Anodal tDCS in Chronic Migraine With Medication Overuse

Study Overview
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Brief Summary
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Non-invasive neuromodulation has been applied in several forms of primary headaches, and its usefulness has been suggested for both episodic and chronic migraine (CM). Transcranial direct current stimulation (tDCS) represents a non-invasive electrical stimulation technique that modulates neural brain activity by means of low amplitude direct current trough surface electrodes. Very little evidence is available on the potential effect of tDCS in medication overuse and in the management of medication overuse headache (MOH), a condition frequently associated to CM. CM associated to MOH still represents a challenge for physicians and patients due to the high prevalence in the general population, the associated severe disability, and the high costs imposed by the treatment. The aim of the study was to investigate the possible application of tDCS in the management of CM associated to MOH. The primary objective of this pilot study was therefore to investigate the efficacy of anodal tDCS delivered on the primary motor cortex (M1) as add-on therapy to an in-hospital detoxification protocol in subjects affected by CM and MOH. The secondary objective was to evaluate the possible changes induced by tDCS on conventional EEG in order to obtain further clues about the effects of tDCS on brain activity.

Detailed Description
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The study was a randomized, double-blind, controlled trial aimed at assessing the efficacy of five daily sessions of anodal t-DCS in add-on to a standardized in-hospital detoxification protocol in patients suffering from CM+MOH. Twenty patients were enrolled among those consecutively attending the outpatient clinic of the IRCCS Mondino Foundation. All subjects underwent a screening visit with a physician of the Headache Science Centre of Mondino Institute. During the screening visit, a complete neurological and general examination was performed , and the inclusion/exclusion criteria were revised. Patients fulfilling criteria were enrolled in the baseline observation period for a month after an adequate training to monitor and record migraine and headache days, type and amount of acute medications and days of acute drug intake in an ad hoc diary. At the end of the baseline observation period, if inclusion/exclusion criteria were still satisfied, patients were randomized to the double-blind phase of the study (T0). To this end, patients were hospitalized on Mondays at the IRCCS Mondino Foundation for a 7-day detoxification protocol, that included: acute withdrawal of the overused drug and e.v. treatment with isotonic 0.9% NaCl saline 500 ml + cyanocobalamin 2500 mcg + folic acid 0.70 mg + nicotinamide 12 mg + ascorbic acid 150 mg + sodic glutathione 600 mg + delorazepam 0.5 mg administered b.i.d. The day of hospital admission (T0), before the first infusion, patients were tested with a complete set of clinical scales and they completed the baseline EEG recording. After these procedures, the patients were randomized (1:1) to two different treatment groups: tDCS group or sham group and received 1 daily session of tDCS/sham stimulation for 5 consequent days (see below). On day 5 (T1) patients underwent a follow-up EEG recording, administration of clinic scales for sleepiness, and attentional functions, evaluation of adverse events. On day 7 patients were discharged from the hospital with or without the prescription of preventive medication (based on the physician judgement) and returned for a follow-up visit after 1 month (T2) and 6 months (T3). An addition EEG recording was obtained at T2. Patients continued to record headache characteristic on the headache diary for the entire study observation period. The study protocol was approved by the local Ethic Committee and all participants provided a written informed consent. Transcranial direct current stimulation (tDCS) was delivered by a technician that was not otherwise involved in the management of patients. The managing physician were instead blind to the type of stimulation. The technician used a specific battery-driven direct current stimulator (Newronika HDCstim, Newronika s.r.l.). The current was transferred by an approved saline-soaked pair of