Glucose and Non-Invasive Brain Stimulation

Sponsor
University of North Carolina, Chapel Hill (Other)
Overall Status
Terminated
CT.gov ID
NCT04031404
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
23
1
2
11.7
2

Study Details

Study Description

Brief Summary

Purpose: In this study, the investigators will delineate how brain network dynamics are modulated by experimentally induced elevated blood glucose levels and examine how glucose levels gate neuronal excitability measured by the response to TMS.

Participants: Participants must be between the ages of 18 and 65 with no known diabetes, no known adverse reaction to finger prick blood draw, and no known neurological or psychiatric illness. Participants must have a body-mass index less than 30.

Procedures: Participants will consume either a drink that contains 75 g of glucose or a placebo, and their response to TMS will be measured to examine the effect of glucose on motor cortex excitability.

Condition or Disease Intervention/Treatment Phase
  • Device: Single-pulse TMS
N/A

Detailed Description

This study will be a placebo-controlled study that investigates brain function with both electroencephalography (EEG) and TMS. On each study visit, a drink (either glucose drink or water) is administered after baseline assessment of fasting glucose. Changes in brain activity and excitability will be measured with resting-state EEG. Periodic high-density EEG of resting-state brain activity and activity during a working memory task will be performed before the administration of the drink, immediately after the administration of the drink, as well as 30 minutes, 60 minutes, 120 minutes, 150 minutes, and 180 minutes after the administration of the drink. The spectral content of the EEG signal will be investigated to identify the relative presence of cortical oscillations. Primarily, there will be a focus on theta (4-8 Hz) and alpha (8-12 Hz) oscillations.

Previous literature indicates that theta and alpha oscillations represent an engaged and disengaged cortical state, respectively [1]. Alpha and theta oscillations are implicated in cognitive function and are altered in depression. Therefore, this study aims to identify a decrease in frontal theta oscillations and an increase in left frontal alpha oscillations, two defining features of impaired top-down control and mood regulation, in response to the glucose drink contrasted with the response to the placebo.

The study will also examine how glucose levels gate neuronal excitability measured by the response to TMS. Cortical excitability will be measured by applying TMS pulses to the motor cortex and measuring the response in the form of a motor evoked potential by electromyography (EMG). TMS will be applied before the administration of the drink, immediately after the administration of the drink, as well as 30 minutes, 60 minutes, 120 minutes, 150 minutes, and 180 minutes after the administration of the drink. Changes in blood glucose will be monitored over this time interval as well.

Study Design

Study Type:
Interventional
Actual Enrollment :
23 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Single (Investigator)
Masking Description:
The researcher that interacts with the subject will not know whether the subject consumed the glucose drink or the placebo.
Primary Purpose:
Basic Science
Official Title:
Modulation of Motor Cortex Excitability by Glucose Administration
Actual Study Start Date :
Sep 11, 2019
Actual Primary Completion Date :
Aug 31, 2020
Actual Study Completion Date :
Aug 31, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Glucose drink followed by placebo

Participants will consume the glucose drink at session 1, then they will consume the placebo (water) at session 2.

Device: Single-pulse TMS
Single-pulse transcranial magnetic stimulation (TMS) on the motor cortex will lead to a twitch in the target muscle and evoke a motor-evoked potential (MEP) measured by electromyography (EMG).
Other Names:
  • MagPro X100
  • Experimental: Placebo followed by glucose drink

    Participants will consume the placebo (water) at session 1, then they will consume the glucose drink at session 2.

