Social Neuroscience

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/psns20

Common neural responses to romantic rejection

and acceptance in healthy adults

David T. Hsu , Anjali Sankar , Mohammad A. Malik , Scott A. Langenecker ,

Brian J. Mickey & Tiffany M. Love

To cite this article: David T. Hsu , Anjali Sankar , Mohammad A. Malik , Scott A. Langenecker ,
Brian J. Mickey & Tiffany M. Love (2020): Common neural responses to romantic rejection and
acceptance in healthy adults, Social Neuroscience, DOI: 10.1080/17470919.2020.1801502

To link to this article: https://doi.org/10.1080/17470919.2020.1801502

Accepted author version posted online: 25

Jul 2020.

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 Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group
Journal: Social Neuroscience
DOI: 10.1080/17470919.2020.1801502
Title: Common neural responses to romantic rejection and acceptance in healthy adults

Authors and Affiliations:

1. *David T. Hsu, PhD1

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Email: david.hsu@stonybrookmedicine.edu
Phone: 1-631-638-1522

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2. Anjali Sankar, PhD1,2

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Email: Anjali.sankar@yale.edu

3. Mohammad A. Malik, MA1

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Email: Mohammad.Malik@alumni.stonybrook.edu

4. Scott A. Langenecker, PhD3

Email: s.langenecker@hsc.utah.edu

5. Brian J. Mickey, MD, PhD3 U

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Email: Brian.Mickey@hsc.utah.edu

6. Tiffany M. Love, PhD3

Email: Tiffany.Love@hsc.utah.edu
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*Correspondence to david.hsu@stonybrookmedicine.edu
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Departments of Psychiatry and Psychology
Stony Brook University, Stony Brook, NY, USA
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Department of Psychiatry
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Yale University School of Medicine, New Haven, CT, USA

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Department of Psychiatry
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University of Utah, Salt Lake City, UT, USA

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 Although romantic rejection and acceptance have a strong impact on mood in adults,

their neural response patterns are relatively unexplored. The present study used functional

magnetic resonance imaging (fMRI) to examine neural responses to romantic rejection and

acceptance in 36 healthy men and women, ages 18-53 years. Activations during rejection

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showed extensive anatomical overlap with activations during acceptance in the ventrolateral

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prefrontal cortex (vlPFC) and anterior insula (AI). In an analysis of sex differences, men and

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women did not differ in behavioral responses, however men showed greater activation to

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romantic rejection and acceptance in the left vlPFC and AI compared to women. The vlPFC

and AI may play a role in social cognition, tuned to detect the intentions and feelings of

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others whether they are positive or negative. In the context of romantic rejection and
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acceptance, this activation may signal the intent of others who are desired by the individual,

leading to changes in mood, self-esteem, and social motivation.

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Keywords: social rejection, social acceptance, romantic, depression, operculum, ventrolateral

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prefrontal cortex, anterior insula

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 Introduction

Forming strong, stable interpersonal relationships is a basic human need, critical for

survival and emotional well being1. Social rejection – when one is not wanted or liked – is a

potent threat to this need that can lead to sadness, anxiety, social withdrawal, impulsivity,

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and aggression2–10. Most neuroimaging studies of social rejection have examined peer

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rejection in adolescents and young adults11–13, given the heightened sensitivity to peer

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rejection in adolescence14. However, there is direct clinical relevance to examining romantic

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rejection in young to middle-aged adults. The median age of onset of mood disorders is 30

years15, and romantic rejection is one of the most stressful life events in adults, leading to

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distinct patterns of depressive symptoms (e.g., sadness, anhedonia, appetite loss, guilt),
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compared to chronic stress and failures, which are more strongly associated with other

symptoms (fatigue, hypersomnia)16. In addition, a recent meta-analysis showed that the

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neural response to social exclusion differs in adolescents compared to young adults17. To

address this gap in understanding, the present study examined neural responses to romantic
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feedback in healthy young to middle-aged adults.

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A review of functional magnetic resonance imaging (fMRI) studies suggest that social

rejection (both peer and romantic) activates the dorsal anterior cingulate cortex (dACC) and
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the anterior insula (AI)11. These areas, which serve multiple functions including adaptive task

control18 and salience processing19,20. However, a meta-analysis also found that romantic
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rejection compared to peer rejection activated several additional areas outside of the dACC-
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AI network12. In addition, peer rejection studies have consistently found that opposite sex

social feedback resulted in greater neural responses compared to same-sex feedback21–24,

although the paradigms used in those studies were ostensibly within a non-romantic context.

Thus, it is possible that romantic feedback, a clinically-relevant social stimulus in adults 16,

activates unique areas compared to peer feedback.

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 Sex differences in the neural response to social feedback (peer or romantic) are virtually

unexplored and may inform how sex moderates the relationship between rejection and

psychiatric disorders. In women, relationship problems and lower levels of social support

have been shown to be more strongly predictive of depression than in men25,26. Two studies

that examined behavioral sex differences using peer rejection23 or Cyberball, a virtual ball-

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tossing game in which the participant is socially excluded27, did not find differences between

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men and women. Thus, a primary aim of the present study was to examine sex differences

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in the behavioral and neural response to social feedback.

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In summary, the present study examined the behavioral and neural responses to both

romantic rejection and acceptance in healthy young to middle-aged men and women (ages

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18-53), an understudied demographic in social feedback experiments, and examined sex
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differences in these responses. In addition to the dACC and AI, we also focused on the

ventrolateral PFC (vlPFC), amygdala (AMY), and nucleus accumbens (NAcc). The vlPFC
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has been associated with the regulation of negative affect during rejection 28–30, and the AMY

and NAcc have been associated with both rejection21 and acceptance22. In light of a recent
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study in adolescents/young adults showing an anatomical overlap in the neural response to

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positive and negative social evaluation31, we performed a conjunction analysis for neural

activation responding to both romantic rejection and acceptance.

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Methods
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Participants
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Participants were 38 right-handed healthy adults (18 men, 20 women; ages 18-53 years;

mean ± SD = 29.7 ± 10.6) recruited from the local community through advertisements. Men

and women were similar with respect to age, racial/ethnic background, sexual orientation,

and relationship status (Table 1). All participants were informed that they would be

participating in an online dating scenario. Participants were screened for current or past

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 psychiatric disorders in themselves or any first-degree relatives using the M.I.N.I.

International Psychiatric Interview32. Other exclusion criteria included the use of psychotropic

substances in the past four weeks, regular tobacco use, history of DSM-IV alcohol or drug

dependence within the past five years, or drug or alcohol abuse in the past two years.

Behavioral and neuroimaging data from the healthy women in the present study were also

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used to compare to data obtained from depressed women, who showed exaggerated

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responses to social feedback33. All protocols were approved by the University of Michigan

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Medical School Institutional Review Board, all methods were performed in accordance with

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the relevant guidelines and regulations, and written informed consent was obtained.

