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Cited by 623Health disparities and outcomesNeuroendocrine regulation and behaviorStress Responses and Cortisol

Toward a neurology of loneliness

Open access
Cacioppo, Stephanie, Capitanio, John P., Cacioppo, John T.·2014·Psychological Bulletin
DOI 10.1037/a0037618PMC PMC5130107
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Abstract

Social isolation has been recognized as a major risk factor for morbidity and mortality in humans for more than a quarter century. The brain is the key organ of social connections and processes, however, and the same objective social relationship can be experienced as caring and protective or as exploitive and isolating. We review evidence that the perception of social isolation (i.e., loneliness) impacts brain and behavior and is a risk factor for broad-based morbidity and mortality. However, the causal role of loneliness on neural mechanisms and mortality is difficult to test conclusively in humans. Mechanistic animal studies provide a lens through which to evaluate the neurological effects of a member of a social species living chronically on the social perimeter. Experimental studies show that social isolation produces significant changes in brain structures and processes in adult social animals. These effects are not uniform across the brain or across species but instead are most evident in brain regions that reflect differences in the functional demands of solitary versus social living for a particular species. The human and animal literatures have developed independently, however, and significant gaps also exist. The current review underscores the importance of integrating human and animal research to delineate the mechanisms through which social relationships impact the brain, health, and well-being.

Integrity signals

Registry

Crossref · 10.1037/a0037618

Cites

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Claims the paper makes

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  • Findingreasoning

    There are important inconsistencies in the animal literature regarding the effects of social isolation on the brain.

    “There are also important inconsistencies in the animal literature regarding precisely what are the effects of social isolation on the brain.”
    Quote in the paperNot a substantial claim
  • Findingnone given

    The effects are not simply weakened recapitulations of what is observed as a result of isolation during development.

    “(c) the effects are not simply weakened recapitulations of what is observed as a result of isolation during development.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    The social control hypothesis is not sufficient to explain the association between loneliness and mortality.

    “and (b) the social control hypothesis is not sufficient to explain the association between loneliness and mortality (e.g., Luo et al., 2012; Seeman, 2000).”
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    • cites Luo et al., 2012

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    • cites Seeman, 2000

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  • Findingnone given

    The mechanism underlying the association between loneliness and cognitive decline has not yet been identified.

    “Although the mechanism underlying the association between loneliness and cognitive decline has not yet been identified”
    Quote in the paperSubstantial claim
  • Findingnone given

    Perceived social isolation (loneliness) is a major risk factor for morbidity and mortality above and beyond objective social isolation.

    “The current review shows a sizeable literature has emerged over the past 15 years showing that (a) the perception of social isolation—or what Weiss (1973) termed loneliness—is a major risk factor for morbidity and mortality above and beyond objective social isolation”
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  • The quote only partly states this claim. 5
  • Classified as probably not a substantial claim. 8

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    Findingnone given

    These effects are not uniform across the brain or across species but tend to be most evident in brain regions that permit adaptation to differences in functional demands of solitary versus social living for a particular species.

    “(b) these effects are not uniform across the brain or across species but instead tend to be most evident in brain regions that permit adaptation to differences in the functional demands of solitary versus social living for a particular species”
    Quote in the paperSubstantial claim

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    Findingnone given

    The human literature focused on social isolation to investigate how the social environment affects social perception, morbidity, and mortality, whereas the animal literature focused on social isolation to investigate brain plasticity/learning or various behavioral disorders.

    “The human research has tended to focus on social isolation (objective and perceived) to investigate how the social environment affects social perception, morbidity, and mortality, whereas the animal literature has tended to focus on social isolation to investigate brain plasticity/learning or various behavioral disorders (e.g., depression, anxiety, schizophrenia, aggression).”
    Quote in the paperSubstantial claim

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    Findingreasoning

    The human and animal literatures on social isolation developed independently and addressed somewhat different questions.

    “As noted in this review, the human and animal literatures on social isolation developed independently to address somewhat different questions.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Social isolation is a recognized major risk factor for human morbidity and mortality, a finding noted for more than 25 years.

    “For more than a quarter century, epidemiological studies have noted an association between objective measures of social isolation—typically operationalized as being unmarried, having less than monthly contact with friends and family, and/or having no participation in organizations, clubs, or religious groups—and health outcomes (e.g., House, Landis, & Umberson, 1988).”
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    • cites House, Landis, & Umberson, 1988

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    Premisecitation

    Loneliness is associated with altered gene expression indicating decreased inflammatory control and increased glucocorticoid insensitivity.