    Device: Single-pulse TMS
    Single-pulse transcranial magnetic stimulation (TMS) on the motor cortex will lead to a twitch in the target muscle and evoke a motor-evoked potential (MEP) measured by electromyography (EMG).
    Other Names:
  • MagPro X100
  • Outcome Measures

    Primary Outcome Measures

    1. Motor Evoked Potential (MEP) [Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.]

      Change in MEP over time to indicate changes in motor cortex excitability

    2. TMS Evoked Potential (TEP) [Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.]

      The TMS Evoked Potential (TEP) is the difference in microvolts from 25 milliseconds after a TMS pulse versus pre-TMS such that greater values indicate greater motor cortex excitability. The measure of the change in TEP over time since either glucose or water was consumed approximates a z-distribution with a range of -20 to 20 with central distribution measures of zero. TEPs were source localized and reported using a pseudo-neural activity index (PNAI) expressing source activation in relation to pre-TMS pulse trial baseline. The difference in the source peaks corresponding to the early P25 component have been reported as differences from baseline. Higher values indicate greater cortical excitation, consistent with the study hypothesis.

    Secondary Outcome Measures

    1. EEG Measure of Alpha Asymmetry Oscillations [Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.]

      Electroencephalography will be used to measure the change in lateralized alpha asymmetry (10-12 Hz electrical activity) over time

    2. EEG Measure of Frontal Midline Theta Oscillations [Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.]

      Electroencephalography will be used to measure the change in frontal midline theta power (5-8 Hz electrical activity) over time

    3. Working Memory Task Accuracy [Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.]

      This outcome will analyze the change in accuracy in a computerized working memory task over time. During the task, subjects will be presented with an array of colored squares. Then, they will need to hold this array in mind during a delay period. Finally, participants will be tested on their memory of the array by responding whether a presented color is the same or different as the corresponding square in the first array. Participants' accuracy will be expressed as the percentage of correct responses (from 0% correct responses to 100% correct responses). An accuracy rate of 50% indicates that the participant is performing at the same accuracy level as random chance.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    • Right-handed

    • BMI <30

    • Free of major neurological conditions and diabetes

    Exclusion Criteria:
    • Diabetes

    • Adverse reaction to finger prick blood draw

    • Known neurological or psychiatric illness

    • Prior brain surgery

    • Any brain devices/implants, including cochlear implants and aneurysm clips

    • Cardiac pacemaker

    • Any other implanted electronic device

    • History of current traumatic brain injury

    • Anything that, in the opinion of the investigator, would place the participant at increased risk or preclude the participant's full compliance with or completion of the study

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UNC Medical School Wing C Chapel Hill North Carolina United States 27514

    Sponsors and Collaborators

    • University of North Carolina, Chapel Hill
    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    Investigators

    • Principal Investigator: Flavio Frohlich, Carolina Center for Neurostimulation

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    University of North Carolina, Chapel Hill
    ClinicalTrials.gov Identifier:
    NCT04031404
    Other Study ID Numbers:
    • 19-1451
    First Posted:
    Jul 24, 2019
    Last Update Posted:
    Sep 27, 2021
    Last Verified:
    Aug 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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.:
    Yes
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Glucose Drink Followed by Placebo Placebo Followed by Glucose Drink
    Arm/Group Description Participants will consume the glucose drink at session 1, then they will consume the placebo (water) at session 2. Single-pulse TMS: Single-pulse transcranial magnetic stimulation (TMS) on the motor cortex will lead to a twitch in the target muscle and evoke a motor-evoked potential (MEP) measured by electromyography (EMG). Participants will consume the placebo (water) at session 1, then they will consume the glucose drink at session 2. Single-pulse TMS: Single-pulse transcranial magnetic stimulation (TMS) on the motor cortex will lead to a twitch in the target muscle and evoke a motor-evoked potential (MEP) measured by electromyography (EMG).
    Period Title: Baseline
    STARTED 10 13
    COMPLETED 8 8
    NOT COMPLETED 2 5
    Period Title: Baseline
    STARTED 8 8
    COMPLETED 6 5
    NOT COMPLETED 2 3
    Period Title: Baseline
    STARTED 6 5
    COMPLETED 6 5
    NOT COMPLETED 0 0
    Period Title: Baseline
    STARTED 6 5
    COMPLETED 5 5
    NOT COMPLETED 1 0
    Period Title: Baseline
    STARTED 5 5
    COMPLETED 5 5
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title All Participants
    Arm/Group Description Participants will consume the glucose drink at session 1, then they will consume the placebo (water) at session 2, or vice versa. Single-pulse TMS: Single-pulse transcranial magnetic stimulation (TMS) on the motor cortex will lead to a twitch in the target muscle and evoke a motor-evoked potential (MEP) measured by electromyography (EMG).
    Overall Participants 23
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    23
    100%
    >=65 years
    0
    0%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    24.64
    (10.49)
    Sex: Female, Male (Count of Participants)
    Female
    15
    65.2%
    Male
    8
    34.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    4.3%
    Not Hispanic or Latino
    21
    91.3%
    Unknown or Not Reported
    1
    4.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    5
    21.7%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    4
    17.4%
    White
    13
    56.5%
    More than one race
    1
    4.3%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    23
    100%