Age range U Men (n = 18)

18 – 53
Women (n = 20)
18 – 53
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Age: mean years ± SD 29.0 ± 10.4 30.3 ± 11.0
Ethnicity: White, Black or African-American, Asian, Hispanic, Mixed 14, 2, 1, 0, 1 14, 3, 2, 0, 1
Sexual orientation: heterosexual, homosexual, bisexual 15, 1, 2 19, 1, 0
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Relationship status: single, in a relationship, married 12, 3, 2 12, 5, 3

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Table 1. Participant demographics. Relationship status was not obtained from one male
participant.
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Social Feedback Task during fMRI

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Several days prior to scanning, participants rated dating profiles from a set of over 400

profiles from the mass media compiled by the experimenters. Participants rated opposite or
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same sex profiles depending on their orientation. Two men reported to be bisexual and
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chose to rate women only. Participants rated profiles on how much they would like the

potential partner and how much they thought that person would like them in return. To

maximize saliency, only the highest rated profiles chosen by each participant was presented

during the Social Feedback Task (SFT). As in our previous studies2,33–35, the SFT did not

involve deception however participants were asked to immerse themselves in the experience

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 and respond as if the feedback was real (see Supplemental Methods for additional detail).

To increase engagement with the scenario, participants submitted photos of themselves and

completed their own dating profile (age, height, major/occupation, interests, and positive

qualities about themselves). During fMRI, the participant’s own photo was shown on the left,

followed by the question “Does this person like me?” along with a picture from a highly-rated

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profile on the right, followed by feedback (Fig. 1).

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Fig. 1. Social Feedback Task trial. Each trial begins with the participant’s own picture
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presented for 500ms, the addition of the question “Does this person like me?” along with
picture from a highly-rated profile (500ms), followed by the feedback (4000ms). A rejection
trial is shown. Figure adapted from Yttredahl et al.33.
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Participants viewed blocks of trials containing one of three types of feedback: rejection
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(Rej), acceptance (Acc), and neutral (Neu). Rej trials contained the feedback “very likely no”

and “definitely no,” Acc trials contained the feedback “very likely yes” and “definitely yes,” and

Neu trials contained the feedback “not completed” (participants were informed that this

indicated that the other person had not yet completed profile ratings). Four trials (5s each) of

the same type were presented in one block. Functional images were collected in 4 scan

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 runs, each containing 6 pseudorandomized blocks (2 blocks each of Rej, Acc, and Neu).

Cross-hair fixations (10-14s) were presented between blocks. The total duration of the task

was 12 min, 48s, plus less than 30s shim time between runs. All stimuli were presented

using E-Prime 2.0 software (Psychology Software Tools, Pittsburgh, PA).

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fMRI Acquisition

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Whole-brain scans were acquired on a 3.0 Tesla GE Signa 9.0 scanner (Milwaukee, WI,

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USA) with a standard frequency coil. Functional images (blood-oxygen-level dependent,

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BOLD signal) were obtained using a T2* -weighted pulse sequence (repetition time, TR,

2000ms; echo time, TE, 30 ms; flip angle, 90°; field of view, FoV, 20 x 20cm, 64 x 64 matrix;

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in-plane resolution, 3.12 x 3.12 mm; slice thickness, 4 mm) with single-shot combined spiral
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in/out sequence was used to reduce signal dropout in subcortical and around sinus regions36.

A high-resolution T1-weighted pulse sequence provided anatomical localization (3D spoiled

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gradient recalled echo; TR, 12 ms; TE, 5 ms; TI, 500 ms; flip angle, 15°; FoV, 26 x 26 cm,

256 x 256 matrix; in-plane resolution, 1.02 x 1.02 mm; slice thickness, 1.2 mm). Participant
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motion was minimized with foam pads secured with a strap around the head. One male and
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one female participant were excluded from fMRI analyses due to excessive head movement

(>3 mm translation or >3° rotation), leaving a total of 36 participants for fMRI data analysis.
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fMRI Data Analysis

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Functional images were preprocessed using FMRIB Software Library (FSL) and included
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slice-time correction, realignment, spatial smoothing (5 mm full-width at half maximum) using

a Gaussian kernel, coregistration, and normalization to MNI standard space (Montreal

Neurological Institute, Quebec, CA). First-level analyses were performed using the General

Linear Model (Statistical Parametric Mapping v.8 (SPM8), Wellcome Institute of Cognitive

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 Neurology, London, UK), and contrast t maps for each participant were created for the main

contrasts of interest: Rej-Neu and Acc-Neu.

Group-level, voxel-wise one-sample two-tailed t-tests were conducted for each contrast in

SPM8 to examine the effect of the task, controlling for sex and age. A two-way repeated

measures ANOVA in SPM8 was used to examine the effect of sex between-subjects (men

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vs. women), contrasts within-subjects (Rej-Neu vs. Acc-Neu), and the interaction effect

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between them, controlling for age and responses to manipulation checks Q2 and Q3 (since

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sex differences were found – see Results/Behavior). In all tests, a whole-brain gray matter

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mask37 was first applied as an exclusion mask, followed by an a priori combined ROI mask

that included the left and right dACC, AI, vlPFC, AMY, and NAcc, which were all anatomically

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defined using Harvard Brain Atlas38 probability masks, thresholded at 0.25 confidence, and
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binarized (Fig. 2). The anterior-posterior boundaries of the dACC was set at y = 0 to 36, and

the posterior boundary of the AI at y = 8, based on a previous study that examined neural
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activation to social exclusion39. Within this mask, activation was considered significant at

family-wise error within small volume (FWE-SVC)-corrected, P < 0.05 (two-tailed), followed
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by an additional minimum extent threshold of kE > 10 voxels.

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Fig. 2. Anatomical regions of interest (ROIs). ROIs in the left and right dorsal anterior
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cingulate cortex (dACC, light blue), ventrolateral prefrontal cortex (vlPFC, green), anterior
insula (AI, orange), nucleus accumbens (NAcc, red), and amygdala (AMY, dark blue),
superimposed on T1-weighted template brain image (Montreal Neurological Institute). Top
image shows a sagittal section, bottom 3 images show coronal sections. R, right
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To determine voxels across the whole brain that were common to both rejection and
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acceptance, a logical “AND” conjunction analysis31,40–42 was performed. In SPM8, ImCalc

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was used to binarize clusters in each contrast (Rej-Neu, Acc-Neu) at a threshold of P <

0.001, uncorrected, kE > 10. Binarized images were used in the formula “i1 + 2(i2)”; the
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resulting image with a value of 3 indicated activated voxels that were common to both

contrasts40,41. Brain regions were identified using the Anatomical Automatic Labeling
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software43, a human brain atlas44, and architectonic maps of the prefrontal cortex45. The
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center of mass coordinates of each conjunction was determined using MarsBar region-of-

interest toolbox (v.0.38) for SPM8.

To test for the degree to which activation during Rej was correlated with activation during

Acc, mean signal intensities (raw values) were extracted from each ROI from each contrast

(Rej-Neu, Acc-Neu) using MarsBar for SPM8. Pearson’s correlations were used with P

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 threshold corrected for multiple ROIs (5 ROIs x 2 hemispheres = 10; Bonferroni-corrected P

threshold = 0.005).

Behavior

In a separate room, participants were seated at a personal computer and performed an

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abbreviated version of the SFT. In this version, participants were reminded of the feedback

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they received during the scan in three blocks, each containing 18 trials of one feedback type.

