Assessing the Effects of Hormones on Noninvasive Transcranial Stimulation

This study is investigating how two types of non-invasive brain stimulation, transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS), affect brain activity, and whether combining them produces stronger or more consistent effects than either one used alone. The motivation for this comes from the observation that TMS, which is FDA-approved for treating depression, tends to work less well in postmenopausal women because lower estrogen levels reduce the brain's ability to respond to stimulation. The research team believes that pairing TMS with TES, which targets a different set of brain cells, may be able to overcome this hormonal barrier and make stimulation more effective. Participants will come into the lab for up to 24 visits over 8 months, beginning with an initial visit to establish the right stimulation settings, followed by a series of stimulation sessions in which brain activity is measured before and after receiving either TES, TMS, or both together. For female participants, sessions will be scheduled at specific points in the menstrual cycle to capture the natural monthly rise and fall of estrogen, while male participants will be scheduled on a comparable fixed interval as a comparison group. The insights gained from this study could directly inform the development of better, more reliable brain stimulation treatments for women with depression.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy; Menopause; Menstrual Cycle; Cortical Excitability; TMS
• Intervention / Treatment: Device: TES + TMS; Device: Transcranial Electrical Stimulation; Device: Transcranial Magnetic Stimulation

Detailed Description

TMS is well understood to have variable effects depending on hormonal levels such as estrogen, progesterone, testosterone, and thyroid hormone. A leading theory for this variability is that these hormones, particularly estrogen, exert neuroprotective effects on NMDA receptors in the brain. These NMDA receptors are ligand/voltage gated ion channels present in neurons in the cortex. Conventional TMS produces electric fields parallel to the skull surface and is therefore more likely to excite Layer 2/3 (L2/3) pyramidal neurons. Under normal circumstances, these neurons excite downstream projections, and this synchronized activation opens NMDA channels, initiating the synaptic plasticity cascade. In postmenopausal patients, however, reduced estrogen leads to diminished NMDA receptor expression, lower glutamate availability, and a corresponding reduction in NMDA current, all of which attenuate the effects of TMS. This represents a significant gap in current treatment capability, as postmenopausal patients with depression may derive substantially less benefit from TMS due to these hormonal influences on cortical excitability. A therapeutic approach capable of rescuing NMDA currents across varying hormonal brain states is therefore needed. The purpose of this protocol is twofold: to validate that TMS efficacy does fluctuate as a function of baseline hormonal levels (in this case estrogen), and to determine whether diminished efficacy can be rescued with the use of concurrent pulsed-TES (pTES). Tracking hormonal levels in perimenopausal and postmenopausal women, however, is not possible without regular blood samples due to the irregularity of hormonal dynamics during this stage of life. In order to circumvent this, this study will follow premenopausal women across the menstrual cycle. Leveraging the natural fluctuations in estrogen levels across the menstrual cycle will allow us to get a crude approximation of hormonal levels without having to do any blood samples. Group average differences in EMG responses as a result of stimulation will help elucidate how TMS responsiveness varies with hormonal levels and directly inform future research on noninvasive neuromodulation for refractory symptoms in postmenopausal and perimenopausal women.

This study will be conducted across at most 24 separate <4-hour sessions across 8 months (that need not be consecutive). At the baseline study visit, prior to stimulation, informed consent will be reviewed and obtained, the participant will complete a Demographic and Medical History and Menstrual Phase Identification Questionnaire (MPIQ) survey and a qualitative history statement will be obtained. Thereafter, the participant will begin the motor mapping wherein TES, TMS, and joint TES+TMS parameters will be adjusted such that motor responses are seen in EMG at a suitable pain (<6 on numerical rating scale). Thereafter, repetitive stimulation with either TMS, TES, or joint TES+TMS will be conducted across at most 16 days over the span of at most 6 months. These 6 months need not be consecutive. At most two stimulation sessions will be conducted per menstrual cycle for premenopausal women. For each intervention arm (TES, TMS, TES+TMS), repetitive stimulation will be scheduled once at estrogen nadir which corresponds to days 1-3 of the menstrual cycle and the late follicular phase (days 10-14). This, however, assumes a 28-day cycle and flexibility in the participants schedule so the exact scheduling of these two sessions will vary and depend on input from the MPIQ and qualitative statement. For each month, a single intervention arm will be used (e.g. if TES is used for estrogen nadir, TES will be used during the late follicular stage). The ordering of each intervention may be randomized (however, there is not a limit on the number of days dedicated to each intervention e.g. days 9-24 may solely be dedicated to TES+TMS). For men (control participants), stimulation sessions will be scheduled such that the first and second session per month are roughly 9 days apart (analogous to the scheduling in the 28-day cycle).