    Outcome Measures

    1. Primary Outcome
    Title Motor Evoked Potential (MEP)
    Description Change in MEP over time to indicate changes in motor cortex excitability
    Time Frame Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.

    Outcome Measure Data

    Analysis Population Description
    From the 10 participants who completed, 3 were excluded from the analysis due to technical reasons. Two participants had to end their glucose visits early due to scheduling conflicts. The reported N below is adjusted where appropriate.
    Arm/Group Title MEP After Glucose Drink MEP After Placebo Drink
    Arm/Group Description Participants receive TMS to motor cortex following consumption of a 75 g glucose drink (~300 mL). Participants receive TMS to motor cortex following consumption of a water control (~300 mL).
    Measure Participants 7 7
    MEP change (0 min vs pre-drink)
    0.14
    (0.15)
    -0.25
    (0.07)
    MEP change (30 min vs pre-drink)
    -0.02
    (0.19)
    -0.12
    (0.11)
    MEP change (60 min vs pre-drink)
    -0.08
    (0.14)
    -0.33
    (0.10)
    MEP change (120 min vs pre-drink)
    -0.05
    (0.16)
    -0.25
    (0.09)
    MEP change (180 min vs pre-drink)
    -0.21
    (0.18)
    -0.18
    (0.10)
    2. Primary Outcome
    Title TMS Evoked Potential (TEP)
    Description The TMS Evoked Potential (TEP) is the difference in microvolts from 25 milliseconds after a TMS pulse versus pre-TMS such that greater values indicate greater motor cortex excitability. The measure of the change in TEP over time since either glucose or water was consumed approximates a z-distribution with a range of -20 to 20 with central distribution measures of zero. TEPs were source localized and reported using a pseudo-neural activity index (PNAI) expressing source activation in relation to pre-TMS pulse trial baseline. The difference in the source peaks corresponding to the early P25 component have been reported as differences from baseline. Higher values indicate greater cortical excitation, consistent with the study hypothesis.
    Time Frame Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.

    Outcome Measure Data

    Analysis Population Description
    From the 10 participants who completed, 3 were excluded from the analysis due to technical reasons. Two participants had to end their glucose visits early due to scheduling conflicts. The reported N below is adjusted where appropriate.
    Arm/Group Title Source-localized TEP After Glucose Drink Source-localized TEP After Placebo Drink
    Arm/Group Description Participants receive TMS to motor cortex following consumption of a 75 g glucose drink (~300 mL). Participants receive TMS to motor cortex following consumption of a water control (~300 mL).
    Measure Participants 7 7
    TEP change (P25: 0 min vs pre-drink)
    -0.04
    (0.08)
    0.28
    (0.16)
    TEP change (P25: 30 min vs pre-drink)
    -0.11
    (0.11)
    0.024
    (0.05)
    TEP change (P25: 60 min vs pre-drink)
    -0.16
    (0.11)
    0.30
    (0.06)
    TEP change (P25: 120 min vs pre-drink)
    -0.16
    (0.12)
    0.24
    (0.07)
    TEP change (P25: 180 min vs pre-drink)
    0.08
    (0.08)
    0.02
    (0.15)
    3. Secondary Outcome
    Title EEG Measure of Alpha Asymmetry Oscillations
    Description Electroencephalography will be used to measure the change in lateralized alpha asymmetry (10-12 Hz electrical activity) over time
    Time Frame Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.

