We found that rTMS could decrease the withdrawal symptom, spontaneous craving and heroin-cue induced craving in the HD group after a 7-times course of rTMS. Our findings are consistent with previous research showing that 10Hz rTMS can reduce withdrawal symptom and craving in the HD (Liu et al., 2020; Mahoney et al., 2020; Shen et al., 2016). In terms of neuroimaging results, we found that rTMS selectively reduce the DMN (left IPL) - ECN (left middle frontal gyrus) coupling and the DMN (left IPL) - right inferior occipital gyrus coupling after rTMS treatment. In addition, this change in functional connectivity between the left IPL and left middle frontal gyrus positively correlated with the change of the drug-cue induced craving score in the HD individuals.
The DMN which are consisted of the MPFC, PCC and bilateral IPL is thought to be related to attention, self-monitoring and introspective thinking (Buckner, Andrews-Hanna, & Schacter, 2008; Greicius et al., 2003; Raichle et al., 2001; Nora D. Volkow, Wang, Fowler, & Tomasi, 2015). Others’ and our previous studies found that the abnormal alterations in the intrinsic functional pattern of DMN are a hallmark of the heroin use disorder (Kuo et al., 2019; Li et al., 2016; W. Li et al., 2015; Ma et al., 2015). The left middle frontal gyrus is a region included in the left DLPFC which is a key hub of the ECN. The ECN plays a key role in decision-making, problem-solving and memory-working (Goldstein & Volkow, 2011; Sridharan, Levitin, & Menon, 2008; Nora D. Volkow et al., 2015). Several studies revealed that the functional change within the ECN and associated with impaired executive control are an important indicator in SUD (Fu et al., 2008; Goldstein & Volkow, 2011). Moreover, more and more evidence revealed that the abnormal intrinsic functional pattern and interaction of the ECN, DMN, and SN (involved in detection and attention capture) may underlie the mechanism of SUD (Geng et al., 2017; Lerman et al., 2014; Li et al., 2018; Liang et al., 2015; Nora D. Volkow et al., 2015). Early studies have shown the anti-correlation between the DMN and ECN in healthy individuals (Fox & Raichle, 2007; Fox et al., 2005; Fox et al., 2009). In our previous fMRI study, the relapsed HD group showed weaker correlation between the DMN and ECN (Li et al., 2018). In a TMS/fMRI study, Chen found that single-pulse excitatory over the DLPFC could induce negative coupling between ECN and DMN in healthy controls (Chen et al., 2013). Listen found that 10Hz TMS could induce anti-correlated coupling between DMN (MPFC) and ECN (left DLPFC) (Liston et al., 2014). Meanwhile, Li found that 10Hz rTMS could decrease the functional connectivity between DMN (medial orbitofrontal cortex) and ECN (left DLPFC) in the nicotine dependent individuals (X. Li et al., 2017). Recently, a study on smokers with transcranial direct current stimulation (tDCS)/fMRI also indicated that stimulating the left DLPFC could change the ECN (left DLPFC) -DMN (bilateral PHG) coupling, and the coupling between the left DLPFC and right PHG were negatively correlated with smoking cravings (L. Z. Yang et al., 2017). Moreover, a recent study also showed the coupling between prefrontal and parietal cortex could shift the visuospatial attention and 5Hz continuous theta burst stimulation (cTBS) over the right frontal gyrus could suppress the blood oxygen level dependence bold (BOLD) signal in lateral frontal region and IPL. Our findings showed similar results, in which 10Hz rTMS over the left DLPFC could reduce the functional connectivity between the DMN (left IPL) and ECN (left DLPFC) with a similar tendency toward that of HC group. Our findings might suggest that the rTMS could decrease the craving for heroin through modulating the functional connectivity between the DMN and ECN, as supported by the positive relationship between the change in DMN (left IPL) - ECN (left DLPFC) coupling and change in craving.
Besides, our findings also showed a reduction of coupling between the DMN (left IPL) and right inferior occipital gyrus in the HD group after rTMS treatment. As a core region of the DMN, the IPL is mainly involved in visuospatial attention (Bokde et al., 2006; Hahn et al., 2007). Others’ and our previous studies also found that the IPL overactivated when exposed to drug-induced cues compared with neutral cues (Wei et al., 2020; Z. Yang et al., 2009). Several studies have implicated the involvement of the IPL during the treatment of addictive disorders. The cocaine dependent individuals under cognitive-behavioral treatment showed a lower activity in the IPL for task-related neural activity (DeVito et al., 2017). Our recent study also found that the HD individuals under protracted abstinence showed lower activity of IPL when exposed to drug related cues in comparison with the HD individuals under MMT (Wei et al., 2020). The occipital gyrus is believed to relate to visuospatial processing which exhibited high activity in cue-induced tasks in SUD (Kleinhans et al., 2020; McClernon, Kozink, & Rose, 2008; Qiu & Wang, 2021). Several studies also found that the activity of occipital gyrus has been reported to be positively correlated with self-reported craving (Charboneau et al., 2013; McClernon et al., 2008). In all, the IPL and occipital gyrus both are visual regions and exhibit high activity in cue-induced tasks, implying that these regions may mediate visual cue aspects of drug craving (Charboneau et al., 2013). As we know, the visual mental imagery of cognitive processes is involved in a brain network, which is consisted of prefrontal, parietal, inferotemporal and occipital cortex (Ragni, Tucciarelli, Andersson, & Lingnau, 2020). The top-down connectivity during visual imagery was found from parietal to occipital cortex using granger causality and dynamic causal modeling analyses (Dentico et al., 2014; Ragni et al., 2020). Meanwhile, several diffusion tensor imaging (DTI) studies found that the parietal lobe connects frontal lobe in the superior longitudinal fasciculus (SLF) and the occipital gyrus connects frontal lobe in the inferior frontal-occipital fasciculus (IFOF), both of which are involved in visual attention and working memory (Ffytche, Blom, & Catani, 2010; Migliaccio et al., 2012; Yu & Shim, 2017). Moreover, the rTMS could modulate remote brain activities distal to the target regions (Fox, Halko, Eldaief, & Pascual-Leone, 2012; Kobayashi & Pascual-Leone, 2003). For example, an interleaved TMS/fMRI study showed that cTBS over the left frontal pole could significantly reduce the BOLD signal in the parietal cortex of cocaine dependent individuals (Hanlon et al., 2017). Our results showed a reduction of coupling between the DMN (left IPL) and right inferior occipital gyrus in the HD group, which might be the remote secondary effects caused by rTMS targeting left DLPFC. It’s suggested that the reduction of left IPL-right inferior occipital gyrus coupling might attenuate visuospatial attention of visual imagery for drug related cues.
Our findings should be interpreted in light of potential limitations. Firstly, this study lacked a sham-rTMS control and we could not exclude the possibility that some changes of coupling after rTMS might be caused by the placebo effect. Secondly, our study was based on the DMN and we did not investigate whether additional networks could be modulated by the rTMS. Thirdly, traditional skull-based landmark stimulation location was used in this study. More accurate location techniques such as MRI guided Neuro-navigation is warranted in future study. Fourthly, we did not evaluate the change in daily methadone dosage and a urine test for heroin use during this study, although many of the HD individuals hoped to reduce the dosage of methadone.