Research Articles: Behavioral/Cognitive The VLPFC vs. the DLPFC in down-regulating social pain using reappraisal and distraction strategies https://doi.org/10.1523/JNEUROSCI.1906-20.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.1906-20.2020 Received: 22 July 2020 Revised: 21 October 2020 Accepted: 23 October 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 Zhao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 The VLPFC vs. the DLPFC in 2 down-regulating social pain using 3 reappraisal and distraction strategies 4 5 Jun Zhao1,2,#, Licheng Mo1,#, Rong Bi1, Zhenhong He1, Yuming Chen1, Feng Xu3, Hui Xie1, 6 Dandan Zhang1,2,4,5,* 7 8 1 School of Psychology, Shenzhen University, Shenzhen, 518060, China 9 2 Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu 610066, 10 China. 11 3 Shenzhen Yingchi Technology Co., Ltd., Shenzhen, 518057, China 12 4 Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, 518060, China 13 5 Shenzhen Institute of Neuroscience, Shenzhen 518060, China 14 15 Running head: the role of LPFC in down-regulation of social pain 16 17 The authors declare that there are no conflicts of interest in relation to the subject of this study. 18 19 # The two authors contributed equally to the study. 20 21 * Corresponding author. E-mail: [email protected] 22 23 Number of pages: 29 24 Number of figures: 4; number of tables: 3 25 Words: abstract (248), introduction (688), and discussion (1652) 1 / 30 26 Abstract 27 The dorsolateral (DLPFC) and ventrolateral prefrontal cortices (VLPFC) are both 28 crucial structures involved in voluntary emotional regulation. However, it remains 29 unclear whether the functions of these two cortical regions that are involved in 30 emotional regulation—which are usually active in non-social situations—could be 31 generalized to the regulation of social pain as well. This study employed transcranial 32 magnetic stimulation (TMS) to examine the causal relationship between the 33 DLPFC/VLPFC and the emotional regulation of social pain via distraction and 34 reappraisal. Ninety human participants (45 males and 45 females) initially underwent 35 either active (DLPFC/VLPFC, n = 30/30) or sham (vertex, n = 30) TMS sessions. 36 Participants were then instructed to use both distraction and reappraisal strategies to 37 down-regulate any negative emotions evoked by social exclusion pictures. 38 Convergent results of the subjective emotional rating and electrophysiological indices 39 demonstrated that: 1) both the DLPFC and VLPFC highly facilitate the 40 down-regulation of affective responses caused by social exclusion, revealing a causal 41 role of these lateral prefrontal cortices in voluntary emotional regulation of both 42 non-social and social pain; and 2) these two cortical regions showed relative 43 functional specificity for distraction (DLPFC) and reappraisal (VLPFC) strategies, 44 which helps to refine the cortical targeting of therapeutic protocols. In addition, the 45 TMS effect was sustainable for at least one hour, showcasing the potential feasibility 46 of using this method in clinical practice. Together, these findings provide cognitive 47 and neural evidence for the targeting of the VLPFC and/or the DLPFC to improve 2 / 30 48 emotional regulation abilities, especially in social contexts. 49 50 Key words: emotional regulation; social exclusion; social pain; ventrolateral 51 prefrontal cortex; dorsolateral prefrontal cortex 52 53 54 Significance Statement 55 This study aimed to examine the role of the dorsolateral and ventrolateral prefrontal 56 cortices in emotional regulation, particularly in response to social pain through the use 57 of distraction and reappraisal strategies, as this is a relatively underexplored area of 58 inquiry. This study makes a significant contribution to the literature because our 59 results provide novel empirical information on the role of these cortical structures in 60 the processing of negative emotions elicited within certain social contexts. As such, 61 our findings have potential clinical implications, paving the way for future clinicians 62 to be able to accurately target specific brain regions among patients struggling with 63 impaired social cognition abilities, including those diagnosed with post-traumatic 64 stress disorder, autism spectrum disorder, social anxiety disorder, and depression. 