    Outcome Measure Data

    Analysis Population Description
    From the 10 participants who completed, one was excluded from the analysis due to technical reasons. Two participants had to end their glucose visits early due to scheduling conflicts. The reported N below is adjusted where appropriate.
    Arm/Group Title Alpha Asymmetry After Glucose Drink Alpha Asymmetry After Placebo Drink
    Arm/Group Description Participants complete a resting state EEG recording following consumption of a 75 g glucose drink (~300 mL). Participants complete a resting state EEG recording following consumption of a 75 g glucose drink (~300 mL).
    Measure Participants 9 9
    Alpha Asymm. Change (0 min vs Baseline)
    0.15
    (0.15)
    0.59
    (0.45)
    Alpha Asymm. Change (30 min vs Baseline)
    -0.01
    (0.20)
    0.42
    (0.42)
    Alpha Asymm. Change (60 min vs Baseline)
    0.14
    (0.22)
    0.19
    (0.25)
    Alpha Asymm. Change (120 min vs Baseline)
    0.18
    (0.22)
    0.33
    (0.22)
    Alpha Asymm. Change (180 min vs Baseline)
    0.18
    (0.33)
    0.28
    (0.33)
    4. Secondary Outcome
    Title EEG Measure of Frontal Midline Theta Oscillations
    Description Electroencephalography will be used to measure the change in frontal midline theta power (5-8 Hz electrical activity) over time
    Time Frame Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.

    Outcome Measure Data

    Analysis Population Description
    From the 10 participants who completed, one was excluded from the analysis due to technical reasons. Two participants had to end their glucose visits early due to scheduling conflicts. The reported N below is adjusted where appropriate.
    Arm/Group Title Midline Frontal Theta Oscillations After Glucose Drink Midline Frontal Theta Oscillations After Placebo Drink
    Arm/Group Description Participants complete a resting state EEG recording following consumption of a 75 g glucose drink (~300 mL). Participants complete a resting state EEG recording following consumption of a 75 g glucose drink (~300 mL).
    Measure Participants 9 9
    Theta Power Change (0 min vs Baseline)
    0.12
    (0.34)
    0.33
    (0.28)
    Theta Power Change (30 min vs Baseline)
    0.56
    (0.25)
    0.57
    (0.27)
    Theta Power Change (60 min vs Baseline)
    0.94
    (0.29)
    1.15
    (0.32)
    Theta Power Change (120 min vs Baseline)
    0.36
    (0.26)
    1.21
    (0.45)
    Theta Power Change (180 min vs Baseline)
    1.48
    (0.32)
    0.72
    (0.34)
    5. Secondary Outcome
    Title Working Memory Task Accuracy
    Description This outcome will analyze the change in accuracy in a computerized working memory task over time. During the task, subjects will be presented with an array of colored squares. Then, they will need to hold this array in mind during a delay period. Finally, participants will be tested on their memory of the array by responding whether a presented color is the same or different as the corresponding square in the first array. Participants' accuracy will be expressed as the percentage of correct responses (from 0% correct responses to 100% correct responses). An accuracy rate of 50% indicates that the participant is performing at the same accuracy level as random chance.
    Time Frame Measurements will be taken before the administration of the drink, as well as 0, 30, 60, 120, and 180 minutes after the administration of the drink.

