STAR Protocols︱Min Zhao's research group proposes a new plan for physical intervention in methamphetamine use disorder psychological craving

Written by ︱ Chen Tianzhen and editor in charge ︱ Sizhen Wang Effective treatment of substance use disorder (SUD) has always been one of the most concerned issues in the field of addiction
.

Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive brain stimulation technique, can modulate abnormal brain activation or neural circuits, thereby improving the clinical symptoms of patients [1,2]
.

At present, the rTMS research on SUD mainly focuses on the dorsolateral prefrontal cortex (DLPFC) [3], which has limited intervention effectiveness and lacks individualized strategies
.

The ventromedial prefrontal cortex (VMPFC) is another prefrontal-striatal circuit brain area closely related to drug cue responsiveness, and is closely related to abnormal reinforcement learning and drug-induced memory formation
.

However, there is still a lack of clinically proven VMPFC single-target and combined-target intervention programs, especially those that are superior to those that stimulate the classical target DLPFC
.

 On December 17, 2021, Zhao Min's research group from the Shanghai Mental Health Center published an experimental protocol article titled "A transcranial magnetic stimulation protocol for decreasing the craving of methamphetamine-dependent patients" in STAR Protocols, a sub-journal of Cell ( Protocol), proposed clinical intervention methods of DLPFC single target, VMPFC single target and dual target combined stimulation, and related works have also been published [4]
.

Since 2016, Zhao Min's research group has explored the effectiveness and neural mechanism of a series of intervention programs for rTMS and transcranial electrical stimulation for addiction-related symptoms, focusing on substance use disorder cravings, cognitive impairment and emotional disorders [5,6] ], providing important clinical evidence
.

Based on previous years of work, this work elaborates three rTMS intervention processes targeting DLPFC and VMPFC, and provides potentially effective treatment strategies for the improvement of clinical symptoms such as psychological craving, mood and sleep in patients with methamphetamine use disorder
.

They chose theta burst stimulation (TBS) as the basic parameter, which has been shown to bring higher benefits in studies of interventional patients with depression
.

Specifically, the TBS parameter of this work is 3 pulses of 50 Hz every 200 ms (Fig.
1), where continuous theta burst pulse stimulation (continuous TBS, cTBS) is a continuous stimulation of 60 seconds (900 pulses in total), Intermittent theta burst stimulation (intermittent TBS, iTBS) is a 5-minute intermittent stimulation (8 seconds rest for every 2 seconds of stimulation, a total of 900 pulses)
.

It is generally believed that the iTBS model can excite the target brain area, and cTBS has the effect of inhibiting the target brain area
.

Figure 1 Demonstration of continuous and intermittent theta burst pulse stimulation modes (Source: Chen T, et al.
, STAR Protoc.
2021) The three rTMS stimulation protocols include: (1) Targeting the left DLPFC with iTBS stimulation parameters , 1 time/day, 5 times/week, for a total of two weeks; (2) using cTBS stimulation parameters to target the left VMPFC, 1 time/day, 5 times/week, a total of two weeks; (3) using iTBS stimulation parameters to target The left DLPFC was combined with cTBS stimulation parameters to target the left VMPFC (ie, the combined stimulation group, the stimulation order was randomized), 1 time/day, 5 times/week, for a total of two weeks
.

 For the VMPFC target volume, the TMS stimulation coil was placed at the center of FP1 (placement method shown in Figure 2), and for the DLPFC target volume, the TMS stimulation coil was placed at the center of F3 (placement method shown in Figure 3)
.

Figure 2 Schematic diagram of ventromedial prefrontal positioning (Source: Chen T, et al.
, STAR Protoc.
2021) Figure 3 Schematic diagram of dorsolateral prefrontal positioning (Source: Chen T, et al.
, STAR Protoc.
2021) How to set A sham-stimulated control group is also an important part of rTMS studies
.

In order to ensure the reliability of the efficacy of the three groups of stimulation intervention strategies, in this work, the intervention parameters of the pseudo-stimulation are randomly selected iTBS parameters or cTBS parameters, and the coils are pseudo-stimulated coils (which hardly bring about the magnetic field stimulation effect)
.

The following series of measures also ensured the effectiveness of the blinding: (1) Each group gradually increased the stimulation intensity during stimulation, thereby enhancing the patient's comfort
.

(2) A thin PE foam board (thickness = 0.
5mm) is placed between the coil and the target site to reduce the impact and discomfort of rTMS directly touching the scalp
.