    “altered gene expression indicative of decreased inflammatory control and increased glucocorticoid insensitivity (Cole, Hawkley, Arevalo, & Cacioppo, 2011; Cole et al., 2007)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cole, Hawkley, Arevalo, & Cacioppo, 2011

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    • cites Cole et al., 2007

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    Premisecitation

    Loneliness is a risk factor for cognitive decline and dementia.

    “Several studies also indicate that loneliness is a risk factor for cognitive decline (Gow, Pattie, Whiteman, Whalley, & Deary, 2007) and dementia (Tilvis et al., 2004; Wilson et al., 2007).”
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    • cites Gow et al., 2007

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    • cites Tilvis et al., 2004

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    • cites Wilson et al., 2007

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    Premisecitation

    Loneliness significantly increased the risk of clinical Alzheimer's disease, and this association was unchanged when objective social isolation and other demographic and health-related factors were included as covariates.

    “Cox proportional hazards models that controlled for age, sex, and education indicated that loneliness significantly increased the risk of clinical Alzheimer’s disease, and this association was unchanged when objective social isolation and other demographic and health-related factors were included as covariates.”
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    • cites Wilson et al., 2007

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    Premisecitation

    After 4 years and covariate adjustment, loneliness and objective isolation were associated with poor memory among those low in education, while objective isolation but not loneliness was associated with declines in cognitive performance.

    “After adjusting for covariates, loneliness and objective isolation were associated with poor memory among those low in education, and objective isolation (but not loneliness) was associated with declines in cognitive performance.”
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    • cites Shankar et al., 2013

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    Premisecitation

    Declines in physical activity were predicted by loneliness, and this association was mediated by executive functioning rather than by social control.

    “Specifically, declines in physical activity were predicted by loneliness, but this association was mediated by the effects of loneliness on executive functioning rather than by social control, again suggesting that neural processes may change as a function of feeling like one is on the social perimeter.”
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    • cites Hawkley, Thisted, & Cacioppo, 2009

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    Premisecitation

    Introversion is rarely a strong risk factor for broad-based morbidity or mortality, whereas perceived isolation is associated with the most harmful mental and physical health effects.

    “However, introversion rarely emerges as a strong risk factor for individual outcomes such as broad-based morbidity or mortality; rather, the most toxic mental and physical health effects were found to be associated with perceived isolation (i.e., loneliness; e.g., J. T. Cacioppo, Hawkley, et al., 2006; Holwerda et al., 2012; Wilson et al., 2007).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites J. T. Cacioppo, Hawkley, et al., 2006

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    • cites Holwerda et al., 2012

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    • cites Wilson et al., 2007

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    Premisecitation

    A 2010 meta-analysis estimated the odds ratio for increased mortality associated with loneliness at 1.45, roughly twice that for obesity and four times that for air pollution.

    “In 2010, a meta-analysis revealed that the odds ratio for increased mortality for loneliness is 1.45, which is approximately double the odds ratio for increased mortality for obesity and quadruple the odds ratio for air pollution (Holt-Lunstad et al., 2010).”
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    • cites Holt-Lunstad et al., 2010

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    Premisecitation

    Health behaviors and objective features of social relationships did not explain the association between loneliness and mortality.

    “Results showed that loneliness was associated with increased mortality risk over a 6-year period and that neither health behaviors nor objective features of social relationships (e.g., marital status, proximity to friends or family) could explain the association between loneliness and mortality.”
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    • cites Luo et al., 2012

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    Interpretationcitation

    Priming for social threats can lead to attentional, confirmatory, and memory biases, more negative interactions, increased feelings of social isolation, and spread across a social network.

    “This priming for social threats, in turn, can lead to attentional, confirmatory, and memory biases that lead an individual to think and act toward others in a more negative fashion, which in turn can increase negative interactions with others (e.g., Duck, Pond, & Leatham, 1994; Rotenberg, 1994; Rotenberg, Gruman, & Ariganello, 2002), fuel feelings of social isolation (J. T. Cacioppo et al., 2014;”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Duck, Pond, & Leatham, 1994

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    • cites J. T. Cacioppo et al., 2014

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    • cites J. T. Cacioppo, Fowler, & Christakis, 2009

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    Interpretationcitation

    Behavioral and fMRI evidence supports the idea that loneliness increases attention to negative social stimuli and to self-preservation.

