Glucose and Non-Invasive Brain Stimulation

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.

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.

The researcher that interacts with the subject will not know whether the subject consumed the glucose drink or the placebo.

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

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

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).

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.

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

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

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.

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.

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

Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.

Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication.

Stitt I, Zhou ZC, Radtke-Schuller S, Frohlich F. Arousal dependent modulation of thalamo-cortical functional interaction. Nat Commun. 2018 Jun 25;9(1):2455. doi: 10.1038/s41467-018-04785-6.