    Outcome Measure Data

    Analysis Population Description
    From the 10 participants who completed, one was excluded from the analysis due to technical reasons. Two participants had to end their glucose visits early due to scheduling conflicts. The reported N below is adjusted where appropriate.
    Arm/Group Title Working Memory Accuracy After Glucose Drink Midline Frontal Theta Oscillations After Placebo Drink
    Arm/Group Description Participants complete a working memory task following consumption of a 75 g glucose drink (~300 mL). Participants complete a working memory task recording following consumption of a 75 g glucose drink (~300 mL).
    Measure Participants 9 9
    WM Accuracy (0 min vs Baseline)
    1.02
    (0.03)
    0.97
    (0.03)
    WM Accuracy (30 min vs Baseline)
    1.02
    (0.02)
    0.99
    (0.03)
    WM Accuracy (60 min vs Baseline)
    1.06
    (0.02)
    1.01
    (0.03)
    WM Accuracy (120 min vs Baseline)
    1.05
    (0.03)
    1.02
    (0.03)
    WM Accuracy (180 min vs Baseline)
    1.03
    (0.03)
    1.03
    (0.03)

    Adverse Events

    Time Frame Up to 2 months per participant
    Adverse Event Reporting Description
    Arm/Group Title TMS-EEG After Glucose Drink TMS-EEG After Placebo Drink
    Arm/Group Description Participants receive TMS to motor cortex following consumption of a 75 g glucose drink (~300 mL). During every session, participants receive single pulse TMS to the motor cortex, and complete EEG recordings and a working memory task at several time points. Participants receive TMS to motor cortex following consumption of a water control drink (~300 mL). During every session, participants receive single pulse TMS to the motor cortex, and complete EEG recordings and a working memory task at several time points.
    All Cause Mortality
    TMS-EEG After Glucose Drink TMS-EEG After Placebo Drink
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/11 (0%) 0/10 (0%)
    Serious Adverse Events
    TMS-EEG After Glucose Drink TMS-EEG After Placebo Drink
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/11 (0%) 0/10 (0%)
    Other (Not Including Serious) Adverse Events
    TMS-EEG After Glucose Drink TMS-EEG After Placebo Drink
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/11 (90.9%) 8/10 (80%)
    Ear and labyrinth disorders
    Ringing or buzzing noise 2/11 (18.2%) 2 0/10 (0%) 0
    General disorders
    Dizziness 3/11 (27.3%) 3 1/10 (10%) 1
    Sleepiness 8/11 (72.7%) 8 5/10 (50%) 5
    Trouble concentrating 4/11 (36.4%) 4 2/10 (20%) 2
    Headache 5/11 (45.5%) 5 3/10 (30%) 3
    Flickering lights 0/11 (0%) 0 0/10 (0%) 0
    Psychiatric disorders
    Worsening mood 5/11 (45.5%) 5 2/10 (20%) 2
    Skin and subcutaneous tissue disorders
    Itching 5/11 (45.5%) 5 4/10 (40%) 4
    Local redness 4/11 (36.4%) 4 1/10 (10%) 1
    Scalp pain 3/11 (27.3%) 3 3/10 (30%) 3
    Tingling 2/11 (18.2%) 2 1/10 (10%) 1
    Burning sensation 0/11 (0%) 0 0/10 (0%) 0
    Neck pain 0/11 (0%) 0 0/10 (0%) 0

    Limitations/Caveats

    The end sample sizes are lower than intended as the trial was ended early due to COVID-19-related research drawdowns. Technical limitations in the Electroencephalogram (EEG) and Transcranial Magnetic Stimulation (TMS) data collection resulted in N=1 and N=3 dataset to be excluded from final analyses, respectively.

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Rachel B. Force, PhD
    Organization University of North Carolina at Chapel Hill
    Phone 9199669929
    Email rachel_force@med.unc.edu
    Responsible Party:
    University of North Carolina, Chapel Hill
    ClinicalTrials.gov Identifier:
    NCT04031404
    Other Study ID Numbers:
    • 19-1451
    First Posted:
    Jul 24, 2019
    Last Update Posted:
    Sep 27, 2021
    Last Verified:
    Aug 1, 2021