    “Evidence from behavioral and functional magnetic resonance imaging (fMRI) studies also supports the notion that loneliness increases attention to negative social stimuli (e.g., social threats) and to self-preservation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Loneliness and posterior superior temporal sulcus size were related to poorer gaze perception, and gaze perception performance mediated the association between loneliness and posterior superior temporal sulcus.

    “Moreover, consistent with the notion that loneliness is related to differences in social perception rather than social contact, Kanai, Bahrami, Duchaine, et al. (2012) found that loneliness and pSTS size were related to poorer performance on gaze perception, and gaze perception performance mediated the association between loneliness and pSTS.”
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    • cites Kanai, Bahrami, Duchaine, et al. (2012)

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    Interpretationreasoning

    If deep evolutionary roots tilt the human brain and biology toward short-term self-preservation when socially isolated, then at least part of what is triggered by feeling socially isolated should be nonconscious.

    “If there are deep evolutionary roots tilting the human brain and biology toward short-term self-preservation when a person feels socially isolated, then at least part of what is triggered when individuals feel socially isolated should be nonconscious.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Gregarious locusts have a larger midbrain-to-optic-lobe ratio and disproportionately larger higher multimodal integration centers relative to primary sensory neuropils.

    “By contrast, the gregarious locust has a larger midbrain to optic lobe ratio, and within both the visual and olfactory systems, higher multimodal integration centers are disproportionately larger than the primary sensory neuropils”
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    • cites Burrows et al., 2011

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    • cites Ott & Rogers, 2010

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    Interpretationreasoning

    Removing mutual protection and assistance should affect brain structures or functions and produce biological and behavioral effects in nonhuman animals, especially phylogenetically close ones.

    “The removal of mutual protection and assistance (e.g., social isolation), therefore, should affect brain structures and/or functions and produce biological and behavioral effects in nonhuman animals, perhaps especially those closest in terms of phylogeny.”
    Quote in the paperSubstantial claim

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    Premisenone given

    The brain is posited to be the central organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others.

    “First, the brain is posited to be the central organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others.”
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    Study design and conductcitation

    Early studies of social rejection were characterized by small sample sizes, which can lead to unreliable effects.

    “The early studies of social rejection were characterized by small sample sizes, which can lead to unreliable effects (Button et al., 2013).”
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    • cites Button et al., 2013

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    Premisecitation

    Lonely individuals showed stronger ventral striatum activation to pleasant pictures of objects than to equally pleasant pictures of people, whereas nonlonely individuals showed the opposite pattern.

    “Lonely individuals showed stronger activation of the ventral striatum to pleasant pictures of objects than to equally pleasant pictures of people, whereas nonlonely individuals showed stronger activation of the ventral striatum when exposed to pleasant pictures of people than of objects (Figure 1C).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites J. T. Cacioppo, Norris, et al., 2009

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    Premisecitation

    The ventral striatum is critical in reward processing and learning and is activated by primary and secondary rewards.

    “The ventral striatum, a key component of the mesolimbic dopamine system, is rich in dopaminergic neurons and is critical in reward processing and learning (Delgado, Miller, Inati, & Phelps, 2005; O’Doherty, 2004).”
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    • cites Delgado, Miller, Inati, & Phelps, 2005

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    • cites O’Doherty, 2004

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    Interpretationcitation

    Feeling socially isolated increases the explicit desire to connect with others but also appears to produce implicit hypervigilance for social threats.

    “For instance, feeling socially isolated increases the explicit desire to connect with others, but it also appears to produce an implicit hypervigilance for social threats (cf. J. T. Cacioppo et al., 2014)—perhaps an adaptation of the predator evasion and aggressiveness documented previously in socially isolated rodents (Hofer, 2009; Kaushal, Nair, Gozal, & Ramesh, 2012).”
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    • cites J. T. Cacioppo et al., 2014

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    • cites Hofer, 2009

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    • cites Kaushal, Nair, Gozal, & Ramesh, 2012

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    Interpretationcitation

    Animal models of the effects of social loss on depression, anxiety, and aggression may be especially relevant given human evidence that social loss leads to loneliness when the loss was not preferred and that loneliness leads to increased depressive symptomatology, anxiety, and hostility.

    “Animal models on the effects of social loss on depression, anxiety, and aggression may be especially relevant in light of the human evidence that (a) social loss leads to loneliness to the extent that the loss of the relationship was not a preferred outcome (Perlman & Peplau, 1981); and (b) loneliness leads to increased depressive symptomatology, anxiety, and hostility (cf. J. T. Cacioppo et al.,”
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    • cites Perlman & Peplau, 1981

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    • cites J. T. Cacioppo et al., in press

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    Premisecitation

    Sociality carries costs such as competition and pathogen transmission as well as benefits such as mutual protection and assistance.