surface sponge electrodes (anode of 3x3 cm and cathode of 6x4 cm). All the participants received daily stimulation sessions for 5 consecutive days (Monday to Friday). For the stimulation, the anode was placed over the primary motor cortex (M1), identified using the International 10-20 system for C3 (left M1) or C4 (right M1), and the cathode positioned over the contralateral supraorbital region (immediately below the Fp position of the 10-20 system). According to data from literature, in patients with a strict or prevalent (>70% of attacks) unilateral headache the contralateral hemisphere was stimulated, instead in patients with bilateral or shifting headache the dominant hemisphere was conventionally stimulated. Patients randomized to the tDCS group were treated with the following parameters: duration of stimulation of 20 minutes per session with a 2 mA intensity of anodal stimulation. In the sham group, the stimulation setting was exactly the same but the stimulation intensity was set according to a ramping up/ramping down method and delivered only in the first and last 30 seconds of each session. This stimulation paradigm is insufficient to produce a meaningful therapeutic effect, but it is necessary to guarantee to blind condition as it mimics the possible initial tingling sensation associated with active stimulation. All participants were informed about possible feelings related to tDCS treatment, such as a tingly sensation under the electrodes at the beginning of the stimulation. These procedures adequately blind participants to their group allocation. At the end of the 5 days stimulation period a blind check was performed. An EEG recording was performed at baseline (T0), at the end of the tDCS/sham treatment (T1), and after 1 month from hospital discharge (T2). The EEG was recorded with 19 Ag/AgCl electrodes which were placed according to the 10-20 EEG International System. The EEG registration was performed in the morning (between 9:00 a.m. and 11 a.m.), in a dedicated sound-attenuated room by a technician blinded to the study procedures. The subjects were instructed to remain awake with their eyes closed. The EEG was recorded for 10 min with a sampling rate of 1024 Hz and it was filtered between 0.4 and 70 Hz. A Notch filter was also applied to avoid 50 Hz interferences. For the EEG signal analysis, the investigators used a spectral analysis through a fast Fourier transformation. The investigators evaluated the power spectral density in these frequency ranges: Delta (1-4 Hz), Theta (4-8 Hz), Alpha (8-12 Hz), Beta (12-30 Hz). The absolute band power values (µV2) for each frequency were computed for each active electrode (Fp1, Fp2, F3, F4, F7, F8, Fz, C3, C4, Cz, P3, P4, Pz, T3, T4, T5, T6, O1, O2), using Cz as ground reference. For statistical purpose, the band power values were expressed as the percentage variation respect to baseline (normalized as 100%). Moreover, in patients with tDCS/sham stimulation of the right hemisphere the investigators performed an offline virtual right to left inversion all the electrodes of the right hemisphere. In this setting, unless differently specified, all the odd electrodes were ipsilateral to the side of stimulation, while all the even electrodes were contralateral to the side of stimulation. At T0 and T2 time points all patients completed a set of questionnaires to assess migraine-related disability, quality of life, sleep disturbances, and psychological aspects. The set included: the Migraine Disability Assessment (MIDAS) test; the Headache Impact Test-6 (HIT-6); Visual Analogue Scale (VAS); the Migraine-Specific Quality-of-Life Questionnaire (MSQ); Short Form Health Survey (SF-36); Sleep Condition Indicator (SCI); Pittsburgh Sleep Quality Index (PSQI); Zung scale for anxiety; Zung scale for depression. Moreover, before every EEG recording (T0, T1, and T2), patients were tested for their level of sleepiness, and attentional functions with: Stanford Sleepiness Scale: 1-item questionnaire, with a score that range from 1 (optimal alertness) to 7 (high level of sleepiness); Symbol Digit Modalities Test (SDMT): the SDMT was administered to test attentive functions. Patients were trained to match numbers and abstract symbols, according to a coded key. The total score (0-110) is represented by the number of correct substitutions in 90 seconds, with higher values representative of better attention.

