Motor Cortex Plasticity Response to Theta-Burst Stimulation After Ketone Monoester Supplementation (KME-TBS)

Priming Effects of Ketone Monoester Supplementation on Theta-Burst Stimulation-Induced Plasticity in the Primary Motor Cortex

Transcranial magnetic stimulation is a medical device that can alter motor cortical (M1) excitability through the scalp via various protocols. Among these, intermittent- and continuous-theta burst stimulation (iTBS/cTBS) are increasingly used protocols to enhance or suppress M1 excitability, respectively, beyond stimulation. However, the poor reproducibility and high inter-individual variability in responses to TBS protocols are matters of concern. This study will explore whether ketone monoester supplementation can boost TBS efficacy via their mechanistic convergence on Brain-Derived Neurotrophic Factor (BDNF).

Study Overview

• Status: Active, not recruiting
• Conditions: Neurophysiology; Healthy Young Adult
• Intervention / Treatment: Dietary supplement: Ketone Monoester (KME); Dietary supplement: Placebo; Device: iTBS; Device: cTBS

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Malaysia
  • Selangor
    • Serdang, Selangor, Malaysia, 43400
      • Hospital Sultan Abdul Aziz Shah

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Healthy young adults (18-35 years old)
• Right-handed
• Fully vaccinated against COVID-19

Exclusion Criteria:

• Subjects with contraindications to TMS based on the screening 13-item questionnaire for TMS safety
• Highly active subjects (athletes)
• Obese (BMI ≥ 30 kg/m2)
• Smokers
• Following intermittent fasting or ketogenic diet
• Long COVID-19

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: KME then placebo supplement with iTBS stimulation; KME drink with iTBS stimulation over the left M1 hand region, followed after a 1-week washout period by a placebo drink with iTBS stimulation over the left M1 hand region	Dietary supplement: Ketone Monoester (KME); 500 mg/kg body weight of the KME supplement; Dietary supplement: Placebo; Taste-matched placebo drink; Device: iTBS; iTBS stimulation will be applied using a butterfly figure-of-eight Cool-B70 coil connected to a MagPro R30 stimulator with add-on Theta Burst option (MagVenture A/S, Farum, Denmark).
Experimental: Placebo then KME supplement with iTBS stimulation; Placebo drink with iTBS stimulation over the left M1 hand region, followed after a 1-week washout period by a KME drink with iTBS stimulation over the left M1 hand region	Dietary supplement: Ketone Monoester (KME); 500 mg/kg body weight of the KME supplement; Dietary supplement: Placebo; Taste-matched placebo drink; Device: iTBS; iTBS stimulation will be applied using a butterfly figure-of-eight Cool-B70 coil connected to a MagPro R30 stimulator with add-on Theta Burst option (MagVenture A/S, Farum, Denmark).
Experimental: KME then placebo supplement with cTBS stimulation; KME drink with cTBS stimulation over the left M1 hand region, followed after a 1-week washout period by a placebo drink with cTBS stimulation over the left M1 hand region	Dietary supplement: Ketone Monoester (KME); 500 mg/kg body weight of the KME supplement; Dietary supplement: Placebo; Taste-matched placebo drink; Device: cTBS; cTBS stimulation will be applied using a butterfly figure-of-eight Cool-B70 coil connected to a MagPro R30 stimulator with add-on Theta Burst option (MagVenture A/S, Farum, Denmark).
Experimental: Placebo then KME supplement with cTBS stimulation; Placebo drink with cTBS stimulation over the left M1 hand region, followed after a 1-week washout period by a KME drink with cTBS stimulation over the left M1 hand region	Dietary supplement: Ketone Monoester (KME); 500 mg/kg body weight of the KME supplement; Dietary supplement: Placebo; Taste-matched placebo drink; Device: cTBS; cTBS stimulation will be applied using a butterfly figure-of-eight Cool-B70 coil connected to a MagPro R30 stimulator with add-on Theta Burst option (MagVenture A/S, Farum, Denmark).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor evoked potential (MEP)	Peak-to-peak MEP amplitude elicited by single-pulse TMS over the left M1 representation of the first dorsal interosseous (FDI) muscle. In each MEP measurement, 12 MEP readings will be collected, elicited by single-pulse TMS at an intensity of 120% resting motor threshold and separated by 15 seconds. In each timepoint post-TBS, the mean value of MEPs (aka, conditioned MEPs) will be averaged and compared to pre-TBS (aka, baseline MEPs) using the following equation: (conditioned MEP amplitude/baseline MEP amplitude) × 100. A value of 90-110 represents no change, while values < 90% represent suppression and > 110% facilitation of the M1 plasticity following TBS.	Pre-TBS (baseline) and post-TBS at 0, 5, 10, 20, and 30 minutes.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TMSens_Q questionnaire	Self-reported side effects using the TMSens_Q questionnaire to evaluate the tolerability of the KME-TBS combination.	At 30 minutes post-TBS stimulation
Corticospinal excitability indices	Resting motor threshold (RMT) followed by motor-evoked potential at 120% RMT intensity	Pre-KME supplementation and at 1 hour post-KME supplementation
Blood pressure	Systolic blood pressure (SBP), Diastolic Blood Pressure (DBP), and Mean Arterial Pressure (MAP) using fully automated oscillometric sphygmomanometer	Pre-supplementation, at 1 hour post-supplementation/pre-TBS stimulation, and serially thereafter every 3-5 minutes until 30 minutes post-TBS
Heart rate	Heart rate (bpm) using pulse oximeter	Pre-supplementation, at 1 hour post-supplementation/pre-TBS stimulation, and continuously thereafter for 30 minutes post-TBS
Blood glucose	On-site using a portable glucometer	Pre-KME supplementation and at 30 minutes post-TBS stimulation
Blood beta-hydroxybutyrate	On-site using a portable glucometer	Pre-KME supplementation and at 30 minutes post-TBS stimulation
Serum brain-derived neurotrophic factor	Serum levels of mature brain-derived neurotrophic factor (mBDNF) and pro-BDNF isoforms	Pre-KME supplementation and at 30 minutes post-TBS stimulation
BDNF genetic polymorphism	BDNF rs6265 single nucleotide polymorphism	At the baseline (pre-KME supplementation)

Collaborators and Investigators

• Sponsor: Universiti Putra Malaysia
• Collaborators: University of Oxford
• Investigators: Study Chair: Wan Aliaa Wan Sulaiman, FRCP, Universiti Putra Malaysia

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: January 2, 2025
• First Submitted That Met QC Criteria: January 22, 2025
• First Posted (Actual): January 29, 2025

Study Record Updates

• Last Update Posted (Estimated): June 25, 2025
• Last Update Submitted That Met QC Criteria: June 18, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Neuroplasticity; Transcranial magnetic stimulation; Blood pressure; Beta-hydroxybutyrate; Heart rate; Brain-derived neurotrophic factor; ketone monoester; Continuous theta-burst stimulation; Primary motor cortex; Intermittent theta-burst stimulation
• Other Study ID Numbers: JKEUPM-2021-485; FRGS/1/2022/SKK01/UPM/02/4 (Other Grant/Funding Number: Ministry of Higher Education, Malaysia)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified raw datasets collected during the trial will be freely available upon completion on the Open Science Framework repository at https://osf.io/

Drug and device information, study documents

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