Cerebellum-Prefrontal Paired-Pulse Stimulation for Methamphetamine Use Disorder

Exploring the Mechanisms and Efficacy of Cerebellum-Medial Prefrontal Cortex-Based Paired-Pulse Repetitive Transcranial Magnetic Stimulation for Methamphetamine Use Disorder

To investigate the mechanism and efficacy of a novel repetitive transcranial magnetic stimulation (rTMS) intervention model with paired cerebellar-medial prefrontal cortex (mPFC) pulses on methamphetamine use disorder patients and to develop a novel physiotherapeutic intervention to optimise the treatment and management.

Study Overview

• Status: Recruiting
• Conditions: Methamphetamine Use Disorder
• Intervention / Treatment: Device: Paired Associative Stimulation Targeting the Cerebellar-mPFC; Device: Sham Intervention over cerebellum and mPFC; Device: Sham stimulation over the cerebellum + real stimulation over the medial prefrontal cortex

Detailed Description

Numerous studies have shown that impaired cerebellar- mPFC functional connectivity leads to impaired social preferences and behavioural flexibility and more persistent drug use in addicts. Cerebellar and mPFC paired-pulse rTMS interventions may enhance functional connectivity, effectively modulate cerebellar-prefrontal loops, reduce craving, improve cognitive flexibility, and modulate cortical excitability. The aim of this project is to investigate the mechanism and efficacy of a novel paired-pulse rTMS intervention targeting the cerebellar-mPFC circuit in patients with methamphetamine use disorder, in order to develop innovative physiotherapeutic interventions and to optimize treatment and clinical management for individuals with addiction.

Prior to initiating the intervention, it was essential to determine the optimal inter-stimulus interval (ISI) for the cerebellar-mPFC paired associative stimulation. Therefore, a mechanistic study was conducted from December 2024 to June 2025 at the Chengdu Drug Rehabilitation Center in Sichuan Province before the interventional trial commenced. A mixed design was employed, contrasting single-pulse mPFC stimulation with cerebellum→mPFC cortico-cortical paired associative stimulation (ccPAS) at inter-stimulus intervals of 6 ms and 45 ms. The results revealed that individuals with methamphetamine use disorder exhibited aberrant mPFC cortical excitability compared to healthy controls. Importantly, cerebellar-mPFC ccPAS with a 6-ms ISI was found to specifically modulate mPFC cortical excitability.

Therefore, based on the identified 6-ms cerebellar-mPFC stimulation interval, the current interventional study continues to implement a long-term, dual-coil combined stimulation protocol to further evaluate and establish its therapeutic efficacy.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Min Zhao, PhD; Phone Number: 64387250; Email: drminzhao@gmail.com
• Study Contact Backup: Name: 64387250 Zhao, PhD; Phone Number: 64387250; Email: drminzhao@gmail.com

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200000
      • Recruiting
      • Min Zhao, PhD
      • Contact: Min Zhao, PhD; Phone Number: 64387250; Email: drminzhao@gmail.com
      • Contact: Min Zhao, PhD; Phone Number: 18017311005; Email: drminzhao@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

Participants will be eligible for inclusion if they meet the following criteria:

1. Methamphetamine is the primary substance of use, and the participant meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for moderate or severe methamphetamine use disorder;
2. aged 18 to 60 years;
3. normal or corrected-to-normal vision and hearing, and right-handedness;
4. primary school education or above, with the ability to understand the questionnaires and behavioral task instructions.

Exclusion Criteria

Participants will be excluded if they meet any of the following criteria:

