key: cord-0274264-t944vfhj
authors: Lieberz, J.; Shamay-Tsoory, S. G.; Saporta, N.; Kanterman, A.; Esser, T.; Kuskova, E.; Schultz, J.; Hurlemann, R.; Scheele, D.
title: Behavioral and neural dissociation of social anxiety and loneliness
date: 2021-08-28
journal: nan
DOI: 10.1101/2021.08.25.21262544
sha: b1f0412d6a77f93517338db608777a3cf7694aef
doc_id: 274264
cord_uid: t944vfhj

Loneliness is a public health concern with detrimental effects on physical and mental well-being. Given phenotypical overlaps between loneliness and social anxiety, cognitive behavioral interventions targeting social anxiety might be adopted to reduce loneliness. However, it is still elusive whether social anxiety and loneliness share the same underlying neurocognitive mechanisms. The current study aimed at investigating to what extent known behavioral and neural correlates of social avoidance in social anxiety are evident in loneliness. We used a pre-stratified approach involving 42 participants with high and 40 control participants with low loneliness scores. During functional magnetic resonance imaging (fMRI), the participants completed a social gambling task to measure the subjective value of engaging in a social situation and responses to positive and negative social feedback. Uni- and multivariate analyses of behavioral and fMRI data replicated known task effects across groups. However, although lonely participants were characterized by increased social anxiety, loneliness was associated with a response pattern clearly distinct from social anxiety. Specifically, Bayesian analyses revealed moderate evidence for equal subjective values of engaging in social situations and comparable amygdala responses to social decision-making and striatal responses to positive social feedback in both groups. Conversely, lonely participants showed significantly altered behavioral responsiveness to negative feedback and opposing striatal brain activity and connectivity compared to controls. Our findings suggest that loneliness is associated with altered emotional reactivity to social situations rather than behavioral tendencies to withdraw from social interactions. Thus, established interventions for social anxiety should be adjusted when targeting loneliness.

Loneliness is a painful condition which can be a catalyst for subjective stress [1] and is 25 associated with detrimental effects on mental and physical health [2, 3] . As such, loneliness 26 has been identified as a risk factor for premature mortality comparable with smoking or obesity 27 [4, 5] . Consequently, loneliness has come into focus of politics and clinicians as a major public 28 health concern with high economic costs for society [6] [7] [8] . With social distancing in place in 29 most countries around the world, COVID-19 is expected to have vast impact on physical and 30 mental health, particularly in people inflicted by poor resilience to social adversity due to pre-31 existing low levels of social integration [9, 10] . Preliminary evidence indicate that the prevalence 32 of loneliness might have increased due to the ongoing COVID-19 pandemic, which 33 emphasizes the urgent need of interventions to target loneliness [11] [12] [13] [14] . 34

Recent findings highlight a close link of loneliness with social anxiety symptoms [15] [16] [17] and 35 identified social anxiety as predictor for future loneliness [18] [19] [20] . For instance, social anxiety 36 was found to be consistently associated with social isolation, lower perceived social support, 37

and decreased relationship satisfaction [21] [22] [23] . Moreover, poor friendship quality promotes 38 increases in social anxiety symptomatology [24] . A perceived discrepancy in the quality and 39 quantity of the actual and desired relationships, in turn, is a key feature of loneliness [25] . 40

Likewise, safety behavior such as the avoidance of social situations is known to be a core 41 mechanism fostering the maintenance of social anxiety and is also hypothesized to be 42 preferred by lonely individuals [26, 27] . 43

Given the phenotypical overlap between loneliness and social anxiety, cognitive behavioral 44 therapies targeting social anxiety might be co-opted as interventions to reduce loneliness. 45

Existing programs are often based on cognitive models of social anxiety [28] , which posit an 46 exaggerated fear of evaluation as a core etiological mechanism of psychopathology. Indeed, 47 current neurocircuitry models of social anxiety disorder emphasize amygdala hyperreactivity 48 to social stimuli [29, 30] and we have recently observed increased amygdala responses during 49 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted  https://doi.org/10.1101/2021.08.25.21262544 doi: medRxiv preprint 7 difference between the estimated CE50 for human partners compared to the computer partner. 105

