be done using an 8 channel EEG device during an eyes-open and eyes-closed paradigm where participant is in a resting state at baseline and after each cross-over session. | up to 60 minutes after tDCS onset | 
| serum BDNF levels | Neuroplasticity biomarker will be assessed using serum brain-derived neurotrophic factor (BDNF) at baseline to be correlated with tdcs effects on primary outcomes | up to 60 minutes before tDCS onset | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Age Groups, Pain Threshold