Discussion
The present pharmacological fMRI trial aimed to determine whether targeting the RAS system via LT can modulate social reward and punishment processing via modulating VTA-striatal-frontal circuits. On the behavioral level LT modulated the motivational significance of social reward and punishment during anticipation while affecting the subsequent affective evaluation of social stimuli. On the neural level the enhanced motivational significance was reflected by increased coupling between the VS and MFG during anticipation of social rewards. During the outcome phase LT enhanced neural signals in the VTA and associated prediction error signals in VTA and DS while attenuating VTA-insula communication and concomitantly enhancing VTA-SFG communication during social punishment. Together, these findings provide a potential mechanism by which LT may enhance social reward motivation while decreasing punishment sensitivity.
On the behavioral level LT shifted the motivational significance and arousal experience for social punishment relative to social reward feedback, an effect that was mainly driven by prolonged reaction times during anticipation of and subsequently reduced arousal reaction towards social punishment stimuli. These findings partly align with observations in previous studies, such that following LT healthy subjects perceived loss outcomes as being less informative resulting in an attenuated loss learning rate (29), and exhibited accelerated extinction and autonomous arousal decreases towards threat (26). Together, these observations indicate that LT may attenuate the impact of negative information thus shifting anticipatory motivation and post encounter learning towards positive information.
On the neural level the relative motivational shift between negative and positive social information was accompanied by a modulation of VS-frontal circuits, such that LT reduced VS-MFG connectivity during anticipation of social punishment but increased connectivity in this circuit during anticipation of social reward. Convergent evidence suggests that the VS plays a key role in dopamine-mediated anticipatory and motivational processes (17, 18, 42) and that the pathways between the VS and frontal regions are critically involved in associated social processes including motivational and reinforcing aspects of social interactions (73, 74). In patients with marked social impairments pharmacological modulation of the coupling between VS and MFG has been associated with improved computation of future positive social outcomes (75, 76) and effects on this circuit may thus reflect a potential mechanism via which LT can increase social motivation.
In contrast to the modulation of VS-centered circuits during the anticipation stage, LT specifically modulated VTA activity as well as its connectivity with insular and frontal regions during the outcome phase. During the social feedback presentation stage LT increased the differential processing of rewarding feedback from both, negative as well as neutral feedback in the VTA. The VTA represents a pivotal node in dopamine-modulated reward processing and learning circuits (17, 22, 40, 77) and together with the amygdala drives dopaminergic signaling in response to social stimuli (22, 74), suggesting that LT rendered positive social signals as more salient. In contrast, LT specifically decreased coupling of the VTA with the bilateral mid-posterior insula in response to social punishment. The insula plays a key role in salience and interoceptive information processing, with the mid-posterior insula being involved in representing the intensity of aversive experiences (78, 79). This suggests that LT may have attenuated the aversive emotional impact of negative social feedback on the insula leading to lower arousal ratings for the negative social stimuli following the experiment.
We further combined a computational modeling framework to determine effects of LT on the neural social prediction error i.e. the difference between expected and actual social feedback. The feedback evoked PE signal is a closely linked to the dopamine transmission based neural teaching signal and thus promotes behavioral adaptations to the external environment (38, 39, 44). LT enhanced the social feedback PE signal on the neural level in the VTA and DS and convergent evidence suggest that the PE signal is strongly influenced by dopaminergic signalling. Previous animal models suggest interactions between the RAS and the DA system, such that LT activiated D1R (34) and inhibited DA release (32, 33) in these circuits, which may suggest that LT enhanced PE encoding in these regions via effects on DA neurons rather than on postsynaptic dopaminergic transmission. In addition, LT also enhanced PE signaling in other regions, including frontal and superior temporal areas as well as the precuneus. Whereas RPE signals have been mostly examined in midbrain and striatal regions, accumulating evidence suggests that depending on the specific domains and context more extended networks encompassing limbic, frontal and parietal regions are involved (43, 44). For instance, the concommitant engagement of the mPFC, amygdala, hippocampus with the precuneus and the default network has been proposed to play a key role in initiating and maintaining exploratory and exploitative behavior (45, 77, 80), while the insula has been strongly associated with negative PEs signaling sensitivity to punishment (24, 81, 82). The regions affected by LT encompass onesinvolved in executive functions and social processes such as self referential processing and theory of mind (80) suggesting that LT in the present context may have modulated not only reward-related PE signals but also other components of the PE.
From a functional neuroanatomy perspective LT modulated neural activity and connectivity of distinct key nodes of the midbrain-striatal system during different aspects of social feedback processing. Thus, VS connectivity was specifically affected during anticipation while VTA networks and VTA/DS PE signaling were modulated during the outcome phase. This dissociation aligns with the distinct functions of these core nodes in feedback-associated social and non-social processes (63, 83, 84). The VTA encompasses the majority of dopaminergic cell bodies and is strongly involved in predicting outcomes including social error signals and guiding flexible adaptation (17, 22, 46, 85), whereas the VS which receives dopaminergic projections from the VTA, is strongly involved in appetitive motivation and reward-expectation for both social and non-social feedback (17, 18) while the DS is stronger involved in learning, action initiation, and habit formation (16, 83). Altough most of these functions encompass social as well as non-social processes their critical role in reward and punishment processing critically influences social behavior (45, 73, 74). The process-specific effects of LT on distinct nodes may reflect that the RAS plays a complex role in regulating social reward and punishment processes.
Social deficits such as decreased social motivation or a hypersensitivity to social punishment represent a core symptom across several mental disoders including depression (2, 3), SAD (4), PTSD (5, 15), ASD (7, 8), and schizophrenia (9). Together with accumulating evidence from previous studies (26, 27, 29) our findings suggest that LT may have a promising potential to enhance social motivation to obtain rewards while decreasing sensitivity to punishment in social contexts and attenuate these dysregulations in patient populations.
Although the current study employed a strict pre-registered and randomized-controlled design the findings and interpretation need to be considered with the following limitations. First, due to the proof-of-concept design the study was conducted in healthy individuals. Although this allowed us to control for a range of potential confounders, effects in patients and on the symptomatic level need to be systematically examined (27). Second, although the findings suggest that interactions between the RAS and the DA system may have contributed to the observed effect no direct measures of DA functioning were assessed and future molecular imaging studies are need.
In conclusion the present findings demonstrate that targeting the RAS via LT modulates the VTA-striatal-frontal cicruits during social feedback processing. LT shifted the motivational significance of social reward vs punishment feedback and concomitantly modulated the VS-prefrontal pathways. During the outcome phase LT attenuated VTA-insula coupling during social punishment yet enhanced the social PE in the VTA/DS suggesting attenuated sensitivity to social punishment in the context of enhanced adaptation. Together with the excellent safety profile of LT the findings may suggest a therapeutic property to enhance social motivation and attenuate the impact of negative social feedback.