Healthy
Conditions
Keywords
transcranial direct current stimulation, muscle fatigue, brain stimulation
Brief summary
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.
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.
Interventions
DEVICESham 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.
DEVICETranscranial 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.
Sponsors
University of Iowa
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fatigue Index From the Isokinetic Fatigue Test | Completed at each visit, spaced approximately 14 days apart for 2 consecutive months | 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. |
| Muscle Activity During the Strength and Fatigue Tests | Completed at each visit, spaced approximately 14 days apart for 2 consecutive months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estrogen Level | Completed at each visit, spaced approximately 14 days apart for 2 consecutive months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eumenorrheic Women Biological women will have the anode (active electrode) placed over the brain area the controls their dominant leg and the cathode (return electrode) above the eyebrow on the opposite side of the head.
Transcranial direct current stimulation 2 mA: Uses weak electrical current (2 mA intensity) to either increase or decrease brain excitability and improve functional or cognitive outcomes. Stimulation is ramped up to 2 mA over the first 30 seconds and stays at 2 mA for the remainder of the stimulation time.
Sham transcranial direct current stimulation 2 mA/4mA: Uses weak electrical current (2 mA or 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. Stimulation is turned on (2 mA or 4 mA) for the 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Eumenorrheic Women |
|---|---|
| Age, Continuous | 24.3 years STANDARD_DEVIATION 5.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
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.
Time frame: Completed at each visit, spaced approximately 14 days apart for 2 consecutive months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eumenorrheic Women | Fatigue Index From the Isokinetic Fatigue Test | tDCS High Estrogen | 61.7 Percent decline | Standard Deviation 10.6 |
| Eumenorrheic Women | Fatigue Index From the Isokinetic Fatigue Test | Sham High Estrogen | 46.7 Percent decline | Standard Deviation 20 |
| Eumenorrheic Women | Fatigue Index From the Isokinetic Fatigue Test | tDCS Low Estrogen | 57.28 Percent decline | Standard Deviation 11.57 |
| Eumenorrheic Women | Fatigue Index From the Isokinetic Fatigue Test | Sham Low Estrogen | 55.90 Percent decline | Standard Deviation 8.67 |
p-value: <0.05ANOVA
Primary
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.
Time frame: Completed at each visit, spaced approximately 14 days apart for 2 consecutive months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eumenorrheic Women | Muscle Activity During the Strength and Fatigue Tests | tDCS High Estrogen | 95.15 Microvolts | Standard Deviation 26.46 |
| Eumenorrheic Women | Muscle Activity During the Strength and Fatigue Tests | tDCS Low Estrogen | 91.83 Microvolts | Standard Deviation 16.48 |
| Eumenorrheic Women | Muscle Activity During the Strength and Fatigue Tests | Sham High Estrogen | 77.53 Microvolts | Standard Deviation 19.71 |
| Eumenorrheic Women | Muscle Activity During the Strength and Fatigue Tests | Sham Low Estrogen | 82.35 Microvolts | Standard Deviation 21.44 |
p-value: <0.05ANOVA
Secondary
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.
Time frame: Completed at each visit, spaced approximately 14 days apart for 2 consecutive months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eumenorrheic Women | Estrogen Level | tDCS High Estrogen | 157.7 (pg/mL) | Standard Deviation 101.5 |
| Eumenorrheic Women | Estrogen Level | tDCS Low Estrogen | 31.9 (pg/mL) | Standard Deviation 10.9 |
| Eumenorrheic Women | Estrogen Level | Sham High Estrogen | 137.2 (pg/mL) | Standard Deviation 114 |
| Eumenorrheic Women | Estrogen Level | Sham Low Estrogen | 42.9 (pg/mL) | Standard Deviation 25.1 |