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After each block, participants rated how “sad”, “rejected”, “happy”, and “accepted” they felt,

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their current level of self-esteem (state version of the Rosenberg Self-Esteem scale46), and

their current desire for social interaction2. Responses were recorded using a 5-button

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response box, corresponding to 5-point Likert-type scales. As in our previous studies2,33–35,
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scores for “sad” were averaged with “rejected,” and scores for “happy” were averaged with

“accepted.” The was done because ratings for “rejected” and “accepted” may be influenced
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by the objective feedback received (i.e., participants may report feeling “rejected” because

they were ostensibly rejected). Therefore, the more affective items “sad” and “happy” were
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included in the overall score. Rej-Neu and Acc-Neu scores for individual items were
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significantly correlated (sadRej-Neu vs. rejectedRej-Neu: r36 = 0.63, P < 0.001; happyAcc-Neu vs.

acceptedAcc-Neu: r36 = 0.38, P = 0.02) and not significantly different (P’s > 0.40), suggesting
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that “rejected” and “accepted” may be used interchangeably with “sad” and “happy.” A two-

way repeated measures ANOVA was used to compare within-subjects behavior during Rej-
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Neu vs. Acc-Neu, between-subjects effect of sex, and interactions.

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As a manipulation check, participants responded to three questions: Q1) “How much

were you able to experience the profiles and feedback as if they were real?”; Q2) “How

similar to a real-life situation was your emotional response to the positive feedback?”; and

Q3) “How similar to a real-life situation was your emotional response to the negative

feedback?”, rated on a 5-point Likert-type scale (1 = very slightly or not at all, 2 = a little, 3 =

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 moderately, 4 = quite a bit, 5 = extremely). Two-way between-subjects ANOVAs tested if

Sex x Relationship Status (i.e., single or in a relationship/married) had an effect on the

responses to each of these questions.

Q2 and Q3 were explored for potential relationships with mean signal intensities in each

ROI during Acc-Neu and Rej-Neu, respectively. To explore the possibility that higher Q2 may

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explain higher mean signal intensities during Acc-Neu compared to Rej-Neu, we examined if

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the differences in how real acceptance felt compared to rejection (Q2 – Q3) correlated with

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differences in mean signal intensities during acceptance compared to rejection [(Acc-Neu) –

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(Rej-Neu)] with Bonferroni-corrected P threshold for each ROI correlation = 0. 005.

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Neural response to romantic rejection and acceptance

In the rejection minus neutral (Rej-Neu) contrast, family-wise error (FWE)-corrected

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voxel-wise analysis (using the combined ROI mask for small volume correction (SVC), P <

0.05, two-tailed, followed by an additional minimum extent threshold of kE > 10), significant
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activation was found within the left vlPFC specifically in the precentral part of the frontal
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operculu m45 (t = 5.46, PFWE-SVC = 0.017; kE = 143; peak activation [MNI x, y, z coordinates,

mm]: -42, 22, -4), and within the right vlPFC specifically in area 47/12 as previously define
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d47, and in the right AI (t = 5.28, PFWE-SVC = 0.027; kE = 210; peak activation: 28, 18, -12) (Fig.

3A). In the Neu-Rej contrast, no significant clusters were found within the ROI mask at this
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threshold. For a list of additional clusters in the whole brain, and results from the Rej-Acc
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and Acc-Rej contrasts, see Supplemental Table S1 and Figs. S1 & S2. Analyses of

relationship status is also reported in Supplemental Data, and data from ROI masks

examined individually are also included in Supplemental Table S2.

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Fig. 3. Activity during rejection and acceptance, and their conjunction. Whole-brain
contrast t maps for A) Rej-Neu, B) Acc-Neu), and C) conjunction of both contrasts (green),
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with magnified view of the vlPFC; R, right; AI, anterior insula; y coordinates in Montreal
Neurological Institute stereotactic space. Contrast t maps displayed at uncorrected P <
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0.001, kE > 10.

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In the acceptance-neutral (Acc-Neu) contrast, within the combined ROI mask (FWE-

corrected voxel-wise analysis, P < 0.05, two-tailed; followed by an additional minimum extent
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threshold of kE > 10), significant activation was found within the left vlPFC specifically in the
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precentral operculum (t = 5.53, PFWE-SVC = 0.014; kE = 184; peak activation: -42, 20, -4), and

within the right vlPFC specifically in area 47/12, and in the right AI (t = 5.58, PFWE-SVC = 0.013;

kE = 338; peak activation: 40, 24, -6) (Fig. 3B). For a list of these and additional clusters, see

Supplemental Table S1 and Fig. S1. In the Neu-Acc contrast, no significant clusters were

found within the ROI mask or whole brain. Analyses of relationship status is also reported in

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 Supplemental Data, and data from ROI masks examined individually are included in

Supplemental Table S2.

The conjunction analysis showed common areas of activation, defined as the overlap in

voxels from independent significant contrasts (Rej-Neu and Acc-Neu)40–42. This analysis (as

previously described31,40–42 is intended to identify this overlap, but does not imply similarities

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in the magnitude of effect. Conjunction was found in the left vlPFC (385 voxels; center of

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mass: -48, 20, 5), right vlPFC (92 voxels; center of mass: 49, 27, 4), and right vlPFC/AI (70

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voxels; center of mass: 37, 24, -9) (Fig. 3C). More specifically, conjunction in the left vlPFC

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spanned the upper and lower bank of the lateral sulcus, in area 47/1247 (Fig. 3C, y = 28).

More caudally, this cluster spread into the precentral operculum and the caudal part of area

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47/12 (Fig. 3C, y = 22). Conjunction in the right rostral vlPFC was located in 47/12 (Fig. 3C,
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y = 28) and spread caudally into the precentral operculum (Fig. 3C, y = 22). The cluster in

the right caudal vlPFC included area 47/12 and the AI (Fig. 3C, y = 28). Additional areas of
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conjunction outside the ROIs (i.e., in the whole brain without masking) are listed in

Supplemental Table S3. Areas of non-overlapping clusters that were unique to Rej-Neu
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and Acc-Neu (whole brain without masking) are listed in Supplemental Table S4. In
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particular, clusters in the left and right caudate were found during Acc-Neu but not during

Rej-Neu.
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A two-way repeated measures ANOVA was used to test the effect of sex between-

subjects (men vs. women), contrasts within-subjects (Rej-Neu vs. Acc-Neu), and the
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interaction effect between them, controlling for age and responses to manipulation checks Q2
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and Q3 (since sex differences were found – see Results/Behavior). Same as above, a

combined ROI mask was used for small volume correction (SVC), with P < 0.05, followed by

an additional minimum extent threshold of kE > 10. This analysis revealed a single cluster for

the main effect of sex (men > women) in the left vlPFC (area 47/12) that spread caudally into

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 the AI (F = 22.83, PFWE-SVC = 0.032; kE = 18; peak activation: -32, 30, 0) (Fig. 4). No

suprathreshold clusters were found for the main effect of contrast, or interactions.