    “Sociality carries costs (e.g., competition for food and mates; increased risk of pathogen transmission; Alexander, 1974) as well as benefits (e.g., mutual protection & assistance).”
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    • cites Alexander, 1974

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    Premisecitation

    Human loneliness results from a discrepancy between desired and achieved interpersonal interactions.

    “Second, human research on loneliness has emphasized the importance of attributional reasoning, with loneliness resulting from the discrepancy between the interpersonal interactions that are desired and those that are achieved (Peplau, Russell, & Heim, 1979).”
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    • cites Peplau, Russell, & Heim, 1979

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    Premisecitation

    Rodents housed alone versus in groups develop smaller cerebral cortex, smaller cell bodies, shorter synapses, and fewer glial cells in specific brain regions important for sensorimotor integration and social behaviors.

    “rodents that are housed alone, in contrast to those housed in groups, develop a smaller cerebral cortex, smaller cell bodies, shorter synapses, and fewer glial cells in specific regions of the brain known to be important for sensorimotor integration and social behaviors”
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    • cites Bhide & Bedi, 1984

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    • cites Bjørnebekk et al., 2007

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    • cites Garrido et al., 2013

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    Premisecitation

    Barnea et al. replicated the NC finding and found isolated songbirds had fewer neurons in the hippocampal complex.

    “Barnea et al. (2006) replicated this finding for the NC and also found isolated, compared to communally housed, songbirds had fewer neurons in the hippocampal complex”
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    • cites Barnea et al., 2006

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    Interpretationcitation

    Prolonged social isolation, via neuronally derived signals, produces changes in nuclear heterochromatin of PFC oligodendrocytes that slow myelin formation.

    “prolonged social isolation, via neuronally derived signals (neuregulins or unknown factors), produces changes in the nuclear heterochromatin”
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    • cites Liu et al., 2012

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    Premisecitation

    Socially isolated rodents relative to controls show regional brain changes in prefrontal cortex, occipital cortex, and hippocampus.

    “socially isolated rodents, relative to controls, show regional brain changes in several areas that are involved in the processing of social information, memory, sensorimotor integration and spatial information processing, such as the prefrontal cortex”
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    • cites Djordjevic et al., 2010

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    • cites Diamond et al., 1975

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    • cites Moser et al., 1997

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    Premisecitation

    Mice isolated for 8 weeks then group housed for 4 weeks had myelin transcripts in PFC and social behavior return to control levels.

    “the myelin transcripts in PFC and social behavior returned to control levels in the social reintegration group.”
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    • cites Liu et al., 2012

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    Interpretationreasoning

    Arthropod studies suggest that behavioral demands of group living and social foraging influence regional brain size, and that social isolation changes volumes of brain regions involved in social behaviors.

    “Together, these studies of arthropods suggest that the behavioral demands of group living and social foraging influence the phenotypic expression of regional brain size, and in turn that social isolation changes the volume of brain regions involved in these social behaviors.”
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    Premisecitation

    In female Sprague Dawley and FSL adult rats, 7 weeks of individual housing increased hippocampal cell proliferation in FSL rats but had no effect in Sprague Dawley rats.

    “Bjørnebekk et al. (2007) found that 7 weeks of individual housing, relative to group housing, led to increased (rather than decreased) cell proliferation in the hippocampus in FSL rats but had no effect on cell proliferation in Sprague Dawley rats.”
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    • cites Bjørnebekk et al., 2007

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    Premisecitation

    Exercise reduced hippocampal neurogenesis in socially isolated male rats, whereas exercise increased neurogenesis in group-housed rats.

    “Stranahan et al. (2006) found that exercise reduced hippocampal neurogenesis in socially isolated male rats, whereas exercise increased neurogenesis in group housed rats.”
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    • cites Stranahan et al., 2006

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    Premisecitation

    After 8 weeks, isolated mice spent less time interacting with a conspecific, had thinner myelin sheaths in PFC, and showed decreased myelin gene transcripts and proteins in PFC.

    “the isolated, relative to group housed, mice spent less time interacting with a conspecific mouse (a sign of social withdrawal), had thinner myelin sheaths in PFC, and showed decreased myelin gene transcripts and proteins in PFC.”
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    • cites Liu et al., 2012

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    Premisecitation

    In Spritzer et al.'s second experiment, social isolation and testosterone each decreased neurogenesis in the dentate gyrus.

