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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
90
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.
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.
Min Zhao, PhD
Shanghai, Shanghai Municipality, China
RECRUITINGCraving
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.
Time frame: 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. ).
Time frame: Probabilistic reversal learning task and volatile reversal learning task : baseline, post-intervention, and at a follow-up session one week 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.
Time frame: 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.
Time frame: before the intervention (baseline) and immediately after the intervention (post-intervention).
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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.
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.
Time frame: SST task: baseline, post-intervention, and at a follow-up session one weeks later.
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.
Time frame: 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.
Time frame: 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.
Time frame: before the intervention (baseline), immediately after the intervention (post-intervention), and at a follow-up session one weeks later.