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.