Table 2.

(A) Task-based fMRI Studies. (B) Resting state fMRI.

(A)
Study, location	Participants	Mean age (SD; range)	% Female	Loneliness measure: mean score (SD)	Task	Finding	Notes
Eisenberger et al. USA [24]	30 healthy adults	20.7 (3.2)	60%	Two-item scale assessing end-of-day social disconnection: NS	Cyberball task: online game that mimics ostracism during a game	Individuals with greater left hippocampal and left mPFC activity response also had a stronger correlation between momentary social distress and end-of-day social disconnection.	—Exploratory whole brain analysis —Cyberball task may have limited external validity
Cacioppo et al. USA [25]	23 healthy undergraduate students	NS	100%	UCLA-LS (20 item): NS	Displaying images with emotional (unpleasant or pleasant) and social (nonsocial or social) content	Loneliness correlated to neural activity (negative for pleasant social images, positive for pleasant nonsocial images) in VS, left dmPFC, right medial frontal gyrus, left fusiform gyrus, and left anterior insula. Loneliness correlated to neural activity (negative for unpleasant social images, positive for unpleasant nonsocial images) in left primary visual cortex, right caudate, right inferior frontal gyrus, left superior temporal gyrus, right superior temporal gyrus, and right secondary visual cortex.	—Exploratory whole brain analysis —All-female sample —Task may have limited external validity for experiencing pleasant and non-pleasant interactions in everyday social interactions.
Lindner et al. Germany [28]	76 total 36 patients with schizophrenia (SZ) 40 Control (NC)	30.1(8.1) SZ: 30.8 (7.9; 18–51) NC: 29.5 (8.3; 19–49)	36% SZ: 39% NC: 33%	Multidimensional loneliness questionnaire: 28.5 (11.9) SZ: 36.8 (12.9) NC: 23.9 (6.6)	Displaying sequences of facial expressions with fear, disgust, happiness, and neutral	In SZ group, but not NC group, bilateral insula activation in response to disgust was positively correlated with loneliness (no significant correlation in NC group). Covariates: Age, gender, trait anxiety, depression severity	—Exploratory whole brain analysis and hypothesis-driven ROI analysis —Task may have limited external validity for experiencing emotions of others in everyday social interactions.
Inagaki et al. USA [34]	31 healthy adults	24.3 (7.6)	48%	UCLA-LS (20 item): 44.2 (8.7)	Displaying images of either close relationships or gender-, race-, and age-matched strangers	Lonely individuals (≥1 SD above mean on UCLA-LS) had greater VS activity in response to images of close others vs. strangers; no such difference observed in non-lonely individuals (>1 SD below mean on UCLA-LS).	—Hypothesis-driven ROI analysis —Task may have limited external validity for seeing others everyday social interactions.
Wong et al. China [51]	54 total 31 with late-life depression (LLD) 23 healthy control (NC)	67.3 (5.1; >60) LLD: 67.5 (5.4) NC: 67.1 (4.8)	57% LLD: 55% NC: 61%	UCLA-LS (20 item): 37.1 (10.5) LLD: 40.0 (11.1) NC: 33.2 (8.3)	Displaying sequence of positive, negative, and neutral human and non-human pictures	Loneliness associated with weaker amygdala-SFG connection. Loneliness associated with increased functional connectivity within the DMN and corticostriatal network in LLD, but negatively correlated in NC when processing negative stimuli. Covariates: age, gender, MMSE, Depressive symptoms	—Whole brain and ROI analysis —Task may have limited external validity for experiencing emotions of others in everyday social interactions.
