4 mA tDCS, Estrogen, and Leg Muscle Fatigability

Estrogen Levels and Leg Muscle Fatigability in Eumenorrheic Young Women After 4 mA Transcranial Direct Current Stimulation

The majority of transcranial direct current stimulation (tDCS) studies have failed to consider sex as a modulating factor. This neglect may partly account for the high inter-subject variability bemoaned by many tDCS investigators (e.g., approximately 50% of participants do not respond to tDCS) and has certainly delayed progress in the field. Therefore, research into how sex influences stimulation-related outcomes is vital to fully understand the underlying mechanisms of tDCS, which has shown great inconsistency.

Because of the menstrual cycle, the hormonal levels of women fluctuate considerably more than in men. Importantly, these hormonal variations might impact the efficacy of neuromodulatory tools, like tDCS. It is suggested that estrogen, which is high in the second follicular phase, reinforces excitatory mechanisms in the motor cortex. However, because anodal tDCS enhances cortical excitation there is also a possibility of excessive excitability. For instance, anodal tDCS may lead to overexcitation and non-optimal performance when it is applied in the second follicular phase of the menstrual cycle. Currently, there is a lack of knowledge on how the phases of the menstrual cycle affect tDCS performance outcomes in healthy young women because no studies have examined if and how the phases of the menstrual cycle alter tDCS efficacy.

This study is critical for determining the optimal time to administer anodal tDCS, and the ideal intensity for that administration, to achieve the most beneficial results. Furthermore, this investigation will emphasize the need for future tDCS studies to test women during the same menstrual cycle phase.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Device: Sham transcranial direct current stimulation 4 mA; Device: Transcranial direct current stimulation 4 mA

Detailed Description

The majority of transcranial direct current stimulation (tDCS) studies have failed to consider sex as a modulating factor. This neglect may partly account for the high inter-subject variability bemoaned by many tDCS investigators (e.g., approximately 50% of participants do not respond to tDCS) and has certainly delayed progress in the field. Therefore, research into how sex influences stimulation-related outcomes is vital to fully understand the underlying mechanisms of tDCS, which has shown great inconsistency.

Because of the menstrual cycle, the hormonal levels of women fluctuate considerably more than in men. There are two main phases of the menstrual cycle: 1) the follicular phase, characterized by low levels of estradiol and progesterone (first follicular phase, days 1-7) followed by increased levels of estradiol and low levels of progesterone (second follicular phase, days 7-14); and 2) the luteal phase (days 14-28), characterized by moderate estradiol and high progesterone levels. Importantly, these hormonal variations might impact the efficacy of neuromodulatory tools, like tDCS.

It is suggested that estrogen, which is high in the second follicular phase, reinforces excitatory mechanisms in the motor cortex. Thus, it appears that higher levels of estradiol increase cortical excitability. However, because anodal tDCS enhances cortical excitation there is also a possibility of excessive excitability. For instance, anodal tDCS may lead to overexcitation and nonoptimal performance when it is applied in the second follicular phase of the menstrual cycle. Currently, there is a lack of knowledge on how the phases of the menstrual cycle affect tDCS performance outcomes in healthy young women because no studies have examined if and how the phases of the menstrual cycle alter tDCS efficacy.

This research will be significant because the changing hormone levels during the different phases of menstruation in women is an especially important factor for minimizing response variability from tDCS. Thus, this study is critical for determining the optimal time to administer anodal tDCS, and the ideal intensity for that administration, to achieve the most beneficial results. Furthermore, this investigation will emphasize the need for future tDCS studies to test women during the same menstrual cycle phase.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Has a regular menstrual cycle
2. Young adult (18-35 years)
3. Right-side dominant
4. At least 30 min of moderate-intensity, physical activity on at least 3 days of the week for at least the last 3 months
5. Without chronic neurological, psychiatric, or medical conditions
6. Not taking any psychoactive medications.

