Participants

Power analyses were conducted with G-Power 3.1.9.3 (effect size = 0.6; means: difference from constant; α < 0.05; 1-β > 0.8).

METH-dependent participants were recruited from the Compulsory Rehabilitation Center in Shiliping, Zhejiang Province, China. Patients admitted to the rehabilitation center first underwent 2 weeks of detoxification. Thereafter, psychologists decided whether or not they would receive psychological treatment. Psychological treatment includes CBT and supportive psychotherapy. In this study, participants did not receive any other treatment except for VRCP before and throughout the testing period. First, they underwent screening, including demographic information, drug use history, and psychiatric evaluation. All participants were evaluated using psychopathological questionnaires including the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Barratt Impulsiveness Scale version 11 (BIS-11). The necessary inclusion criteria were the diagnosis of METH dependence based on the DSM-IV, as determined by an experienced psychiatrist. Exclusion criteria were: (1) taking medications at the time of the study, (2) other concurrent neuropsychiatric diseases that might induce EEG alteration, and (3) other psychoactive substance usage history. In total, 35 male participants with METH dependence were enrolled in this study, 6 of whom quit compulsory intervention before completing the study procedure. Finally, 29 participants with METH dependence completed all measurements.

In addition, 30 healthy male participants were recruited from the local community through advertisements. None had a history of drug use or any neurological/psychiatric disorder or major physical disease.

MethodsAssessment procedure

Figure 1 is a schematic diagram of the assessment procedure. First, participants were seated in a quiet room for EEG recording, which included a six-minute eyes-open resting-state EEG. They were then introduced to the VR device (i.e., VR helmets and headphones). After participants adapted to the VR scene, they were instructed to watch an eight-minute VR video that simulates a real METH-related social context including various METH-related cues, and the concurrent EEG signals were recorded (i.e., cue-induced EEG). Before the EEG recording and immediately after the VR video, participants in the METH group were asked to answer three questions on a visual analog scale (VAS) (i.e., VAS-craving, VAS-liking, and VAS-using). For the HCs, these questions were asked only after the VR video.

Fig. 1

Flow chart of present work

After the assessment, participants in the METH group were instructed to receive six sessions of VRCP treatment. In each session, participants were required to watch one VR video following a VRCP (VR treatment system, Hangzhou Seventh Science and Technology Co., Ltd.). The VRCP sessions were run twice a week. After completing all six sessions of treatment, resting-state and cue-induced EEGs were recorded with the same settings as mentioned above. The VAS assessment was performed only after the cue video.

EEG recording

The EEG data were recorded using a 32-channel system with a sampling rate of 2048 Hz, and the electrode placement followed the international 10–20 system (eegoTM mylab, ANT Neuro, The Netherlands). The reference electrode was placed on the CPz, and all channel impedances were kept below 10 kΩ.

VR videos

The METH-cue VR video comprised several drug-related social scenes including visual, auditory, and action cues and social information such as facial expressions and social interactions. Preliminary work has indicated that this virtual social environment could efficiently elicit reliable craving.

In addition, six VR videos were used in the VRCP, and each video lasted approximately five minutes. All these videos had similar beginnings, depicting a story of men/women using METH together. The participants then viewed the characters in the videos to experience different adverse consequences caused by using METH. Preliminary work has indicated that this treatment procedure is useful for suppressing cue-induced reactivity in patients with METH dependence. More details regarding the METH-cue VR video and VRCP can be found in our previous study.

VAS assessments

Participants were asked to answer three questions on a VAS by choosing the most suitable option for each question. The first question was regarding METH-craving: “How much do you crave METH/ice right now?” (ranging from 0 to 10, with 0 indicating “no craving at all” and 10 indicating “extremely strong craving”). The second question enquired about METH usage: “If you have access to METH/ice right now, how likely would you be to use it?” (ranging from 0 to 10, with 0 indicating “certainly not” and 10 indicating “certainly”). The third question was: “To what extent do you find METH/ice pleasant/unpleasant?” (ranging from 0 to 10, with 0 indicating “very unpleasant,” 5 indicating “neither unpleasant nor pleasant,” and 10 indicating “very pleasant”).

EEG data preprocessing and analysis

All EEG data were processed using MATLAB (MathWorks, Natick, MA, USA). Preprocessing procedures were performed to exclude artifacts. EEG data were bandpass filtered between 0.1 and 70 Hz, with the notch frequency set to 50 Hz. The EEG data were subsequently down-sampled to 200 Hz and re-referenced to the mastoid electrodes (i.e., average M1–M2). An independent component analysis was performed to decompose the EEG signals. Components containing artifacts of eye/muscle movements were rejected. Then, the EEG was segmented into 2-second epochs. Epochs with excessive motor activity were removed if necessary.

A spectral analysis was performed using the EEGLAB plugin (Darbeilial, https://github.com/embar-/eeglab_darbeliai/wiki/0.%20EN). The window length and frequency resolution were set to two seconds and 0.1 Hz, respectively. Thus, for each 2-s segment of the EEG, Power Spectral Density data were obtained and then averaged. For statistical purposes, scalp electrodes were divided into nine clusters comprising one or two electrodes: Anterior Left (F3–F7), Anterior Central (Fz), Anterior Right (F4–F8), Central Left (T7–FC5), Central Central (Cz), Central Right (T8–FC6), Posterior Left (P7–CP5), Posterior Central (Pz), and Posterior Right (P8–CP6). The clustering resulted in a 3 × 3 grid along a two-dimensions-defined region (anterior-central-posterior) and hemisphere (left-central-right). Spectrum power (dB) in the gamma range (30–49 Hz) was computed separately for each cluster (for clusters comprising two electrodes, the power was averaged).

Statistical data analysis

A two-sample t-test and paired t-test were conducted to compare age and VAS score between groups and between conditions, respectively. Gamma activity was analyzed using four-way repeated-measures ANOVAs. For the contrasts between the METH and HC groups, the within-subject factors considered were Condition (rest/cue-induced) and Region and Hemisphere. Group was considered the between-subject factor. We conducted another rmANOVA to compare the data recorded before and after VRCP (METH group only). The Condition, Region, Hemisphere, and Intervention (before VRCP/after VRCP) were considered as within-subject factors. Bonferroni corrections were used for the multiple comparisons.

Table 1 Demographic characteristics and VAS scores