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Fig. 4. Sex differences. Whole-brain F maps for the main effect of sex revealed a significant
cluster (men > women) in the vlPFC (area 47/12; y = 31), and AI (y = 27). R, right; y

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coordinates in Montreal Neurological Institute stereotactic space. F maps displayed at
uncorrected P < 0.001, kE > 10.
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Region-of-interest correlations
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For all ROIs, activity in Rej-Neu was significantly correlated with activity in Acc-Neu,

except in the NAcc (Bonferroni-corrected P threshold for each correlation = 0. 005) (Fig. 5).
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Activity was correlated in the dACC (left: r36 = 0.51, P = 0.001; right: r36 = 0.56, P = 0.0004),
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AI (left: r36 = 0.75, P = 1.2 x 10-7; right: r36 = 0.67, P = 8.8 x 10-6), vlPFC (left: r36 = 0.65, P =

1.5 x 10-5; right: r36 = 0.61, P = 0.0001), AMY (left: r36 = 0.47, P = 0.004; right: r36 = 0.51, P =
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0.002), and NAcc (left: r36 = 0.44, P = 0.007; right: r36 = 0.37, P = 0.028). Outlier values from

the same participant appeared in the Acc-Neu contrast in the left and right dACC (Figs. 5A,
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B). Spearman’s rank order correlation, which is less sensitive to strong outliers, confirmed a
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significant correlation in the left (ρ36 = 0.50, P = 0.002), but not the right dACC (ρ36 = 0.42, P

= 0.01). After removing this data point, the Pearson correlation coefficient remained

significant in the left dACC (r36 = 0.48, P = 0.003), but not in the right dACC (r36 = 0.42, P =

0.01).

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Fig. 5. Correlated activity in anatomical regions of interest (ROIs). In each of 10 ROIs,

extracted mean signal intensities from Rej-Neu contrasts (x axis) were correlated with
extracted mean signal intensities from Acc-Neu contrasts (y axis). All correlations were
significant (except for the left and right NAcc) at Bonferroni-adjusted P threshold = 0.005.

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 Behavior

After fMRI scanning, participants were seated at a personal computer in a separate room

and performed an abbreviated version of the fMRI task (SFT) (see Methods). The purpose

here was to measure subjective responses to the SFT in a separate behavior-only testing

session. Performing subjective ratings of emotionally salient stimuli in the scanner has been

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shown to attenuate activity in areas such as the AI and AMY48. Our primary interest was in

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the neural response social feedback, not the explicit evaluation of internal mood states.

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Responses to 5-point Likert-type scales were recorded using a 5-button response box. A

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two-way repeated measures ANOVA was used to compare within-subjects behavior during

Rej-Neu vs. Acc-Neu, between-subjects effect of sex, and interactions. Results showed

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significant within-subject effects of Condition (Rej-Neu vs. Acc-Neu) for “sad and rejected”
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(F1,36 = 10.98, P = 0.002, Rej-Neu > Acc-Neu), “happy and accepted” (F1,36 = 9.87, P = 0.003,

Acc-Neu > Rej-Neu), and Desire for Social Interaction (F1,36 = 5.14, P = 0.03, Acc-Neu > Rej-
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Neu). There was no significant main effect of Sex for any behaviors, and no significant

interactions.
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For all subjects, mean scores ± SD for manipulation checks were Q1 (“How much were
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you able to experience the profiles and feedback as if they were real?”): 3.34 ± 1.07; Q2

(How similar to a real-life situation was your emotional response to the positive feedback?”):
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3.74 ± 1.03; Q3 (How similar to a real-life situation was your emotional response to the

negative feedback?”): 3.03 ± 1.13. These scores were further explored as a function of Sex
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or Relationship Status. For Q1 and Q3, there were no significant main effects of Sex or
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Relationship Status, and no significant interactions. For Q2, there was a significant main

effect of Sex (F1,33 = 4.71, P = 0.04, men > women), but no significant main effect of

Relationship Status, and no significant interactions. Q2 did not correlate with Acc-Neu mean

signal intensities extracted from any ROIs in men (P’s > 0.41).

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 Q2 was significantly higher than Q3 (t37 = 5.05, P < 0.001). Q2 correlated with the left

NAcc during Acc-Neu (r36 = 0.35, P = 0.04), and Q3 correlated with the left NAcc during Rej-

Neu (r36 = 0.40, P = 0.02), although not significant with Bonferroni-corrected P threshold =

0.005. No significant correlations in any ROIs were found (P’s > 0.31) between the

differences in how real acceptance felt compared to rejection (Q2 – Q3) and differences in

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mean signal intensities during acceptance compared to rejection [(Acc-Neu) – (Rej-Neu)].

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Discussion

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Romantic rejection and acceptance are powerful cues affecting emotional well-being and,

from an evolutionary perspective, the chance for reproductive success. We found extensive

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overlap between neural activation during romantic rejection (Rej-Neu) and acceptance (Acc-
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Neu) in healthy adult men and women, primarily in the vlPFC and AI, areas that were

previously shown to be involved in social rejection/exclusion. Novel findings in the present

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study include 1) the significant activation and extensive overlap in the left/right precentral

operculum and the right AI in response to rejection and acceptance 2) the high degree of
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correlated activity between rejection and acceptance, and 3) significantly greater activation in
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the left vlPFC and AI in men compared to women during social feedback.

There are several functional implications for the extensive overlap between Rej-Neu and
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Acc-Neu in the vlPFC (which includes the precentral operculum and area 47/12), and in the

AI. The vlPFC is involved in emotion regulation49,50 and has been suggested to reduce social
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distress during social exclusion29,51, however it also appears to be activated when regulating
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both pleasant and unpleasant emotions52. The precentral operculum, on the other hand,

plays a role in making inferences about other people’s intentions and goals53,54 and may have

been activated as a participant’s response to perceiving others’ intentions of rejection and

acceptance in the present study. In line with this idea, the precentral operculum and the

adjacent AI together have been shown to be involved in emotional awareness, empathy, and

17
 understanding other people’s feeling states and intentions55–58. Another possibility is that

overlap in the right AI may result from general activation during awareness of emotionally

salient information59.

In summary, the vlPFC (including precentral operculum and area 47/12), and AI may be

involved in evaluating others’ intentions – whether positive or negative – in order to inform

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how one should behave in that situation. Consistent with this interpretation, a recent study

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showed that AI activation was not significantly different between rejection vs. acceptance,

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and that the AI responded more strongly when the feedback was directed towards the

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participant compared to when the feedback is directed towards others60. This suggests

involvement of the AI in processing both positive and negative salient information, which may

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include social feedback directed at the self in social situations.
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Activations in the vlPFC and AI were also highly correlated during Rej-Neu vs. Acc-Neu

(Fig. 5C,E), providing further support for their similar functions. Our previous PET study
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showed that endogenous opioid release in the AI was also highly correlated during rejection

and acceptance (left AI, r = 0.79; right AI, r = 0.62). Indeed, common neural pathways are
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activated during both pain and pleasure, involving endogenous opioid and dopamine
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neurotransmitter systems61, however, the functional relationship between blood-oxygen-level

dependent (BOLD) signal and these neurotransmitter systems are not known. In the present
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study, significantly correlated activations were also found in the dACC and AMY, but not in

the NAcc (after strict Bonferroni correction).