    “Spritzer et al. (2011) found that social isolation and testosterone each decreased neurogenesis in the dentate gyrus.”
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    • cites Spritzer et al., 2011

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    Premisecitation

    Both social isolation and cerebral ischemia activate the HPA axis and inflammatory mechanisms, which can impact infarct size and functional recovery.

    “Both social isolation (e.g., Sapolsky et al., 1997) and cerebral ischemia activate the HPA axis”
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    • cites Sapolsky et al., 1997

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    • cites DeVries et al., 2001

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    • cites An et al., 2013

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    Premisecitation

    The increase in ischemic damage in socially isolated mice was accompanied by decreased poststroke survival (40% vs 100%) and an altered neuroinflammatory response measured by IL-6.

    “The increase in ischemic damage in socially isolated mice was accompanied by a decrease in poststroke survival rate (40% for socially isolated mice compared to 100% in socially housed mice) and an altered neuroinflammatory response, as measured by IL-6.”
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    • cites Karelina, Norman, Zhang, et al., 2009

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    Premisecitation

    Socially isolated adult rats showed increased anxiety and depressive behavior and reduced CREB activity in NAcSh compared with pair-housed rats.

    “Wallace et al. (2009) also compared adult rats that were socially isolated or pair-housed for 10–12 weeks and found increased anxiety and depressive behavior as well as reduced CREB activity in the NAcSh in the socially isolated, relative to pair-housed, animals.”
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    • cites Wallace et al., 2009

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    Premisecitation

    Egr-1 expression is down-regulated by social isolation as early as 7 days after isolation, whereas Egr-2 to Egr-4 protein levels are not affected.

    “the expression of Egr-1 is down-regulated by social isolation as early as 7 days after isolation, whereas Egr-2 to Egr-4 protein levels were not affected.”
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    • cites Matsumoto et al., 2012

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    Premisecitation

    Social isolation's effect on Egr-1 protein levels is limited to the cerebral cortex, particularly frontal cortex, and is not uniform across the brain.

    “the effect of social isolation on Egr-1 protein levels was not uniform across the brain but rather was limited to the cerebral cortex and particularly to the frontal cortex.”
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    • cites Matsumoto et al., 2012

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    Premisecitation

    In adult male baboons, blood pressure was higher and heart rate lower when individually housed than when housed with familiar companions.

    “Results showed that blood pressure was higher and heart rate was lower when the experimental animals were individually housed than housed with familiar companions.”
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    • cites Coelho et al., 1991

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    Premisecitation

    Socially isolated nonhuman primates show elevated HPA activity, greater depressive-like behavior, lower heart rates, and higher blood pressure compared with normally housed primates.

    “Socially isolated, compared to normally housed, nonhuman primates were characterized by (a) elevated hypothalamic pituitary adrenocortical activity”
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    • cites Sapolsky et al., 1997

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    • cites Cross et al., 2004

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    • cites Li et al., 2013

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    Premisecitation

    Allopregnanolone levels correlate with heightened aggressive behavior in socially isolated mice, and infusion into basolateral amygdala mitigated these behavioral effects.

    “The levels of allopregnanolone were also found to correlate with the heightened levels of aggressive behavior found in the socially isolated, compared to group housed, mice, and the infusion of allopregnanolone into the basolateral amygdala mitigated these behavioral effects”
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    • cites Nelson & Pinna, 2011

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    Premisecitation

    Peripheral IL-6 was higher and central IL-6 was lower in socially isolated mice than in pair-housed mice.

    “peripheral IL-6 was higher in socially isolated than pair housed mice, whereas central IL-6 was down-regulated in isolated relative to pair-housed mice.”
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    • cites Karelina, Norman, Zhang, et al., 2009

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    Premisecitation

    Enhanced NF-κB activity was associated with social isolation effects on stroke outcome, and inhibiting the NF-κB signaling difference with PDTC eliminated differences in stroke outcome between socially isolated and pair-housed mice.

    “The enhanced NF-κB activity was also associated with the effects of social isolation on stroke outcome, and inhibition of the NF-κB signaling difference using a pharmacological inhibitor (PDTC) eliminated the differences in stroke outcome between the socially isolated and pair-housed mice”
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    • cites Venna et al., 2012

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    Premisecitation

    Oxytocin administration eliminated the effects of social isolation on infarct size by decreasing infarct size in socially isolated mice, whereas oxytocin receptor antagonist eliminated the effects by increasing infarct size in pair-housed mice.

