IRON DEPOSITIONS IN PREFRONTAL CORTEX INFLUENCES THE EFFECTIVENESS OF CORTICAL PAIRED ASSOCIATIVE STIMULATION IN HEROIN-DEPENDENT PATIENTS: A RANDOMIZED SHAM-CONTROLLED STUDY

Abstract Background Brain iron homeostasis, which may be disrupted in substance dependence, will cause cell death and influence the neural plasticity function when out of balance. Transcranial magnetic stimulation (TMS) protocols in paired associative stimulation (PAS) are increasingly used to influence spike-timing-dependent plasticity and behaviors. The use of heroin causes severe brain damage; however, it is unclear whether PAS protocols in healthy people can benefit heroin patients’ cognitive behaviors and mechanisms. Aims & Objectives The aim of this study was to explore the role of a PAS stimulation protocol based on dorsolateral prefrontal-medial prefrontal cortex in modulating cognitive function in patients with heroin dependence, as well as the role of brain iron deposition levels in modulating the intervention effects. Methods A total of forty heroin patients were randomized to accept one of the following PAS protocols for 100 trials: left dorsolateral prefrontal cortex (DLPFC) stimulation preceding left ventromedial prefrontal cortex (VMPFC) stimulation by 4 ms (DLPFC+4ms), reverse the order (VMPFC+4ms), or placebo stimulation setting (DLPFC+100ms/VMPFC+100ms). Subjects were tested on the Quantitative susceptibility mapping and two cognitive tasks (i.e., stop signal task and two-back task) at baseline and after stimulation. Thirty healthy controls also accepted the DLPFC+4ms or VMPFC+4ms stimulation and finished two cognitive tasks during the PAS setting. Results Among the healthy controls, DLPFC+4ms stimulation significantly improved the accuracy rate of the two-back task (TWOB-ACC) than the VMPFC+4ms setting (p=0.01), while the VMPFC+4ms significantly increase the stop signal reaction time (SSRT) than DLPFC+4ms (p=0.03). However, three stimulation groups of heroin patients did not show a difference in two cognitive tasks during the PAS stimulation. Magnetic susceptibility of left DLPFC has positive predictive effect in the change of TWOB- ACC in the DLPFC+4ms group of heroin patients (p=0.002). In contrast, the magnetic susceptibility of left DLPFC has positive predictive effect in the change of SSRT in the VMPFC+4ms group of heroin patients (p=0.04). Discussion & Conclusion The brain magnetic susceptibility influences the functional plasticity induced by PAS, and the stimulus parameters applicable to the healthy controls cannot cause cognitive changes in the heroin-dependent population. Brain magnetic susceptibility should be considered an important modulating factor in TMS studies.