TMS evoked EMG responses will be recorded before and after >2000 pulses of either TMS, TES, or combined TES and TMS during these sessions. The delta in trail averaged EMG responses between estrogen nadir and the late follicular phase will be compared between these three techniques. Short-Interval Intracortical Inhibition (SICI), Long-Interval Intracortical Inhibition (LICI), and Intracortical Facilitation (ICF) responses will also be recorded to gain a better insight into the modulation of cortical activity as a function of either/both the intervention or hormonal levels. The insights gained from this study could directly inform the development of better, more reliable brain stimulation treatments for women with depression, especially those undergoing perimenopause/postmenopause.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pulkit Grover; Phone Number: 412-268-3644; Email: pgrover@andrew.cmu.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Carnegie Mellon University
      • Contact: Rabira Tusi; Phone Number: 661-220-4232; Email: rtusi@andrew.cmu.edu
      • Principal Investigator: Pulkit Grover

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age between 18 and 40 years old
• Female subjects must have regular menstrual cycles (defined as a cycle that occurs at predictable intervals, typically between 24 and 38-days length) via self-report

Exclusion Criteria:

• Allergies to henna
• Allergies to gel used for electrodes
• History of seizures or epilepsy
• Subjects must not have any serious disease, disorder, infection, or cognitive impairments that could affect their ability to participate in this study.
• Female subjects of child-bearing potential must not be pregnant
• Subjects must not have any implanted stimulators or pulse generators
• Subjects must not have heart disease, including known arrhythmia
• Subjects must not have any metal implants in their head