    “OT administration eliminated the effects of social isolation on infarct size by decreasing the infarct size observed in socially isolated mice, whereas OTA administration eliminated the effects of social isolation on infarct size by increasing the infarct size observed in pair-housed mice.”
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    • cites Karelina et al., 2011

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    Premisecitation

    In Craft et al.'s study, social isolation did not affect intra-ischemic or post-ischemic corticosterone concentration, suggesting corticosteroids are not sufficient to explain the effects of social isolation on ischemic outcome.

    “social isolation did not have an effect on intra-ischemic or post-ischemic corticosterone concentration, which suggests that corticosteroids are not sufficient to explain the effects of social isolation on ischemic outcome.”
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    • cites Craft et al., 2005

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    Premisecitation

    Chronic imipramine normalized CREB activity in NAcSh and reversed anxiety-like and depressive-like behaviors in socially isolated rats.

    “Chronic administration of imipramine, a tricyclic antidepressant, normalized CREB activity in the NAcSh and reversed the anxiety-like and depressive-like behaviors in the socially isolated rats.”
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    • cites Wallace et al., 2009

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    Premisecitation

    Socially isolating adult rats for 10-12 weeks induced anxiety and decreased CREB activity in NAcSh, and this local reduction mediated isolation-induced increases in anxious behavior.

    “Barrot et al. (2005) tested and found that socially isolating adult rats for 10–12 weeks induced anxiety and decreased CREB activity in the NAcSh and that this local reduction in CREB activity mediated the isolation-induced increases in anxious behavior.”
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    • cites Barrot et al., 2005

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    Premisecitation

    Central administration of IL-6 neutralizing antibody increased central IL-6 in pair-housed mice and eliminated differences in serum IL-6 and infarct size between socially isolated and pair-housed mice.

    “central administration of IL-6 neutralizing antibody increased central IL-6 levels in the pair-housed mice, and this was shown to eliminate the differences in serum (peripheral) IL-6 and in infarct size between socially isolated and pair-housed mice”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Karelina, Norman, Zhang, et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rats, social isolation significantly reduced BDNF protein concentrations in the hippocampus but not in the striatum or prefrontal cortex.

    “Scaccianoce et al. (2006) showed that the significant reduction in BDNF protein concentrations was observed in the hippocampus but not in the striatum and prefrontal cortex.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Scaccianoce et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Social isolation alone did not affect NF-κB transcriptional activity, but stroke increased NF-κB signaling more in socially isolated than pair-housed mice.

    “social isolation per se did not affect nuclear factor-kappaB (NF-κB) transcriptional activity but that stroke increased NF-κB signaling, with this increase being greater in the socially isolated than pair-housed mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Venna et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Male adult mice housed individually for 4-8 weeks showed shorter pentobarbital-induced sleeping time than group-housed mice, indicating decreased hypnotic activity of barbiturates.

    “male adult mice who were housed individually for 4–8 weeks, compared to group housed mice, showed shorter pentobarbital-induced sleeping time”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Baumel et al., 1970

      Not checked in the free run.

    • cites Watanabe et al., 1992

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Human studies alone cannot fully delineate the causal role of perceived social isolation on morbidity and mortality or the mechanisms through which perceived isolation has such effects.

    “It is difficult in human studies alone to delineate fully the causal role of perceived social isolation on morbidity and mortality or the mechanisms through which perceived isolation has such effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    After sleep deprivation, the increase in EEG delta power in NREM sleep did not persist throughout the dark period in socially isolated mice, indicating less deep sleep and poorer sleep quality than matched pair-housed mice.

    “this increase in EEG delta power did not persist throughout the dark period in socially isolated mice, indicating less deep sleep and poorer sleep quality compared to matched pair-housed mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kaushal et al., 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The complexity of social life, plethora of brain mechanisms, and nascent understanding of the social brain may explain in part these inconsistencies.

    “The incredible complexity of social life within and across species and gender, the plethora of brain mechanisms needed to make sense of and respond to an ever-changing social world, and the still nascent level of understanding of the social brain may explain in part these apparent inconsistencies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Experimental studies suggest loneliness increases depressive symptomatology, anxiety, aggressiveness, and impulsive responding.

    “For instance, experimental studies designed to examine the short-term effects of loneliness suggest that it increases depressive symptomatology, anxiety, aggressiveness, and impulsive responding (e.g., Baumeister & DeWall, 2005; J. T. Cacioppo, et al., 2006)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Baumeister & DeWall, 2005

      Not checked in the free run.

