The Intervention Of RTMS On Response Inhibition In Methamphetamine Addicts

Methamphetamine(MA)addiction is a serious public health problem worldwide due to its adverse effects and pervasiveness.Thus,effective treatment of MA-related disorder is a matter of great urgency.Methamphetamine dependents with increased impulsivity sank into a persistent state in which there is reduced capacity to control compulsive drugseeking,though it involves risk of negative consequences,namely they deficit the ability to inhibit maladaptive behavior.In recent years,Transcranial magnetic stimulation(TMS),as a non-invasive tool,is able to modulate neuronal activity,cortical excitability and dopaminergic neurotransmission,this suggests that TMS could be used in the treatment of substance addiction.There are accumulating evidences that TMS could reduce craving or consupmtion in nicotine,alcohol,cocaine,heroin dependents,but little regards to methamphetamine disorder,and that they mainly depend on subjective craving,which is susceptible to social approval effect.To our knowledge no study to date have examined whether and how rTMS alters impulsive behavioral actions in meth addicts,a population characterized by hyperarousal and impulsivity.Therefore,the present study one investigated the effect of TMS on the behavioral impulsivity inhibition in methamphetamine addicts through Go/no go task.In the study one,forty-seven male MA-addicted subjects(aged from 21 to 50 years old,average 33.1±6.2 years old)were recruited for the present study.In addition,a sample of age-matched healthy male subjects were recruited from local community as the healthy control subjects.All MA subjects were from Nanjing Compulsory Rehabilitation Center and met Diagnostic and Statistical Manual of Mental Disorders criteria(DSM-V)criteria for MA use disorders.All healthy subjects were recruited in Chongqing and matched with the MA groups in gender,age,education,drinking and smoking status.In study one,a Go/Nogo task was used to measure impulsive behavior inhibition.The Go/No go task consisted of 150 trials,and each trial started with a jittered fixation varying from 500 to 1500 ms.Then the task stimulus was presented.Subjects were required to make a buttonpress as quickly as possible when the frequent letter “W”(80% of the trials)was presented,while withhold motor response when the infrequent letter “M” was presented(20% of the trials).Response impulsivity was indicated as the decreased accuracy rates during No go compared to Go condition.Forty-seven male meth addicts were randomly assigned into low frequency,high frequency or sham rTMS of the left dorsolateral prefrontal cortex(DLPFC).The parameter of sham rTMS is similar with 1 hz rTMS,except that the coil was turned away from the skull for 90 degrees.All the METH addicts performed the Go/No go task twice a day,that is,pretest and posttest.The participants performed the task 5 minutes before and 5 minutes after the rTMS or sham stimulation.The healthy control subjects performed the Go/No go task for once,to set up a criterion of the normal performance in healthy group.The healthy group didn’t receive the rTMS or sham stimulation.The result showed that 1Hz rTMS significantly improved the addicts’ inhibition of impulsive responses.This improvement remained robust 7 days later.The study one showed that 1 Hz rTMS of the left DLPFC reduces behavioral impulsivity in MA addicts.However,whether and how this impulsivity reduction may be related to the intervention of meth addiction remain unclear.This issue was therefore examined in study 2 which directly measures impulsivity and addiction at pre and post the 1 Hz rTMS protocol.Study 2 applied the same task and a cue-induced craving test to another methaddicts(who didn’t participated in study 1 and didn’t receive any rTMS intervention).Twenty-four male METH addicts whose age ranged from 23 to 57 years(M=38 ± 11.06 years),were randomly assigned into 1-Hz real rTMS condition(n=15)or sham condition(n=9).The low-frequency and the sham rTMS protocol were the same as those in Experiment 1.Behavioral tests across rTMS(either 1 Hz or sham)consist of the same Go/No go task as in Experiment 1,and subsequently,a cue-induced craving test.Seven days later,an unexpected craving test with the same procedure was administered to the 1-Hz rTMS group,to see the robustness of the intervention effect on meth addiction.The results replicated the above intervention effect during 1Hz rTMS and observed a positive correlation between the behavioral impulsivity and cue-induced addiction measures.Cue-induced cravings decreased significantly with 1Hz rTMS,and this effect stayed robust 7days later.These intervention effects were mediated by the improvement of behavioral impulse inhibition.Study 2 showed that 1hz rTMS could reduce MA subjects’ subjective craving and improve their impulsivity inhibition,and this study showed that impulsivity reduction was significantly related to the intervention of meth addiction.However,what mechanism supported the improvement of impulse control by the 1 Hz rTMS remains unclear,requiring further investigation.This issue was therefore directly examined in study 3 which employs a new paradigm—two choice oddball task,to measure impulsivity at pre and post the 1 Hz rTMS protocol.The two-choice oddball task is similar to Go/No go task,except that subjects were required to press buttons to both stimuli,instead of only responding to go stimuli in a Go/no go task.In this way,we could analyze the accuracy and reaction time.Study 3 used two-choice oddball task to investigate the mechanism behind the 1Hz rTMS specific enhancement of impulse inhibition.In study 3,Thirty-two male methaddicted subjects(aged from 26 to 52 years old,M=36.125±6.29 years),were recruited for the present study.They were randomly assigned into 1 Hz rTMS group(n=22),or the sham rTMS group(n=10).In addition,a sample of age-matched healthy male subjects were recruited from local community as the healthy control subjects(n=23,aged from 25 to 59 years,M=37.26±9.78).There were no difference in age(p=0.63),education background(p=0.69),smoking status(p=0.63),drinking habits(p=0.26)between the two groups.All the METH addicts performed the two-choice oddball task twice a day,that is,pretest and posttest.The participants performed the task 5 minutes before and 5 minutes after the rTMS or sham stimulation.As the 1-Hz rTMS group showed improved task performance post relative to pre rTMS,these subjects were followed for 7 days to retest their behavioral inhibitory function unexpectedly by the same task.The healthy subjects performed the task just for the once,to establish the age-controlled accuracy level in healthy population.The healthy group didn’t receive the rTMS or sham stimulation.The results showed that 1 Hz real rTMS significantly enhanced response accuracy for deviant stimulus,but not standard stimulus.In addition,the RT delay,defined as the deviant relative to standard RT increases,was significantly enlarged post relative to pre rTMS,indicating more conservative and goal-directed response profile(for accurate response)after 1-Hz rTMS intervention.Results from these three studies suggested that,low frequency rTMS over the left DLPFC could promote impulsivity inhibition and craving in MA subjects.Besides,the intervention effect on addiction measures should be accounted for the enhancement of impulse response inhibition.