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TES + TMS; Participants receive concurrent TMS and TES stimulation delivered to the primary motor cortex (M1), with sessions scheduled at two points per menstrual cycle - once at estrogen nadir (days 1-3) and once during the late follicular phase (days 10-14). Prior to the stimulation train, diagnostic TMS measuring SICI, LICI, and ICF is conducted to establish baseline cortical excitability. Participants then undergo a train of up to 2,000 paired TMS and TES pulses, with a 1-3 ms latency maintained between the two modalities. Following the train, diagnostic TMS is repeated to assess changes in cortical excitability relative to baseline. Participants remain seated throughout the session.	Device: TES + TMS; The combined TMS+TES intervention delivers concurrent transcranial magnetic and electrical stimulation using the DuoMag XT-100 rTMS system and the Digitimer DS8R/DS5 current stimulators simultaneously. The DuoMag XT-100 is a CE-certified Class IIa device manufactured by DEYMED Diagnostic, delivering monophasic and biphasic pulses with a 290 µs pulse duration and 265 J maximum discharge energy, capable of 100% intensity at 22 Hz and up to 100 Hz at less than 50% intensity. The Digitimer DS8R/DS5 are CE-certified stimulators delivering brief duration (50-2000 µs) current pulses via surface electrodes, with current output adjustable from 0mA to 1000mA, compliance voltage up to 400V, and energy limit of 300mJ. Standard adhesive electrodes are replaced with Soterix Sintered Ag/AgCl ring electrodes featuring radial slits to impede induced eddy currents. Magnetic pulses are delivered via the DuoMag 70BF liquid-cooled butterfly coil. Pulses are interleaved with a 1-3 ms latency.
Experimental: TES; Participants receive focal electrical stimulation delivered to the primary motor cortex (M1), with sessions scheduled at two points per menstrual cycle - once at estrogen nadir (days 1-3) and once during the late follicular phase (days 10-14). Prior to the stimulation train, diagnostic TMS measuring SICI, LICI, and ICF is conducted to establish baseline cortical excitability. Participants then undergo a train of up to 2,000 TES pulses, with timing, amplitude, and location varied to achieve targeted cortical stimulation. Following the train, diagnostic TMS is repeated to assess changes in cortical excitability relative to baseline. Participants remain seated throughout the session.	Device: Transcranial Electrical Stimulation; SharpFocus transcranial electrical stimulation (TES) uses a multichannel stimulator connected to a scalp electrode to deliver precisely timed, intensity-modulated electrical pulses. By varying the timing, amplitude, and location of these pulses, the system achieves focal stimulation of targeted cortical regions. Investigators will use Digitimer DS8R and/or Digitimer DS5 current stimulators to apply all current stimuli. These stimulators are CE certified and are intended for use in human research applications. The stimulator safely delivers brief duration (50-2000µs) current pulses for transcranial electrical stimulation and activation of nerves and muscles via surface electrodes. The current output of the DS8R is adjustable over the range 0mA to 1000mA, with a compliance voltage of up to 400V and an energy limit of 300mJ.
Experimental: TMS; Participants receive repetitive transcranial magnetic stimulation delivered to the primary motor cortex (M1), with sessions scheduled at two points per menstrual cycle - once at estrogen nadir (days 1-3) and once during the late follicular phase (days 10-14). Prior to the stimulation train, diagnostic TMS measuring SICI, LICI, and ICF is conducted to establish baseline cortical excitability. Participants then undergo a train of up to 2,000 pulses of standard rTMS or up to 600 pulses of iTBS (3 pulses at 50 Hz, burst repetition rate of 5 Hz, 2 seconds ON and 8 seconds OFF for 20 cycles at 80% motor threshold). Following the train, diagnostic TMS is repeated to assess changes in cortical excitability relative to baseline. Participants remain seated throughout the session.	Device: Transcranial Magnetic Stimulation; Transcranial magnetic stimulation (TMS) uses an electromagnetic coil placed over the scalp to deliver precisely timed magnetic pulses that induce electric fields in targeted cortical regions. By varying the frequency, intensity, and coil position, the system achieves non-invasive stimulation of specific brain areas. Investigators will use the DuoMag XT-100 rTMS system manufactured by DEYMED Diagnostic. The device is a CE-certified Class IIa medical device intended for use in human research and clinical applications. The DuoMag XT-100 delivers both monophasic and biphasic pulses with a total pulse duration of 290 µs and a maximum discharge energy of 265 J, capable of stimulating at 100% intensity at 22 Hz and up to 100 Hz at less than 50% intensity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor Evoked Potential Amplitude Change	Motor evoked potential (MEP) amplitude is recorded via surface EMG electrodes placed on the upper or lower limb musculature in response to single-pulse diagnostic TMS delivered to the primary motor cortex (M1). MEP amplitude is measured as the peak-to-peak voltage of the evoked muscle response in millivolts. The primary outcome is the change in trial-averaged MEP amplitude from before to after a train of up to 2,000 pulses of TMS, TES, or combined TMS+TES. This delta is compared across two hormonal phases of the menstrual cycle - estrogen nadir (days 1-3) and the late follicular phase (days 10-14) - and across the three intervention arms. A larger positive delta indicates greater corticospinal excitability / synpatic potentiation following stimulation, while a negative delta indicates suppression of corticospinal excitability / synpatic potentiation.	