Exclusion Criteria:

1. Pregnant
2. Known holes or fissures in the skull
3. Metallic objects or implanted devices in the skull (e.g., metal plate)
4. Women on hormonal contraceptives/supplements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Eumenorrheic Women; Participants will have the anode (active electrode) placed over the brain area that controls their dominant leg and the cathode (return electrode) above the ipsilateral eyebrow. tDCS is administered in the early follicular phase, late follicular phase, and mid-luteal phase of their menstrual cycle. tDCS: Stimulation is ramped up to 4 mA over the first 30 seconds and stays at 4 mA for the remainder of the simulation time. Sham: Stimulation is turned on (4 mA) for 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time.

Device: Sham transcranial direct current stimulation 4 mA; Uses weak electrical current (4 mA intensity) at the beginning and the end of a given stimulation period to control for potential placebo-like effects or participant expectation bias.; Other Names: Sham tDCS 2 mA; Device: Transcranial direct current stimulation 4 mA; Uses weak electrical current (4 mA intensity) to either increase or decrease brain excitability and improve functional or cognitive outcomes.; Other Names: tDCS 4 mA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fatigue Index From the Isokinetic Fatigue Test	Perform 40 consecutive flexion and extension repetitions of the knee on the dominant leg. After a 10 minute rest, do the same task on the non-dominant leg. The fatigue index was calculated using the greatest torque from the relevant repetitions of the fatigue test as follows: ([mean of reps 3 through 7-mean of last five reps]/mean of reps 3 through 7) X 100 and is expressed as a percentage of decline in torque production.	Completed at each visit, spaced approximately 14 days apart for 2 consecutive months
Muscle Activity During the Strength and Fatigue Tests	Collect electromyographic (EMG; muscle activity) information during the fatigue tests. Muscle activity is measured as electrical signals/voltages. The muscle activity of the knee extensors (rectus femoris, vastus medialis, and vastus lateralis) was averaged to represent the cumulative activity of this muscle group. The first two repetitions of the fatigue test were considered adaptation repetitions and were removed. Therefore, the remaining 38 repetitions were used for the average EMG analyses. The subsequent 38 repetitions were also organized into 8 windows. The first seven windows consisted of five consecutive and non-overlapping repetitions (e.g., window 2 = reps 8-12; window 3 = reps 13-17, etc.) while the last (eighth) window was comprised of the final three repetitions.	Completed at each visit, spaced approximately 14 days apart for 2 consecutive months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estrogen Level	Staff nurses collected 4.5 mL of blood from the median cubital vein of the left arm (total volume collected per subject = 9 mL) for the estrogen assay. Samples were immediately analyzed for serum estrogen levels after the blood draws by University of Iowa Hospitals and Clinics Pathology technicians using an Electrochemiluminescence Assay (Roche Diagnostics, Basel, Switzerland). The estrogen assay had a lower limit of detection of 5 pg/mL and a coefficient of variation of 8%. Because menstrual cycles have great inter- and intrasubject variability, the peak estrogen levels of the subjects were not consistently found in the late-follicular phase, which is a common failing of menstrual cycle phase calendar estimation. Thus, estrogen levels were grouped as high or low according to each individual subject's estrogen serum levels, irrespective of the anticipated/targeted phase.	Completed at each visit, spaced approximately 14 days apart for 2 consecutive months

Collaborators and Investigators

• Sponsor: University of Iowa
• Investigators: Principal Investigator: Thorsten Rudroff, PhD, Health and Human Physiology

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2020
• Primary Completion (Actual): November 1, 2021
• Study Completion (Actual): November 1, 2021

Study Registration Dates

• First Submitted: July 10, 2020
• First Submitted That Met QC Criteria: July 10, 2020
• First Posted (Actual): July 15, 2020

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: April 17, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: transcranial direct current stimulation; muscle fatigue; brain stimulation
• Other Study ID Numbers: 202005124

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No