1. presence of metal objects in the body, such as metal dentures, orthodontic braces, bone fixation plates, aneurysm clips, or other metallic implants;
2. severe physical illness or chronic disease, including heart disease, severe hypertension, stroke, epilepsy, or history of head trauma;
3. comorbid psychiatric disorders, such as bipolar disorder, schizophrenia, or severe depression;
4. previous participation in transcranial magnetic stimulation- or electroencephalography-related studies;
5. refusal to participate in the study, poor compliance, or any other contraindications to transcranial magnetic stimulation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham Cerebellar Stimulation + Sham mPFC Stimulation Group; This is the sham stimulation group. The coil will be placed vertically over the cerebellar and mPFC brain regions, allowing participants to perceive the coil's vibration and sound without receiving effective intervention. All other stimulation parameters are identical to those in the active intervention group.	Device: Sham Intervention over cerebellum and mPFC; The coil will be placed vertically over the cerebellar and mPFC brain regions, allowing participants to perceive the coil's vibration and sound without receiving effective intervention. All other stimulation parameters are identical to those in the active intervention group.
Experimental: Cerebellar-mPFC Dual-Coil Paired-Pulse TMS Intervention Group; The stimulation protocol involved delivering a pulse to the cerebellum first, followed by a pulse to the mPFC after a 6ms inter-stimulus interval (ISI). This 6ms interval was determined based on findings from our prior mechanistic study.	Device: Paired Associative Stimulation Targeting the Cerebellar-mPFC; The protocol consisted of 180 pulse trains. Each train contained 5 pulse pairs delivered over 1 second, resulting in a stimulation frequency of 5 Hz. Within each pulse pair, the cerebellum was stimulated first, followed by the mPFC after a 6-ms inter-stimulus interval (ISI). In total, 900 pulse pairs were administered, and a complete intervention session lasted 11 minutes and 57 seconds.
Active Comparator: Cerebellar Sham + Real mPFC Stimulation Group; This group serves as the positive control group for single-site stimulation. Participants in this group will receive real stimulation over the medial prefrontal cortex combined with sham stimulation over the cerebellum. This design allows us to determine whether the therapeutic effects of paired cerebellum-medial prefrontal cortex stimulation are attributable to the paired stimulation protocol itself, rather than to the effect of single-target stimulation of the medial prefrontal cortex alone.	Device: Sham stimulation over the cerebellum + real stimulation over the medial prefrontal cortex; Participants in this group will receive sham stimulation over the cerebellum (The coil will be placed vertically over the cerebellum) combined with real stimulation over the medial prefrontal cortex.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Craving	The intensity of psychological craving in MA dependents was assessed using the Visual Analogue Scale (VAS), where individuals rated their cravings on a scale from 0 to 100, with higher scores indicating greater levels of craving.	before the intervention (baseline), immediately after the intervention (post-intervention), and at a follow-up session one weeks later.
cognitive flexibility	Based on tasks and scales assessing cognitive flexibility, including: 1.Probabilistic reversal learning task (The matching of symbols and pictures was reversed without informing the subjects and their cognitive flexibility in the reversed condition was assessed); 2.Volatile reversal learning task (participants were presented with two stimuli associated with their potential feedback magnitude. They were instructed to choose one of the two stimuli to receive feedback, but only one stimulus would result in feedback. ).	Probabilistic reversal learning task and volatile reversal learning task : baseline, post-intervention, and at a follow-up session one week later;

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depression	The reduction rate of Beck Depression Inventory (BDI) scores was calculated from baseline to post-intervention and follow-up assessments to quantify the decrease in depressive symptom severity.	before the intervention (baseline), immediately after the intervention (post-intervention), and at a follow-up session one weeks later.
Anxiety	The reduction rate in the Beck Anxiety Inventory (BAI) scores was calculated from baseline to post-intervention and follow-up assessments to quantify the decrease in anxiety symptom severity.	before the intervention (baseline), immediately after the intervention (post-intervention), and at a follow-up session one weeks later.
sleep quality	The reduction rate of Pittsburgh Sleep Quality Index (PSQI) global scores was calculated from baseline to post-intervention and follow-up assessments to quantify the improvement in sleep quality.	before the intervention (baseline), immediately after the intervention (post-intervention), and at a follow-up session one weeks later.
Other craving scales	1、Desires for drug questionnaire (DDQ) consists of 13 items designed to assess an individual's current thoughts and preoccupations related to drug use. 2、Obsessive Compulsive Drug Use Scale (OCDUS)consists of 13 items designed to assess an individual's current thoughts and preoccupations related to drug use.	before the intervention (baseline), immediately after the intervention (post-intervention), and at a follow-up session one weeks later.
Electroencephalographic (EEG) Electrophysiological Results	This includes analyses of TMS-EEG, resting-state EEG, and task-state EEG data across temporal, frequency, and time-frequency domains.	before the intervention (baseline) and immediately after the intervention (post-intervention).
response inhibition	The Stop-Signal Task (SST) is a seminal experimental paradigm in cognitive psychology and neuroscience designed to objectively measure an individual's response inhibition-the ability to actively suppress a prepotent or already-initiated motor response. To gain a more comprehensive understanding of an individual's inhibitory control, it is highly informative to complement this with a trait-based, self-reported measure of impulsivity.	SST task: baseline, post-intervention, and at a follow-up session one weeks later.

Collaborators and Investigators

• Sponsor: Shanghai Mental Health Center
• Collaborators: Chengdu Drug Rehabilitation Center; Sichuan Ziyang Compulsory Isolation Drug Rehabilitation Center; Mental Health Center, West China Hospital of Sichuan University, Chengdu; Wuhan Mental Health Center, The Ninth Clinical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan; HanYang Comoulsory Isolation Drug Rehabilitation Center, Wuhan
• Investigators: Study Chair: Min Zhao, PhD, Shanghai Mental Health Center

Study record dates

Study Major Dates

• Study Start (Actual): December 24, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: June 10, 2024
• First Submitted That Met QC Criteria: June 10, 2024
• First Posted (Actual): June 13, 2024

Study Record Updates

• Last Update Posted (Actual): June 24, 2026
• Last Update Submitted That Met QC Criteria: June 21, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Repetitive transcranial magnetic stimulation; Cerebellum; Methamphetamine; medial prefrontal cortex; Cortico-Cortical Paired Associative Stimulation
• Other Study ID Numbers: MZhao-015; 2021ZD0202105 (Other Grant/Funding Number: Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project); 2024YFF0507604 (Other Grant/Funding Number: National Key R&D Program of China); 82130041, 82471510, U25C2016 (Other Grant/Funding Number: National Nature Science Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after de-identification, will be made available at the discretion of the corresponding author, following a formal request and execution of a data use agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No