Wong et al. Chinaa [63]	99 total community-dwelling adults 33 concordant [C; similar levels of loneliness (L) and social isolation (SI)] 33 robust (R; lower L despite high SI) 33 susceptible (S; higher L despite low SI)	33.4 (18.6; 14–69) C: 32.9 (16.8) R: 38.7 (20.1) S: 28.6 (17.7)	52% C: 61% R: 36% S: 58%	UCLA-LS (20 item): 38.1 (8.7) C: 37.9 (8.1) R: 33.4 (7.7) S: 43.0 (7.8)	Two-run modified emotion-word Stroop	C group had a stronger and more negative association between loneliness and activity in the right posterior cerebellum, compared to R and S groups. During positive processing, loneliness positively predicted the right posterior cerebellum functional connectivity with the right visual cortex.	—Hypothesis-driven ROI analysis —Task may have limited external validity as it only displayed words of emotions. —Task did not include tasks that explicitly assess social cognition or emotion. —No explicit assessment of the participants’ state or trait affect.
D’Agostino et al. USA [62]	99 total students and community-dwelling older adults 50 young (Y) 49 old (O)	41.4 (21.8; 18–81) Y: 20.4 (2.0; 18–28) O: 62.9 (6.1; 55–81)	57% Y: 52% O: 61%	UCLA-LS (20 item): 40.6 (8.1) Y: 43.6 (8.9) O: 37.6 (7.9)	Displaying pleasant and unpleasant social and nonsocial images	No significant association between measures of loneliness and any regions in the brain, including two ROIs—the VS and the amygdala —in both Y and O groups.	—Exploratory whole brain and hypothesis-driven ROI analysis —Task may have limited external validity for experiencing pleasant and non-pleasant interactions in everyday social interactions. —Used different types of social images compared to Cacioppo et al. [25].
Golde et al. Germany [60]	41 adolescent students	15.2 (0.5; 14–16)	69%	UCLA-LS (10 item): 2.25 (0.5) for 33 participants	Trait-judgment task: rating self, friends, teachers, and politicians with respect to 30 personality traits	Loneliness was related to lower vmPFC activation during self-processing in the adolescent brain. No significant associations during friends and teacher parts of the task.	—Hypothesis-driven ROI analysis —Task may have limited external validity for seeing others everyday social interactions.
Gao et al. Taiwan [45]	45 total 21 adults with major depressive disorder (MDD) 24 controls (NC)	50.2 (5.7) MDD: 52.0 (5.0) NC: 4158.7 (6.0)	76% MDD: 71% NC: 79%	UCLA-LS (20 item): 41.1 (12.6) MDD: 50.2 (11.2) NC: 33.2 (7.4)	n-back (0- and 1-back) working memory task	Loneliness was positively associated with IPC-rostral dmPFC connectivity in both MDD and NC groups. Loneliness was positively associated with SMA-caudal dmPFC connectivity in NC, but negatively associated in the MDD group.	—Exploratory whole brain and hypothesis-driven ROI analysis —Limited external validity for task-based MRI
Courtney et al. USA [44]	50 recruited college students and community-dwelling adults. 43 analyzed	20.2 (4.6; 18–47)	60%	UCLA-LS: 41.8 (9.4)	Reflection task on self, close friends, acquaintances, and celebrities, others of varying degrees of closeness reflection task	Loneliness modulates activation to the self and others in mPFC and posterior cingulate cortex. Loneliness was also associated with less mPFC activation.	—Exploratory whole brain and hypothesis-driven ROI analysis —Limited external validity for task-based MRI neural self-other overlap