    • cites J. T. Cacioppo, et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loneliness and neuropathological measures were each inversely related to global cognition at last assessment prior to death, but loneliness was unrelated to neuropathological measures.

    “Loneliness and the neuropathological measures derived from the brain autopsy were each inversely related to global cognition at the last assessment prior to death, but loneliness was unrelated to the neuropathological measures.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wilson et al. (2007)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, social isolation decreases central anti-inflammatory responses and survival rate and increases infarct size and edema development following stroke induction.

    “studies in mice have found that social isolation decreases central anti-inflammatory responses and survival rate and increase the infarct size and edema development, following the induction of stroke in mice (Karelina, Norman, Zhang, & DeVries, 2009; Karelina, Norman, Zhang, et al., 2009; Venna et al., 2012).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Karelina, Norman, Zhang, & DeVries, 2009

      Not checked in the free run.

    • cites Karelina, Norman, Zhang, et al., 2009

      Not checked in the free run.

    • cites Venna et al., 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    The brain is the central organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others, in humans and likely in other social species.

    “However, the brain is the central organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others; this is true for humans and is likely to be true for other species for whom sociality has been a central feature of life for millions of years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Loneliness at baseline predicted greater cognitive declines in multiple cognitive domains and increased risk for dementia even after controlling for objective social isolation, education, gender, age, and other health-related factors.

    “As but one example, the large prospective study by Wilson et al. (2007) showed that loneliness at baseline predicted greater cognitive declines in multiple cognitive domains and increased risk for dementia even after controlling for objective social isolation, education, gender, age, and other health-related factors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wilson et al. (2007)

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Animal studies of social isolation are an important complement to human studies because human randomization and experimental manipulations are limited by possible damaging effects, and appropriate brain measures limit mechanisms that can be investigated.

    “Animal studies of social isolation are an important complement to human studies because randomization and experimental manipulations of isolation in humans are limited in intensity and duration by the possible damaging effects, and the manipulations and measurements of brain structures and function that are appropriate for human studies limits the mechanisms that can be investigated.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Integration of human and animal research holds promise for development of biomarkers and more effective interventions for loneliness.

    “The integration of human and animal research also holds promise for the development of biomarkers and more effective interventions for loneliness to improve well-being and to mitigate the deleterious behavioral, neurological and health effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In humans, loneliness is related to increased gene expression of proinflammatory NF-κB transcripts and inflammation.

    “research in humans has shown loneliness to be related to increased gene expression of proinflammatory NF-κB transcripts (Cole et al., 2007, 2011) and inflammation (e.g., Jaremka et al., 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cole et al., 2007, 2011

      Not checked in the free run.

    • cites Jaremka et al., 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Given aging population and rise in perceived isolation, integration of animal and human studies is needed now more than ever.

    “Given an aging population in industrialized nations and the rise in the prevalence of perceived isolation, the integration of animal and human studies of isolation to determine underlying mechanisms and treatments is needed now more than ever before.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The number of Americans living alone was about 31 million in 2010 and is projected to range between 43.2 and 57 million by 2050.

    “According to the U.S. Census Bureau, about 31 million Americans were living alone in 2010. By 2050, the U.S. Census Bureau (2009) projects this number to range between 43.2 and 57 million Americans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites U.S. Census Bureau (2009)

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A closer integration of human and animal research would help overcome these limitations.

    “A closer integration of human and animal research would help overcome these limitations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Experimental research in adult rodents shows isolation-induced differences in myelination in prefrontal cortex, neurosteroid concentrations, and growth factors, and these differences relate to behaviors that also characterize lonely individuals.

    “The extant experimental research in adult rodents showing, for instance, isolation-induced differences in myelination in the prefrontal cortex (Liu et al., 2012) and concentrations of neurosteroids (e.g., Nin et al., 2011) and growth factors (BDNF, CREB, Egr-1; e.g., Matsumoto et al., 2012; Wallace et al., 2009)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Liu et al., 2012

      Not checked in the free run.

    • cites Nin et al., 2011

      Not checked in the free run.

    • cites Matsumoto et al., 2012

      Not checked in the free run.

69 of 69

  • The paper relies on this without support.

    There is no animal literature on perceived social isolation (loneliness) itself.

    “There is no animal literature on perceived social isolation (loneliness) per se, but there is a large literature in which social animals are randomly assigned to either normal social living conditions or socially isolated living conditions.”