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In the manipulation checks, participants reported that acceptance felt more real
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compared to rejection, raising the possibility that NAcc activation during Acc-Neu may reflect

greater salience regardless of valence. However, in testing this possibility, we found that

differences in how real the acceptance felt compared to rejection (manipulation check Q2

scores – Q3 scores) were not significantly correlated with differences in activity during

acceptance or rejection [(Acc-Neu) – (Rej-Neu)], in the NAcc or any other ROI. In addition,

18
 activity in the left NAcc in Acc-Neu and Rej-Neu contrasts were correlated with how real the

acceptance felt (manipulation check Q2: r36 = 0.35, P = 0.04) and how real the rejection felt

(manipulation check Q3: r36 = 0.40, P = 0.02) to the participant (although not significant after

strict Bonferroni correction). Taken together, data from the manipulation checks suggest that

salience (i.e., how real the feedback felt) did not explain greater activity in the NAcc during

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acceptance compared to rejection, but salience was associated with the magnitude of activity

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within each type of feedback in the left NAcc. To further specify the role of the NAcc in

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processing salience and valence during social feedback, future fMRI studies may examine

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NAcc functional connectivity to unique networks during each condition. Neurotransmitter

systems in the NAcc may also be explored for their role in valence and salience of social

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feedback including oxytocin and serotonin, which play a role in social reward62, or
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endogenous opioids in the NAcc, which play a role in both social reward/acceptance34,63 and

rejection2.
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The conjunction that was found in the right superior frontal gyrus and the left middle and

superior temporal gyrus (Supplemental Table S3) should also be highlighted. In a previous
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study13, these two areas (identified as the rostromedial prefrontal cortex, and posterior
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superior temporal sulcus, respectively) were activated when participants were unexpectedly

liked or disliked after a “speed-dating” paradigm, suggesting involvement of these areas in

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expectancy violation. However, in the present study, only the first of four trials in each block

of the SFT were unpredictable, since each of the 3 subsequent trials in that block contained
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the same type of feedback. Thus, an alternative explanation is that activation of these two
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areas in the present study may instead be associated with “mentalizing” the intentions of

others, since both of these areas are part of a network shown to be involved in encoding and

updating beliefs about the intentions and feelings of others13,64, and the rostromedial

prefrontal cortex has also been shown to be involved in relating one’s own self-image with

the mental state of others65. Of clinical relevance, patients with borderline personality

19
 disorder showed stronger engagement of dACC and mPFC (compared to healthy controls) to

all conditions (inclusion, exclusion, control condition) of a social exclusion paradigm,

suggesting that patients “hypermentalize”66 during social interactions regardless of inclusion

or exclusion.

In an analysis of sex differences, we found greater activation in the left vlPFC (area

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47/12) and AI in men compared to women during social feedback (combined effect of Rej-

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Neu and Acc-Neu). Consistent with this, a previous study found that men and women recruit

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a different set of brain regions in response to emotion-evoking images, with men exhibiting

SC
higher activity within the insula and cingulate cortex67. Significant sex differences in the

subjective responses to the SFT were not found, however in the manipulation check, men

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more than women reported that acceptance felt similar to a real-life situation. This difference
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was not related to differences in neural activity, since there was no Sex x Condition

interaction, nor a correlation in Q2 scores vs. any ROIs during Acc-Neu in men (P’s > 0.41).
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Although sex differences in brain activation were not accompanied by differences in behavior,

other behavioral measures may have revealed potential sex differences in behavior. For
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example, men have been shown to be more risk-seeking than women following physical
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stress68, and the vlPFC and AI appears to be involved in this process69. Thus, identifying

these regions in the present study may form the basis for future investigations to include
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measurements of risk-taking behavior to test if the left vlPFC and AI in men mediates the

relationship between emotionally salient social cues and risk-taking behavior. This has
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implications for why, for example, men more often than women take externalizing paths
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(impulsivity, risk-taking) towards risky behaviors such as heavy alcohol use70,71.

The present findings are consistent with overlapping activations found during Rej-Neu

and Acc-Neu in two recent studies from different labs, using different social feedback

paradigms albeit in younger age groups than in the present study. Importantly, similar to the

present study, these studies examined Rej and Acc relative to a Neu condition, allowing for

20
 the analysis of overlapping and unique activations. In the first study72, young healthy adults

(ages 18-27 years) were informed that peers didn’t like (Rej), liked (Acc), or didn’t know what

to think (Neu) of their personal profile. Rej-Neu and Acc-Neu contrasts showed overlapping

activation in the bilateral vlPFC/AI, and mPFC, similar to the overlapping activation in the

present study (Fig. 3C), although overlapping mPFC activity in the present study was found

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more anteriorly (BA 9/10, Supplemental Table S3). That study72, also found increased

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activity in the striatum that was unique to Acc-Neu, consistent with our finding that a cluster of

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activation unique to Acc-Neu was found in the striatum (i.e., bilateral caudate, Supplemental

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Table S4). In the second study31, young healthy adults (ages 17-20 years) received Rej,

Acc, and Neu feedback from a group of judges about a pre-recorded video of themselves.

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Both Rej-Neu and Acc-Neu contrasts showed overlapping activations in the dACC and AI,
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and Acc-Neu feedback specifically activated the ventral striatum and ventral mPFC31. In

summary, these prior studies31,72 along with the present study – three independent labs using
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three different social feedback tasks – converge to demonstrate that the vlPFC and AI

respond to both rejection and acceptance, with the striatum showing more activation during
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acceptance. As described above, novel findings in the present study include the extensive
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overlap specifically in the left precentral operculum, the high degree of correlated activity

between Rej-Neu and Acc-Neu, and sex differences in the vlPFC (area 47/12) and AI
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response to social feedback. Interestingly, no study (including the present study) found

greater activation during rejection compared to acceptance.

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Several limitations should be noted. Unlike most social feedback tasks, our task did not
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use deception to inform participants that they were receiving feedback from “real” people;

instead, participants were asked to imagine that they were real. It is not known if deception

would have produced greater emotional responses, however we have demonstrated here

and in previous studies2,33–35 that our task without deception produced significant changes in

emotional states following rejection or acceptance (see Supplemental Methods for

21
 additional detail). It is also not known whether our task resulted in more cognitive reappraisal

(i.e., participants may have been reminding themselves that the feedback was not real),

although participants under deception may also use reappraisal or other cognitive strategies

unless explicitly instructed not to do so. Nevertheless, we found patterns of neural activation

that were similar to those in studies using deception31,72. On the other hand, a task that does

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not use deception may be valuable for studying social feedback in vulnerable populations

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(e.g., suicidal ideation, borderline personality disorder) in which deception is unfeasible or

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unethical. A second limitation is that behavioral responses to the task were measured after

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the scanning session. Thus, it was not possible to associate real-time subjective experiences

to neural activity. In addition, the salience of the task may have decreased after the scan

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session. Nevertheless, we found significant effects of the task on several behavioral
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measures after the scan session. A third limitation is that each participant’s task used

different photos of potential partners and different self-photos, which may have introduced
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noise. Photos of potential partners were different because they were self-selected by each

participant for increased saliency of the feedback, and self-photos were presented in every
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trial to increase engagement of the online dating scenario (the same self-photo was used in
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every trial including the neutral condition, which was subtracted from rejection and

acceptance conditions). Lastly, the present study did not uniquely identify brain areas
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activated during social feedback vs. other social stimuli (e.g., facial expressions) or non-

social stimuli. Future studies will need to determine differences between these types of
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stimuli, and control for valence and/or salience. As an example, one study in adolescents
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controlled for the valence and salience of social feedback and found that the dACC and AI

were involved only when feedback was directed towards the participant, but not when the

feedback was directed towards others60. These types of fine-grained social feedback

paradigms may be used to better understand psychiatric disorders such as borderline

22
 personality disorder, which is characterized by extreme sensitivity to social feedback and a

heightened sense of self-awareness73.