After finishing the task, the pleasantness of each feedback video was rated on a visual 106 analogue scale ranging from 0 ("not pleasant at all") to 100 ("very pleasant"). The task was 107 then repeated during functional magnetic resonance imaging (fMRI) with randomly chosen 108 partners (human or computer) for each trial. The fixed payoff offered as safe option varied 109 randomly between the individually determined values CE20, CE50, and CE80. 110

We further measured the individual monetary value associated with receiving positive or 111 avoiding negative social feedback during a virtual auction task. Specifically, participants were 112 informed that they were participating in a virtual auction against the computer using a random 113 algorithm to invest money. Participants were then asked with no imposed time limit to invest 114 any amount of money between 0 € and 1 € (in increments of 5 cents) to (1) increase the 115 probability of watching a positive social feedback video or (2) to decrease the probability of 116 watching a negative social feedback video (see supplementary material). 117 118

Behavioral data were analyzed in SPSS 24 (IBM Corp., Armonk, NY) by calculating analyses 120 of variance (ANOVAs) and Bonferroni-corrected (Pcor) post-hoc t-tests. P-values < 0.05 (two-121 tailed) were considered significant. To analyze the fMRI data, we used a two-stage approach 122 as implemented in SPM12 (Wellcome Trust Center for Neuroimaging, London, UK; 123 http://www.fil.ion.ucl.ac.uk/spm). On the first level, data were modeled using a fixed-effects 124 model. Within-subject contrasts of interest were entered to a random-effects model on the 125 second level to assess group-specific response patterns by calculating two-sample t-tests. 126

Specifically, to probe the hypothesis of increased amygdala activation during social decision-127 making in HL participants, we compared brain activity during risky decisions involving a human 128 partner between groups by calculating two-sample t-tests (i.e., HL risky decision human > safe decision human 129 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted 

We conducted a multivariate pattern analysis using the Decoding Toolbox [42] to test whether 150 decisions of the participants could be decoded from amygdala activation (cf.

[31]). Contrasts 151 revealing significant group effects in the univariate activity analyses (see above) were further 152 examined by generalized psychophysiological interaction (gPPI) analyses using the CONN 153 toolbox 19.b (www.nitrc.org/projects/conn, RRID:SCR_009550). Mediation and moderation 154 analyses were run to examine the potential influence of depressive and social anxiety 155 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted Anxiety Scale, LSAS [44] ) and childhood maltreatment (assessed by the Childhood Trauma 157

Questionnaire, CTQ [45] ) on observed loneliness effects. For hypotheses that could not be 158 confirmed, we conducted Bayesian t-tests using JASP [46] to quantify the evidence for an 159 absence of group differences. For details of the explorative analyses, see supplementary 160 material. 161 162 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262544 doi: medRxiv preprint

As expected, social anxiety was significantly increased in HL participants (t(67.74) = 3.25, P = 166 0.002, d = 0.72; mean LSAS score ± SD in HL: 18.64 ± 15.91; LL: 9.28 ± 9.56; see [37] ) and Table S1 for a comprehensive presentation of whole-brain 214 task effects. 215

Importantly, however, amygdala activation during the decision or feedback stage did not 216 significantly differ between HL and LL participants. Conversely, we observed significant The same pattern of results was observed for amygdala activation during the decision stage 281 of the social gambling task as our data were up to four times more likely under the assumption 282 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. and striatal brain activity and connectivity compared to control participants. 317

Our results thus indicate that loneliness might be more associated with altered emotional 318 reactivity to social situations than with behavioral tendencies to withdraw from social 319 interactions. Human and animal research have consistently shown that the amygdala is 320 crucially involved in the processing of threat-related stimuli and hyperactivation of the 321 amygdala is known as a core mechanism underlying anxiety disorders [30, 47] . Moreover, 322 amygdala habituation to threat-related stimuli and amygdala connectivity with prefrontal 323 regions predict subsequent avoidance behavior [48] [49] [50] . Likewise, we have previously found 324 that amygdala activation during decisions in the social gambling task increases with social 325 anxiety symptomatology and negatively correlates with the subjective value to engage in social 326 situations [31]. By contrast, the subjective value of engaging in a social situation did not differ 327 between HL participants and controls and Bayesian analyses revealed evidence for 328 comparable amygdala activation during the decision and feedback stages. In line with our 329 findings, neuroanatomical correlates of social avoidance behavior were previously found to be 330 unaffected by loneliness [51] . This notion is consistent with etiological theories that highlight 331 maladaptive social cognitions in the development and maintenance of loneliness [27, 52] . 332