65 66 67 68 69 3 / 30 70 Introduction 71 While the key brain regions for emotional regulation are primarily located in the 72 prefrontal cortex (Ochsner et al. 2012), some studies have demonstrated that explicit 73 emotional regulation using varying strategies do not involve the exact overlapping 74 neural substrates (Morawetz et al. 2017; Vrtička et al. 2011). In particular, although 75 the dorsolateral (DLPFC) and ventrolateral prefrontal cortices (VLPFC) are both 76 important in distraction and reappraisal (Buhle et al. 2014; Kohn et al. 2014), e.g., the 77 two regions often activate together during reappraisal (Morawetz et al. 2017; Ochsner 78 et al. 2012), neuroimaging studies have revealed that while the VLPFC is consistently 79 involved during reappraisal, the DLPFC is more associated with distraction (Dörfel et 80 al. 2014; Moodie et al. 2020). However, it remains unclear to what extent these two 81 brain regions are essential and specific for both of these strategies. This study 82 employed transcranial magnetic stimulation (TMS) to examine the roles of the 83 VLPFC and the DLPFC in emotional regulation via distraction and reappraisal 84 strategies. 85 Meanwhile, a more urgent question is whether the brain regions involved in 86 emotional regulation observed in general, especially non-social, situations can be 87 generalized to functioning similarly in social contexts. Most previous studies have not 88 disentangled the specific brain regions involved in emotional regulation for social vs. 89 non-social emotion-eliciting events (but see Vrtička et al. 2011). Uncovering the 90 neural substrates critical for emotional regulation in social contexts is necessary not 91 only for understanding the neural mechanisms behind emotional regulation, but also 4 / 30 92 in the development of effective therapeutic protocols in clinics. For one thing, 93 negative social experiences, including dysfunctional family interactions and traumatic 94 or stressful interpersonal events are all considered major risk factors in the 95 development of psychiatric disorders such as post-traumatic stress disorder, social 96 anxiety, depression, and autism spectrum disorder (Nolan et al. 2003; Durodié and 97 Wainwright 2019). For another, growing evidence indicates that these aforementioned 98 psychiatric disorders are all associated with the maladaptive regulation of social pain 99 (Davey et al. 2011; Masten et al. 2011). Therefore, it is implied that improving one’s 100 emotional regulation abilities in response to negative social events is highly beneficial 101 for the remission of symptoms and recovery from psychiatric disorders (Laceulle et al. 102 2017). This study was designed to examine the causal relationship between the 103 VLPFC/DLPFC and the emotional regulation of social pain in order to provide neural 104 targets for clinical interventions. 105 Previous studies have demonstrated that both the VLPFC and the DLPFC are 106 associated closely with the reduction of social pain (Koban et al. 2017a; 107 Koenigsberg et al. 2010; Vijayakumar et al. 2017; Wang et al. 2017). Typically, 108 researchers have observed that the right or bilateral VLPFC is activated significantly 109 when individuals experienced social exclusion (Eisenberger et al. 2003; Hooker et al. 110 2010; Hsu et al. 2015; Masten et al. 2009; Onoda et al. 2010; Riva et al. 2012, 111 2015). Also, fMRI studies have found that enhanced activation in the DLPFC was 112 associated with a decline in subjective social distress (Koban et al. 2017b; Nishiyama 113 et al. 2015) and aggressive behaviors (Achterberg et al. 2016, 2020) following the 5 / 30 114 experience of social rejection. However, while these studies have demonstrated an 115 association between the DLPFC/VLPFC and reduced social pain, very limited studies 116 have examined the role of these regions on explicit emotional regulation within social 117 contexts (but see Koenigsberg et al. 2010). Recently, we used tDCS/TMS in an 118 explicit emotional regulation task and provided direct evidence for the role of the 119 right VLPFC on emotional regulation following the experience of social exclusion 120 (He et al. 2018, 2020a, 2020b). However, until now, no study has explored the causal 121 role of the DLPFC in the explicit regulation of social pain. This study was thus 122 inspired by this literature gap. 123 Our hypothesis is two-fold. First, the critical role of the VLPFC and the DLPFC in 124 emotional regulation during non-social situations is generalizable to social ones, 125 because previous studies have revealed a close association between the 126 VLPFC/DLPFC and