In conclusion, the present study found a common neural response to romantic rejection

and acceptance in adults in the vlPFC and AI. The results contribute to the social feedback

literature by showing that romantic rejection and acceptance activated a common neural

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network (including the vlPFC, AI, RMPFC, and pSTS) that may not be specific to negative or

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positive emotional responses, but rather serve a social cognitive function to evaluate others’

R
intentions, or to detect socially salient information. Men appeared to respond more strongly

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to romantic feedback at the neural level compared to women, however it will be important to

examine sex-specific emotion regulation strategies. Romantic rejection is one of the most

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salient life events in adults, and future studies may examine how this pattern of activation
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found in healthy adults is different in psychiatric disorders, perhaps becoming more strongly

activated during rejection compared to acceptance in depressione.g.,33, anxiety, or borderline

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personality disorder, all of which exhibit high sensitivity to rejection74. Novel treatments may

involve neuromodulation of the right vlPFC, which has been shown to reduce the negative
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impact of social rejection29,30, potentially bringing responses to rejection and acceptance back
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into balance in these disorders.

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Acknowledgement. We are deeply thankful to Ben Sanford for participant recruitment, MRI

scanning, and assistance with data processing.

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Disclosure of interest. The authors report no conflict of interest. This research was

supported by the National Institute of Mental Health under Grant K01 MH085035 (DTH) and
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R01 MH102264 (DTH).

Data Availability. The data that supports the findings of this study are available from the
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corresponding author upon reasonable request.

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 Supplemental Information
Title: Common neural responses to romantic rejection and acceptance in healthy adults

Authors: David T. Hsua,b, Anjali Sankara, Mohammad Malika,b, Scott A. Langeneckerc, Brian
J. Mickeyc, Tiffany M. Lovec
a
Department of Psychiatry, Stony Brook University
b
Department of Psychology, Stony Brook University

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c
Department of Psychiatry, University of Utah

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Supplemental Data

Contrast Region Brodmann MNI kE t

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Area coordinates (voxels)
(x,y,z) mm

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Rejection L Superior Frontal Gyrus 6 -8, 10, 68 240 6.13
-Neutral L Ventrolateral Prefrontal Cortex 47/12 -42, 22, -4 475 5.46
(Rej-Neu) (vlPFC) (includes Operculum)
R Superior Frontal Gyrus 9 10, 50, 44 549 5.46
L Occipital Gyrus 18 -20, -88, -12 60 5.36
R vlPFC/Anterior Insula (AI)
R Occipital Gyrus U 47/12
19
28, 18, -12
28, -84, -18
220
23
5.28
4.83
AN
L Medial Temporal Gyrus 21 -54, -30, -4 154 4.82
L Medial Frontal Gyrus 6 -44, 0, 52 155 4.77
R vlPFC 47/12 50, 28, 2 111 4.49
L Supramarginal Gyrus 39 -56, -50, 30 38 4.37
M

L Putamen -22, 10, 8 19 4.30

R Superior Frontal Gyrus 6 10, 22, 62 32 4.28
L Occipital Gyrus 19 -34, -70, -18 22 4.26
L Precentral Gyrus 6 -46, -2, 36 14 3.96
D

L Superior Frontal Gyrus 8 -10, 36, 50 14 3.96

L Medial Temporal Gyrus 21 -46, -48, 10 18 3.94
TE

L Caudate -16, 4, 18 18 3.92

L Cerebellum -14, -82, -22 10 3.78

Acceptance L Occipital Gyrus 19 -30, -78, -12 958 6.72*

EP

-Neutral L Inferior Frontal Gyrus 45 -48, 22, 8 1303 5.93

(Acc-Neu) includes L vlPFC (Operculum) 47/12 -42, 20, -2 5.60
R vlPFC (includes AI) 47/12 40, 24, -6 740 5.58
R Caudate 8, 8, 2 220 5.48
C

L Superior Temporal Gyrus 21 -54, -44, 8 238 5.33

R Superior Frontal Gyrus 9 8, 54, 24 236 5.12
L Superior Frontal Gyrus 6 -2, 10, 58 613 5.12
AC

L Caudate -14, 12, 6 200 4.92

L Fusiform Gyrus 37 -38, -46, -16 75 4.82
R Superior Frontal Gyrus 8 12, 20, 38 15 4.80
Cerebellum 0, -54, -32 43 4.69
R Fusiform Gyrus 37 32, -52, -16 95 4.62
R Occipital Gyrus 18 24, -92, 2 336 4.59
L Superior Frontal Gyrus 10 -22, 54, 26 58 4.51
L Caudate -16, -2, 20 66 4.41
L Superior Frontal Gyrus 9 -2, 40, 28 151 4.38
R Superior Temporal Gyrus 22 50, -18, -8 75 4.37
L Posterior Orbital Gyrus 47 -26, 26, -16 13 4.26

28
 L Superior Frontal Gyrus 8 -14, 40, 48 54 4.16
L Frontal Operculum 45 -30, 24, 14 11 4.11
R Precentral Gyrus 6 54, -4, 38 15 3.96
R Superior Frontal Gyrus 8 8, 40, 48 15 3.92
R Precentral Gyrus 44 46, 6, 26 10 3.91
L Substantia Nigra -8, -12, -16 12 3.90
L Sup. Transverse Frontopolar 10 -2, 58, 10 24 3.85
Gyrus 17 8, -94, 0 24 3.78
R Occipital Gyrus 39 -46, -50, 28 14 3.75
L Superior Temporal Gyrus 6 42, 2, 40 21 3.68

T
R Precentral Gyrus -20, -4, -12 17 3.66
L Amygdala 6 46, 6, 50 11 3.54

IP
R Precentral Gyrus

Neu-Rej L Precuneus 7 -4, -60, 48 1705 6.41*

R
L Posterior Insula 13 -38, -24, 0 82 5.75
L Inferior Temporal Gyrus 37 -56, -56, -6 158 5.51

SC
L Medial Frontal Gyrus 6 -28, 8, 58 204 5.42
R Parietooccipital Area 39 46, -72, 40 50 4.57
L Parietooccipital Area 19 -42, -82, 26 58 4.43
R Postcentral Gyrus 1 30, -42, 62 33 4.25
L Parietal Operculum 40 -48, -34, 20 63 4.19
R Medial Temporal Gyrus
L Parietal Operculum U 37
41
58, -54, -2
-66, -12, 10
27
60
4.17
4.15
AN
R Medial Frontal Gyrus 6 30, 12, 54 12 4.13
L Parietooccipital Transition Zone 19 -34, -86, 36 12 4.10
L Parahippocampal Gyrus 36 -32, -42, -8 22 4.05
L Angular Gyrus 39 -38, -52, 38 10 4.01
M