MEP recorded at the same time as the diagnostic TMS pre-intervention and post-intervention of the 2,000 pulse stimulation at every session for at most 8 months / 24 sessions. Delta/change assessed after each session.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Numerical Rating Scale	A numerical rating scale (NRS) uses numbers to quantify subjective experiences of pain. NRS scores will be self-reported on a scale of 0-10 with 0 being no pain and 10 being worst pain imaginable. NRS will be presented to patients during calibration phases of Transcranial Electrical Stimulation (TES), during heat pain thresholding, and during pressure pain thresholding in the form of a visual scale and be asked to vocalize a number between 0 and 10 in response to a pain stimulus.	Recorded at the same time as 2,000 pulses of stimulation (intraprocedurally) at every session after a block of "N" stim pulses for at most 8 months / 24 sessions. The number of stim pulses vary by intervention arm.
Menstrual Phase Identification Questionnaire	The Menstrual Phase Identification Questionnaire (MPIQ) is a short self-reported survey used to identify the current stage of the participant's menstrual cycle. It is administered at baseline and periodically throughout the study, including at home via Qualtrics up to once per day when necessary, to confirm whether the participant is at estrogen nadir (days 1-3) or in the late follicular phase (days 10-14) prior to each stimulation session. This measure is used to verify accurate scheduling of stimulation sessions relative to hormonal phase and to serve as a proxy for circulating estrogen levels, which are expected to be low at estrogen nadir and elevated during the late follicular phase. Accurate phase identification is critical to the study design as the primary outcome measure - change in MEP amplitude - is compared across these two hormonal phases.	At most daily from enrollment to the end of intervention period (up to 8 months). Will be recorded online at an unspecified time during the experimental period depending on the participants preference.
Paired Pulse Responses	Paired-pulse EMG responses are recorded via surface EMG electrodes placed on the upper or lower limb musculature in response to paired-pulse diagnostic TMS delivered to the primary motor cortex (M1). Three paired-pulse paradigms are employed: Short-Interval Intracortical Inhibition (SICI), measured at an interstimulus interval (ISI) of 1-5 ms, which reflects GABAergic inhibitory interneuron activity and is expressed as a reduction in MEP amplitude relative to an unconditioned test stimulus; Intracortical Facilitation (ICF), measured at an ISI of 7-20 ms, which reflects glutamatergic excitatory interneuron activity and is expressed as an increase in MEP amplitude relative to an unconditioned test stimulus; and Long-Interval Intracortical Inhibition (LICI), measured at an ISI of 100-200 ms, which reflects GABA-B mediated inhibition and is expressed as a reduction in MEP amplitude relative to an unconditioned test stimulus. The outcome is the change in each of measure from baseline.	Immediately prior to intervention/Immediately post-intervention at every session for at most 24 sessions/8 months
EMG responses	In addition to peak-to-peak MEP amplitude and paired-pulse responses, a range of additional quantitative metrics derived from the surface EMG signal are recorded before and after each repetitive stimulation train. These include but are not limited to MEP latency, MEP duration, MEP waveform morphology, and trial-to-trial variability of evoked responses. EMG is recorded via HD-EMG grids and/or bipolar electrode configurations placed on the upper and lower limbs, capturing muscle activity evoked by single-pulse diagnostic TMS delivered to the primary motor cortex (M1). These measures provide supplementary characterization of corticospinal excitability and neuromuscular response properties beyond MEP amplitude alone, and are compared across hormonal phases and intervention arms to gain a broader understanding of how repetitive TMS, TES, and combined TMS+TES modulate cortical output.	Recorded at the same time as 2,000 pulses of stimulation (intraprocedurally) at every session for at most 8 months / 24 sessions.

Collaborators and Investigators

• Sponsor: Carnegie Mellon University

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: May 29, 2026
• First Submitted That Met QC Criteria: June 4, 2026
• First Posted (Actual): June 9, 2026

Study Record Updates

• Last Update Posted (Actual): June 9, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Electromyography; Transcranial Magnetic Stimulation; Cortical Excitability; Hormones; Perimenopause; Transcranial Electrical Stimulation; Noninvasive Neuromodulation; Synaptic Plasticity
• Additional Relevant MeSH Terms: Therapeutics; Behavioral Disciplines and Activities; Magnetic Field Therapy; Electric Stimulation Therapy; Convulsive Therapy; Psychiatric Somatic Therapies; Electroshock; Psychological Techniques; Transcranial Magnetic Stimulation; Transcranial Direct Current Stimulation
• Other Study ID Numbers: STUDY2026_00000239

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

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