Official Title
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Anodal Transcranial Direct Current Stimulation in Chronic Migraine With and Medication Overuse Headache: a Pilot Randomized Sham-controlled Trial

Conditions
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Chronic Migraine, Medication Overuse Headache

Intervention / Treatment
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* Device: Transcranial direct current stimulation (tDCS) group
* Device: Sham group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 to 65 years; chronic migraine according to the criteria of the InternationaI Classification of Headache Disorders (code 1.3 ICHD-III) and Medication Overuse Headache (code 8.2 ICHD-III) present for at least 6 months at inclusion; previous failure of at least three prophylactic treatments. Exclusion Criteria: other neurologic or neuropsychiatric diseases; other chronic painful syndromes; other types of primary or secondary headaches; use of a preventive medication at baseline; use of central nervous system modulating drugs; epilepsy; metallic head implants or use of a cardiac pacemaker; pregnancy or lactation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Pilot randomized sham-controlled trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transcranial direct current stimulation (tDCS) group<br>7-day detoxification protocol + 5 consecutive days of anodal tDCS treatment over the primary motor cortex. | Device: Transcranial direct current stimulation (tDCS) group<br>* Patients randomized to the tDCS group were treated with the following parameters: duration of stimulation of 20 minutes per session with a 2 mA intensity of anodal stimulation.<br>|
| Sham Comparator: Sham group<br>7-day detoxification protocol + 5 consecutive days of sham treatment over the primary motor cortex. | Device: Sham group<br>* In the sham group, the stimulation setting was exactly the same but the stimulation intensity was set according to a ramping up/ramping down method and delivered only in the first and last 30 seconds of each session.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Headache frequency | Headache frequency measured by number of migraine days per month recorded in a headache diary. | Change in number of migraine days from T0 (baseline) to T2 (1 month after hospital discharge) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Migraine Disability Assessment (MIDAS) | Migraine related disability measured by the MIDAS. MIDAS test: 0-5 (grade I): minimal disability, 6-10 (grade II): mild disability, 11-20 (grade III): moderate disability, 21-40 (grade IVa): severe disability, 41 and higher (grade IVb): very severe disability. | Baseline (T0), after 1 month from hospital discharge (T2) | 
| Headache Impact Test-6 (HIT-6). | Migraine related disability measured by the HIT-6. A score of 49 or less: no impact, 50-55: some impact, 56-59: substantial impact, 60-78 severe impact. | Baseline (T0), after 1 month from hospital discharge (T2) | 
| Visual Analogue Scale (VAS) | Migraine related disability measured by VAS for pain intensity. VAS is a validated, subjective measure for acute and chronic pain. Scores are recorded by making a handwritten mark on a 10-cm line that represents a continuum between no pain and worst pain. | Baseline (T0), after 1 month from hospital discharge (T2) | 
| Migraine-Specific Quality-of-Life Questionnaire (MSQ) | Migraine related disability measured by MSQ. It is a 14-item assessment, with each item rated on a 6-point scale (ranging from none of the time to all of the time). The investigators evaluated 3 scores, namely Role Function-Restrictive (RR), Role Function- Preventive (RP), and Emotional Function (EF). Raw scores have been transformed to a 100-point scale, with higher scores indicating better quality of life. | Baseline (T0), after 1 month from hospital discharge (T2) | 
| Short Form Health Survey (SF-36). | Migraine related disability measured by SF-36.It gives information about 8 different domains: physical functioning (10 items), role-physical (4 items), bodily pain (2 items), and general health (5 items). The mental health measure is composed of vitality (4 items), social functioning (2 items), role-emotional (3 items), and mental health (5 items). | Baseline (T0), after 1 month from hospital discharge (T2) | 
| Sleep Condition Indicator (SCI) | Sleep quality measured by SCI. It is a 8-item questionnaire, with a score that range from 0 to 32. A higher score points toward a better sleep, while a score below 16 is significant for insomnia disorders. | Baseline (T0), after 1 month from hospital discharge (T2) | 
| Pittsburgh Sleep Quality Index (PSQI) | Sleep quality measured by PSQI. The questionnaire differentiates poor from good sleepers. A global score greater than five indicates poor sleep quality, with a maximum score of 21 (the worst overall sleep). | Baseline (T0), after 1 month from hospital discharge (T2) | 
| Zung scale for anxiety | Psychological aspects measured by the Zung scale for anxiety. It is a 20-item questionnaire, with a score that range from 20 to 80. A score above 36 is clinically significant for the presence of anxiety. | Baseline (T0), after 1 month from hospital discharge (T2) | 
| Zung scale for depression | Psychological aspects measured by the Zung scale for depression. It is a 20-item questionnaire with a score that range from 20 to 80. A score above 40 is clinically significant for the presence of depression. | Baseline (T0), after 1 month from hospital discharge (T2) | 
| EEG power spectrum (µV2) of alpha frequencies | For the EEG signal analysis, the investigators used a spectral analysis through a fast Fourier transformation. Epochs with eye movements, artifacts or periods of drowsiness were excluded from analysis. Power spectral density was calculated on the whole track, using a time windows of 5 seconds, with an overlapping of the samples equal to 50% and introducing zeropadding to reach a resolution of 0.1 Hz. | Percentage modification of EEG power spectrum of alpha frequencies from T0 (baseline) to T2 (1 month after hospital discharge) | 
| EEG power spectrum (µV2) of beta frequencies | For the EEG signal analysis, the investigators used a spectral analysis through a fast Fourier transformation. Epochs with eye movements, artifacts or periods of drowsiness were excluded from analysis. Power spectral density was calculated on the whole track, using a time windows of 5 seconds, with an overlapping of the samples equal to 50% and introducing zeropadding to reach a resolution of 0.1 Hz. | Percentage modification of EEG power spectrum of beta frequencies from T0 (baseline) to T2 (1 month after hospital discharge) | 
| EEG power spectrum (µV2) of theta frequencies | For the EEG signal analysis, the investigators used a spectral analysis through a fast Fourier transformation. Epochs with eye movements, artifacts or periods of drowsiness were excluded from analysis. Power spectral density was calculated on the whole track, using a time windows of 5 seconds, with an overlapping of the samples equal to 50% and introducing zeropadding to reach a resolution of 0.1 Hz. | Percentage modification of EEG power spectrum of theta frequencies from T0 (baseline) to T2 (1 month after hospital discharge) | 
| EEG power spectrum (µV2) of delta frequencies | For the EEG signal analysis, the investigators used a spectral analysis through a fast Fourier transformation. Epochs with eye movements, artifacts or periods of drowsiness were excluded from analysis. Power spectral density was calculated on the whole track, using a time windows of 5 seconds, with an overlapping of the samples equal to 50% and introducing zeropadding to reach a resolution of 0.1 Hz. | Percentage modification of EEG power spectrum of delta frequencies from T0 (baseline) to T2 (1 month after hospital discharge) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EEG, Neuromodulation, Transcranial direct current stimulation, Chronic migraine, Medication overuse headache