L Occipital Gyrus 18 -12, -68, 24 45 3.95

R Superior Frontal Gyrus 9 28, 38, 36 20 3.90
R Superior Frontal Gyrus 31 8, -22, 44 10 3.86
R Superior Parietal Lobule 7 16, -48, 70 31 3.80
D

R Precuneus 31 8, -60, 18 15 3.74

R Superior Frontal Gyrus 6 18, -6, 68 11 3.74
TE

Neu-Acc R Precuneus 31 6, -44, 52 17 4.08

R Superior Frontal Gyrus 6 28, 20, 62 10 3.85
EP

Rej-Acc No clusters

Acc-Rej L Paracentral Lobule 7 -6, -46, 66 260 5.21

R Medial Temporal Gyrus 37 58, -54, -4 36 5.02
L Parietooccipital Transition Zone 19 -40, -86, 24 28 4.82
C

L Superior Frontal Gyrus 8 -2, 36, 30 69 4.77

L Medial Frontal Gyrus 44 -40, 14, 28 35 4.62
AC

R Inferior Frontal Gyrus 45 60, 30, 12 13 4.60

R Cingulate Gyrus 24 6, -8, 38 45 4.58
R Intermediate Orbital Gyrus 11 20, 42, -12 17 4.52
L Superior Parietal Lobule 7 -18, -42, 62 49 4.42
L Superior Frontal Gyrus 8 -24, 34, 46 13 4.38
L Medial Frontal Gyrus 6 -28, 8, 58 73 4.34
L Superior Parietal Lobule 7 -6, -72, 52 16 4.32
L Pretectal Area -8, -30, -8 19 4.29
L Cingulate Gyrus 23 -4, -58, 14 110 4.26
R Cingulate Gyrus 32 6, 8, 34 55 4.25
L Parietal Operculum 40 -42, -32, 22 37 4.22

29
 L Superior Frontal Gyrus 6 -10, -18, 64 21 4.16
L Fusiform Gyrus 19 -10, -64, -8 24 4.10
L Cerebellum -10, -50, -22 57 4.09
R Inferior Rostral Gyrus 10 12, 48, -10 97 4.08
L Superior Frontal Gyrus 8 -4, 30, 40 34 4.03
L Superior Temporal Gyrus 22 -66, -40, 18 14 4.01
L Precentral Gyrus 8 -34, 2, 32 13 3.99
L Caudate -8, 14, 0 18 3.95
L Parietooccipital Transition Zone 7 -28, -80, 42 12 3.93
R Superior Frontal Gyrus 6 24, -2, 62 11 3.91

T
L Cerebellum -18, -40, -24 13 3.90
L Occipital Gyrus 18 -40, -90, 6 15 3.90

IP
R Frontal Operculum 44 44, 16, 4 14 3.87
R Cerebellum 4, -54, -34 16 3.79
R Cingulate Gyrus 32 10, 18, 36 11 3.77

R
L Cingulate Gyrus 23 -4, -38, 36 21 3.77
R Frontal Operculum 1 44, -16, 18 17 3.70

SC
L Superior Frontal Gyrus 6 -2, -20, 74 16 3.68

Supplemental Table S1. Activation in the entire brain (no masking) in the entire sample (n =
36). One-sample t-tests were performed for each contrast, controlling for sex and age.

U
Whole-brain uncorrected threshold was set at P < 0.001 with minimum extent threshold
of kE > 10 voxels. Voxel-wise peaks are listed in MNI standard space (Montreal Neurological
AN
Institute). *Whole-brain family-wise error (FWE)-corrected P < 0.05 (2-tailed).
M
D
TE
EP
C
AC

30
 T
IP
R
SC
U
AN
M

Supplemental Fig. S1. Distribution of neural activation. A) Rej-Neu and B) Acc-Neu

D

contrasts (controlling for sex and age) from Table S1. R, right; Coordinates in Montreal
Neurological Institute stereotactic space. Contrast t map displayed at P < 0.001 (one-sample
TE

t-tests, whole-brain uncorrected, no masking), kE > 10.

EP
C
AC

31
 T
IP
R
SC
U
AN
Supplemental Fig. S2. Distribution of neural activation. A) Neu-Rej and B) Acc-Rej
M

contrasts (controlling for sex and age) from Table S1. R, right; Coordinates in Montreal
Neurological Institute stereotactic space. Contrast t map displayed at P < 0.001 (one-sample
t-tests, whole-brain uncorrected, no masking), kE > 10.
D

Activation in the precuneus

TE

An exploration of significant whole-brain voxel-wise activation (kE > 10, whole-brain FWE-
corrected P < 0.05, two-tailed) yielded an unexpected finding of significant deactivation in the
left precuneus during rejection (Neu-Rej) (t = 6.41, PFWE-whole-brain = 0.034; kE = 1705; peak
activation: -4, -60, 48; Table S1, Fig. S2C). Previous work has shown that the precuneus,
EP

which is part of the “default mode” network1, is involved in self-related mental representations
during rest2 and reflection of one’s own personality traits2. Thus, it is possible that during
Neu blocks, when participants are viewing their own picture plus a picture of a person who
had “not completed” their ratings, participants were left with more of an opportunity for self-
C

reflection compared to blocks when they were rejected. Although it is not clear why
activation in the precuneus was not found during Neu-Acc, it is possible that being accepted
AC

caused more first-person self-reflection similar to Neu, whereas being rejected caused more
engagement of goal-directed actions, which is associated with reductions in default mode of
brain function1. Given that the finding in the precuneus was unexpected, and no data on self-
reflection was collected, our interpretation of this finding is speculative and requires further
study.

32
 Contrast ROI MNI coordinates t kE Punadjusted Padjusted
(x,y,z) mm (voxels)
Rej-Neu L Dorsal Anterior Cingulate No clusters
Cortex (dACC)
R dACC No clusters
L vlPFC -42, 22, -4 5.46 131 0.0018 0.036*
R vlPFC 38, 22, -20 5.24 190 0.0032 ns
L AI -40, 20, -4 4.91 12 0.0032 ns
R AI 28, 18, -12 5.28 20 0.0013 0.026*

T
L Nucleus Accumbens No clusters
(NAcc)

IP
R NAcc No clusters
L Amygdala (AMY) No clusters
R AMY No clusters

R
Acc-Neu L dACC -2, 36, 26 3.77 16 0.049 ns

SC
R dACC 10, 18, 36 3.81 4 0.063 ns
L vlPFC -42, 20, -4 5.53 125 0.0016 0.032*
R vlPFC 40, 24, -6 5.58 299 0.0014 0.028*
L AI -40, 20, -2 5.36 59 0.0010 0.020*
R AI
L NAcc
R NAcc U38, 22, -4
No clusters
8, 10, -2
4.36

3.77
39

6
0.0124

0.0106
ns

ns
AN
L AMY -20, -4, -12 3.66 15 0.037 ns
R AMY No clusters

Neu-Rej No clusters within any ROI mask

M

Neu-Acc No clusters within any ROI mask

Supplemental Table S2. Activation in individual ROI masks in the entire sample (n = 36).
D

One-sample t-tests were performed for each contrast, controlling for sex and age. Whole-
brain uncorrected threshold was set at P < 0.001 with minimum extent threshold of kE > 10
TE

voxels, followed by small volume correction for each ROI mask (KE values in some ROI
masks were less than 10 if clusters spread across more than one ROI mask). Voxel-wise
peaks are listed in MNI standard space (Montreal Neurological Institute). P values (FWE-
EP

small volume corrected, SVC) are listed as unadjusted, or Bonferroni-adjusted for a two-
tailed test (x2) across 10 ROI masks (x10). No clusters indicate no clusters present at the
set threshold; *P < 0.05; ns, not significant.
C

Relationship Status
Similar to our previous study3, relationship status was examined by comparing those who
AC

were single (n = 24) with those who were in a relationship or married (n = 11). Group-level,
voxel-wise two-sample t-tests were conducted for each contrast. No significant clusters were
found in the ROI mask (threshold PFWE-SVC < 0.05), or in the whole brain (threshold PFWE-whole-
brain < 0.05).