(B)
Authors	Participants	Mean age (SD; range)	% Female	Loneliness measure mean (SD)	Finding	Notes
Lan et al. Taiwan [49]	85 Han Chinese veteran males	80.3 (5.6; >65)	0%	UCLA-LS (20 item): 29.6 (8.7)	Loneliness was positively correlated with short-range functional connectivity over the bilateral lingual gyrus.	—Exploratory analysis —Used functional connectivity density mapping —All-male sample
Layden et al. USA [37]	55 healthy young adults	23.7 (2.1; 20–29)	56%	UCLA-LS (20 item): 40 (8.1)	Loneliness associated with increased brain-wide functional connectivity in the right central operculum and right supramarginal gyrus, which corresponds to the cingulo-opercular network. Covariates: age, gender, objective social isolation, and depressive symptoms	—Exploratory and hypothesis-driven analysis —Post-hoc secondary analysis.
Tian et al. China [39]	30 total 15 men with UCLA-LS score >45 15 men with UCLA-LS score <28	21.3 (2.4)	0%	UCLA -LS: NS	Loneliness associated with decreased causal flow from the affective to the visual network, causal flow from dorsal attentional to ventral attentional network.	—Exploratory and hypothesis-driven analysis —Did not control for objective social isolation or transient mood states —All-male sample
Feng et al. China [41]	75 healthy adults	21.9 (3.0)	17%	Revised UCLA-LS (20 items): NS	Loneliness predicted key nodes that contributed to the prediction model comprised regions previously implicated in loneliness, including the dlPFC, lateral orbital frontal cortex, ventral mPFC, caudate, amygdala, and temporal regions. Covariates: age, gender, relationship status, and motion	—Exploratory analysis —Did not completely examine the specificity of the predictive model
Mwilambwe-Tshilobo et al. USA [43]	942 healthy adults; Human Connectome Project	28.0 (3.5; 23–37)	54%	Loneliness survey from the NIH Toolbox on Emotion: 51.0 (8.5)	Loneliness associated with dense, lower modularity (increased integration) between default, frontoparietal, attention and perceptual networks.	—Exploratory analysis
Yi et al. USA [40]	92 healthy adults; Human Connectome Project	NS (22–35)	57%	Loneliness survey from the NIH Toolbox on Emotion: 50.5 (8.6)	Loneliness was positively related to the mean ALFF value within right ITG. The negative relation between emotional support and loneliness was explained by a decrease in the spontaneous neural activity within right ITG, but this pattern was not observed for instrumental support.	—Exploratory analysis
Liégeois et al. USA [42]	419 unrelated adults; Human Connectome Project	NS (22–35)	NS	Loneliness survey from the NIH Toolbox on Emotion: NS	Static and dynamic FC explain loneliness equally well, while specifically dynamic FC encodes cognitive tasks like working memory.	—Exploratory analysis —Limited analysis to percentage of variance explained by static vs. dynamic functional connectivity
Saris et al. Netherlands [47]	74 patients with major depressive disorder	36.9 (11.9)	66%	de Jong-Gierveld Loneliness questionnaire (11 items): 6.4 (3.4)	Higher social dysfunction was associated with decreased DMN connectivity, specifically within rostro mPFC and posterior superior frontal gyrus.	—Exploratory and hypothesis-driven analysis —Focused on a composite index of social dysfunction (composite score including loneliness, higher social disability, and smaller social network)

(A) ^aAlso featured in the structural MRI work; C concordant, DLPFC dorsal lateral prefrontal cortex, DMN default mode network, dmPFC dorsal medial prefrontal cortex, fMRI functional magnetic resonance imaging, GMV gray matter volume, L loneliness, LLD late-life depression, MDD major depressive disorder, mPFC medial prefrontal cortex, NS not stated, NC non-psychiatric control group, O old, R robust, ROI region of interest, S susceptible, SFG superior frontal gyrus, SI social isolation, SMA supplementary motor area, SZ individuals with schizophrenia, UCLA-LS University of California Los Angeles Loneliness Scale, VS ventral striatum, vmPFC ventromedial prefrontal cortex, Y young.

(B) ACC anterior cingulate cortex, ALFF amplitude of low-frequency fluctuations, DMN default mode network, dlPFC dorsal lateral prefrontal cortex, FC functional connectivity, fMRI functional magnetic resonance imaging, ITG inferior temporal gyrus, mPFC medial prefrontal cortex, NIH National Institutes of Health, NS not stated, UCLA-LS University of California Los Angeles Loneliness Scale.