Likewise, cognitive-behavioral interventions were found to be more effective in targeting social 333 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262544 doi: medRxiv preprint biases than social skill trainings [53, 54] . There is preliminary evidence that established 334 cognitive-behavioral treatments targeting social anxiety concurrently decrease feelings of 335 loneliness and vice versa [55] [56] [57] [58] [59] , but our findings of distinct behavioral and neural substrates 336 suggest that loneliness-adjusted protocols might improve therapeutic outcomes. 337

Moreover, our results provide new insights into the neural pathways underlying loneliness. 338

Unexpectedly, striatal activity during negative social feedback was reduced while pleasantness 339 ratings were increased in HL participants. Notably, activation of the NAcc is associated with 340 goal-directed approach and avoidance behavior and involved in avoiding social punishment 341 [60] [61] [62] . As HL participants rated the negative social feedback videos as more pleasant than 342 the control participants, reduced NAcc responses to negative social feedback might thus reflect 343 reduced tendencies to avoid this negative social feedback. Furthermore, the enhanced 344 functional coupling of the NAcc with a hippocampal cluster that correlated with individual 345 pleasantness ratings is in line with the involvement of this neural circuit in hedonic processing 346 [63] and might reflect the rewarding experience of a social feedback for socially deprived 347 individuals [64] . Nevertheless, we have recently found a compromised neural integration of 348 social information in HL participants evident in various brain regions including the NAcc [37] . 349

Furthermore, loneliness has been associated with a reduced recognition of negative vocal 350 expressions [65] . Thus, the reduced NAcc activity might also reflect diminished differentiation 351 between positive and negative feedback, resulting in a dysregulated reward system 352 responsiveness to negative social stimuli as observed for the NAcc-hippocampus connectivity. 353

However, inference about cognitive processes from neural activation should always be drawn 354 with restraint [66] and results regarding biased emotion recognition in loneliness are 355 inconclusive [67] . Future studies are warranted to further investigate the impact of loneliness 356 on the processing of negative social feedback. 357

Interestingly, differences between HL and control participants were restricted to behavioral and 358 neural responses to negative social feedback, whereas Bayesian analyses revealed evidence 359 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262544 doi: medRxiv preprint for a comparable responsiveness to positive social feedback between groups. Conversely, 360 social anxiety has been consistently found to affect the processing of social rewards [31] [32] [33] [34] . 361

Previous studies point to various negative effects of loneliness on the processing of positive 362 social interactions [37, 68, 69] , but findings about the association between loneliness and NAcc 363 reactivity to positive social stimuli are mixed. The involvement of the NAcc in loneliness might 364 be context-dependent, with feelings of social isolation promoting the hedonic experience of 365 positive social stimuli in an acute stage [64] , which may be different from chronic loneliness. 366

Similarly, lonely individuals might experience a social stimulus as more rewarding only if the 367 stimulus is already familiar (e.g. a romantic partner and not a stranger [70] ). Along these lines, processing. In addition, moderation and mediation analyses indicate that the observed 380 associations with loneliness were not driven by psychiatric symptoms that were also more 381 pronounced in HL individuals. However, our study specifically focused on high-lonely healthy 382 individuals who may represent a resilient subsample of the population because they did not 383 develop acute psychiatric disorders. Thus, clinical studies with psychiatric patients are 384

warranted to uncover the direction of the observed associative relationships and to further 385 disentangle shared and distinct mechanisms underlying loneliness and psychopathology. 386 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262544 doi: medRxiv preprint Collectively, the current results suggest that loneliness and social anxiety are distinct 387 constructs with specific behavioral and neural substrates. Along these lines, interventions 388 targeting loneliness-specific cognitive biases may be more effective in reducing loneliness than 389 cognitive behavioral therapies focused on reducing avoidance behavior. 390 391 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262544 doi: medRxiv preprint Vindegaard N, Benros ME. COVID-19 pandemic and mental health consequences:

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