(3) Inform patients not to discuss the details of treatment with each other
.

(4) Inform the patient not to inform the outcome assessor of the specific treatment course
.

(5) Investigators conducting outcome assessments or statistical analyses were unaware of the specific study groupings
.

Figure 4 Comparison of the efficacy of three interventions or sham stimulation in patients with methamphetamine use disorder (Source: Chen T, et al.
, STAR Protoc.
2021) What is the efficacy of these three regimens? The study found that all three stimulation regimens significantly reduced psychological craving in patients with methamphetamine use disorder compared with sham stimulation (Figure 4)
.

In addition, the mean time to treatment response of the three stimulation regimens was also significantly shorter than that of the sham stimulation group
.

Patients who received the combination regimen had a shorter time to response than those who received the DLPFC iTBS regimen
.

In terms of adverse reactions, the symptoms of adverse reactions of the three stimulation regimens were mild and tolerable, and gradually improved during the treatment period, and there was no significant difference between the groups
.

Figure 5.
Transcranial Magnetic Stimulation Intervention Program Flow (Source: Chen T, et al.
, STAR Protoc.
2021) Conclusion and discussion, inspiration and prospect Single-target and dual-target combined stimulation protocols for substance use disorders such as amphetamine (Figure 5) further enhance the effectiveness of the treatment
.

Before that, Zhao Min's group published the first work exploring the classic high-frequency (10Hz) stimulation regimen in the treatment of methamphetamine use disorder, and revealed its potential therapeutic mechanism[7]
.

It is believed that through the continuous development and optimization of treatment plans, physical interventions such as transcranial magnetic stimulation will also be expected to bring greater benefits to the improvement of symptoms, prognosis and quality of life of people with addictive diseases
.

Link to the original text: https://doi.
org/10.
1016/j.
xpro.
2021.
100944 Shanghai Mental Health Center Dr.
Chen Tianzhen (first from left) and postdoctoral fellow Su Hang (second from left) are the co-first authors of this work, Professor Zhao Min (Right one) is the corresponding author
.

This work has received strong support from the Brain Film Research Office of the Shanghai Mental Health Center (Wang Jijun, Qian Zhenying, etc.
), the Shanghai Anti-Narcotics Bureau, and the Compulsory Isolation Drug Rehabilitation Center of the Shanghai Public Security Institute.
Strong support from the Natural Science Foundation of China, the Shanghai Municipal Science and Technology Commission and other institutions and funds
.

(Photo provided from Zhao Min's laboratory) Zhao Min's research group of Shanghai Mental Health Center is recruiting research assistants (several) in related fields such as physical intervention, brain film image acquisition and analysis, primate experiments, etc.
as research assistants in the team for a long time.
Members participate in interdisciplinary research
.

Candidates are welcome to apply for jobs based on their own backgrounds! Treat favorably! The email address in the article can be directly contacted
.

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Wilson MT, et al.
Biophysical modeling of neural plasticity induced by transcranial magnetic stimulation.
Clin Neurophysiol.
2018; 129:1230-41.
2.
Ekhtiari H, et al.
Transcranial electrical and magnetic stimulation (tES and TMS) for addiction medicine:a consensus paper on the present state of the science and the road ahead.
Neurosci Biobehav Rev.
2019; 104:118–40.
3.
Zhang JJQ, et al.
Effects of repetitive transcranial magnetic stimulation (rTMS) on craving and substance consumption in patients with Substance dependence: a systematic review and meta-analysis.
Addiction.
2019; 114:2137–49.
4.
Chen TZ, et al.
The exploration of optimized protocol for repetitive transcranial magnetic stimulation in the treatment of methamphetamine use disorder: A randomized sham-controlled study.
EBioMedicine.
2020; 60:103027.
5.
Xu XM, et al.
The transcranial direct current stimulation over prefrontal cortex combined with the cognitive training reduced the cue-induced craving in female individuals with methamphetamine use disorder: A randomized controlled trial.
J Psychiatr Res.
2021;134:102-110.
6.
Su H, et al.
Intermittent theta burst transcranial magnetic stimulation for methamphetamine addiction: A randomized clinical trial.
Eur Neuropsychopharmacol.
2020; 31:158-161.
7.
Su H, et al.
High frequency repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex for methamphetamine use disorders: A randomised clinical trial.
Drug Alcohol Depend.
2017; 175:84-91.
Plate making︱Sizhen Wang End of this article