33
 Region Brodmann Center of mass, MNI Voxels
Area coordinates (x, y, z)
L vlPFC (includes Precentral 47/12 -48, 20, 5 385
Operculum) 47/12 49, 27, 4 92
R vlPFC (includes Precentral 47/12 37, 24, -9 70
Operculum)
R vlPFC (includes AI)
R Superior Frontal Gyrus 9/10 4, 54, 29 182
L Superior Frontal Gyrus 6/8 -7, 10, 63 177

T
L Medial Frontal Gyrus 6 -43, -1, 52 105
L Middle and Superior Temporal Gyrus 22/21 -51, -36, 1 71

IP
L Occipital Gyrus 18 -23, -86, -11 50
L Superior Frontal Gyrus 8 -10, 48, 44 15

R
Supplemental Table S3. Conjunction of Rej-Neu & Acc-Neu contrasts controlling for sex
and age (whole-brain, no masking).

SC
Contrast Region
U Brodman
n Area
Center of mass, MNI
coordinates (x, y, z)
Voxels
AN
Rej-Neu Superior Frontal Gyrus 9 0, 51, 37 344
R vlPFC (includes AI) 47/12 35, 21, -14 150
L Medial Temporal Gyrus 21 -52, -33, -3 83
L Interior Frontal Gyrus 45 -54, 21, 1 64
M

L Superior Frontal Gyrus 6 -9, 17, 61 56

L Medial Frontal Gyrus 6 -48, 4, 51 47
L Superior Temporal Gyrus 39 -57, -48, 29 34
R Superior Frontal Gyrus 6 9, 25, 61 31
D

L Putamen -21, 9, 8 18
R Inferior Frontal Gyrus 45 55, 24, 5 15
TE

L Superior Temporal Gyrus 21 -48, -49, 11 14

L vlPFC (includes Precentral 47/12 -42, 23, -9 11
Operculum)
EP

Acc-Neu L Occipital Gyrus 18 -35, -83, -7 896

L Precentral Gyrus 44 -45, 9, 25 798
R vlPFC (includes Precentral 47/12 43, 27, 1 578
Operculum) 6 -1, 12, 58 433
L Superior Frontal Gyrus 18 33, -90, -2 321
C

R Occipital Gyrus 10, 11, 6 220

R Caudate -9, 5, 6 199
AC

L Caudate 21 -50, -40, 6 163

L Superior Temporal Gyrus 32 -4, 39, 25 151
L Cingulate Gyrus 37 35, -53, -20 95
R Fusiform Gyrus 37 -38, -50, -17 75
L Fusiform Gyrus 22 49, -26, -1 75
R Superior Temporal Gyrus 10 -18, 55, 29 58
L Superior Frontal Gyrus -17, 1, 20 55
L Caudate 1, -53, -35 43
R Cerebellum 8 -13, 39, 48 33
L Superior Frontal Gyrus 10 7, 60, 17 27
R Frontopolar Gyrus 10 -1, 58, 9 24

34
 L Frontopolar Gyrus 17 8, -93, -2 24
R Striate Area 6 42, 4, 40 21
R Precentral Gyrus -20, -5, -13 17
L Amygdala 8 10, 19, 38 15
R Superior Frontal Gyrus 6 54, -4, 39 15
R Medial Frontal Gyrus 47/12 -26, 27, -15 13
L vlPFC -7, -14, -16 12
L Substantia Nigra 45 -29, 23, 12 11
L Frontal Operculum 8 48, 7, 50 11
R Medial Frontal Gyrus

T
Supplemental Table S4. Non-overlapping clusters of Rej-Neu & Acc-Neu contrasts

IP
controlling for sex and age (whole-brain, no masking).

Supplemental Methods

R
The SFT did not involve deception, however participants were asked to imagine that the

SC
profiles they were rating and the feedback they received were real. A previous study showed
that social exclusion was aversive even when participants knew that they were being
excluded by a computer during Cyberball, or when they knew that others (unseen and unmet)
were following a script to exclude them4. In several pilot studies, we maximized the

U
emotional impact of the SFT without using deception by 1) having participants pre-select their
most-liked profiles, thus personalizing the task for each participant and 2) having participants
AN
submit their own photo, which was presented during the task (Fig. 1). These procedures
helped to create an immersive experience and made it easy for participants to access
genuine emotional responses from the feedback, without using deception. Our manipulation
checks (see Results) showed that without deception, the mean response was above
M

“moderately” for all three manipulation check questions, suggesting that the SFT produced
emotional responses that were more than moderately similar to real-life situations. The SFT
without deception has been used in our previous studies3,5–7. To ensure that participants
D

understood the meaning of the feedback, participants were given the following instructions
prior to performing the task:
TE

‘You will see a picture of yourself, followed by a picture of someone you liked.
Below his/her picture, you will see whether or not s/he likes you, based on your picture
and the information that you provided about yourself. His/her answer to the question
"Would I like this person?" are categorized as follows:
EP

"very likely no" or "definitely no" = this person does not like you.
"very likely yes" or "definitely yes" = this person likes you.
"not completed" = this person left the study early and did not complete the profile ratings.’
C

References
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1. Gusnard, D. A., Raichle, M. E. & Raichle, M. E. Searching for a baseline: functional

imaging and the resting human brain. Nat. Rev. Neurosci. 2, 685–694 (2001).
2. Cavanna, A. E. & Trimble, M. R. The precuneus: a review of its functional anatomy and
behavioural correlates. Brain J. Neurol. 129, 564–583 (2006).
3. Hsu, D. T. et al. Response of the μ-opioid system to social rejection and acceptance.
Mol. Psychiatry 18, 1211–1217 (2013).
4. Zadro, L., Williams, K. D. & Richardson, R. How low can you go? Ostracism by a
computer is sufficient to lower self-reported levels of belonging, control, self-esteem, and
meaningful existence. J. Exp. Soc. Psychol. 40, 560–567 (2004).

35
 5. Hsu, D. T. et al. It still hurts: altered endogenous opioid activity in the brain during social
rejection and acceptance in major depressive disorder. Mol. Psychiatry 20, 193–200
(2015).
6. Yttredahl, A. A. et al. Abnormal emotional and neural responses to romantic rejection and
acceptance in depressed women. J. Affect. Disord. 234, 231–238 (2018).
7. Sankar, A. et al. Dissociable Neural Responses to Monetary and Social Gain and Loss in
Women With Major Depressive Disorder. Front. Behav. Neurosci. 13, 149 (2019).

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