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.

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.

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.