  • The paper relies on this without support.

    There is a large animal literature in which social animals are randomly assigned to normal social living or socially isolated living conditions.

    “There is no animal literature on perceived social isolation (loneliness) per se, but there is a large literature in which social animals are randomly assigned to either normal social living conditions or socially isolated living conditions.”

  • The paper relies on this without support.

    Social species create emergent organizations beyond the individual, ranging from dyads and families to societies.

    “Social species, by definition, create emergent organizations beyond the individual—structures ranging from dyads and families to societies.”

  • The paper relies on this without support.

    Social structures and associated behaviors evolved together with neural, hormonal, and genetic mechanisms because their net effect helped organisms survive and reproduce.

    “These social structures and associated behaviors evolved hand in hand with neural, hormonal, and genetic mechanisms to support them because their net effect helped these organisms survive and reproduce.”

  • The authors state this as an assumption.

    The brain evolved to put individuals into a short-term self-preservation mode when they lack mutual protection or assistance.

    “According to the social neuroscience model, the brain evolved to put individuals into a short-term self-preservation mode when they find themselves without mutual protection or assistance.”

  • The paper relies on this without support.

    The human and animal literatures on social isolation developed independently.

    “It should be noted that the human and animal literatures on social isolation developed independently, with an emphasis in the human literature on the potential role of social relationships/isolation on social cognition, morbidity and mortality (e.g., J. T. Cacioppo & Patrick, 2008), and an emphasis in the animal literature on the effects of environmental enrichment/isolation on brain plasticity”

  • The paper relies on this without support.

    Animal social isolation is a valid model for the effects of perceived social isolation on the human brain.

    “The study of invertebrates may be a valuable model for abstracting principles involved in the effects of perceived social isolation on the brain.”

  • The paper relies on this without support.

    The neuroendocrine and pressor effects of social isolation in nonhuman primates share underlying processes with human loneliness.

    “The neuroendocrine and pressor effects observed in the nonhuman primate studies are reminiscent of the longitudinal findings putatively attributable to perceived social isolation in the human literature”

  • The paper relies on this without support.

    The human brain categorizes, abstracts, and evaluates incoming stimuli in light of current states, goals, prior experiences, and predispositions rather than responding invariantly.

    “The human brain does not simply respond to stimuli in an invariant fashion but rather categorizes, abstracts, and evaluates incoming stimuli in light of current states and goals as well as prior experiences and predispositions.”

  • The paper relies on this without support.

    Members of many species need the aid and companionship of others to survive and prosper.

    “In sum, in ontogeny and across phylogeny, members of many species need the aid and companionship of others to survive and prosper.”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Non-systematic reviews have identified associations between social isolation/loneliness and changes to brain structure and processes, sympathetic neural tone, vascular stress responses, altered sleep and reduced sleep quality, cortisol secretion patterns, impaired cellular and humoral immunity, and reduced inflammatory responses.

    “a number of non-systematic reviews have identified associations with changes to brain structure and processes, sympathetic neural tone, vascular stress responses, altered sleep and reduced sleep quality, cortisol secretion patterns, impaired cellular and humoral immunity, and reduced inflammatory responses 61, 80, 96, 102-106 .”

    From An overview of systematic reviews on the public health consequences of social isolation and loneliness (2017) · cites this paper as [102]

  • A 2000 national survey in China found that 29.6% of older adults aged 60 years and older reported that they often felt lonely.

    “In China, for example, a national survey conducted in 2000 (n = 20,255) found that 29.6% of older adults (age 60 years and older) reported that they ‘often felt lonely’ [19].”

    From Loneliness and health in older adults: a mini-review and synthesis (2016) · cites this paper as [19]

  • Loneliness is a strongly aversive emotional state in humans and detrimental to physical and mental well-being.

    “Social isolation, social exclusion, or feelings of social disconnection can lead to loneliness, which is a strongly aversive emotional state in humans and detrimental to physical and mental well-being (Cacioppo et al., 2006, Cacioppo et al., 2014, Holt-Lunstad et al., 2010, House et al., 1988).”

    From Dorsal raphe dopamine neurons represent the experience of social isolation (2016) · cites this paper as Cacioppo et al., 2014

  • Social isolation, social exclusion, or feelings of social disconnection can lead to loneliness.

    “Social isolation, social exclusion, or feelings of social disconnection can lead to loneliness, which is a strongly aversive emotional state in humans and detrimental to physical and mental well-being (Cacioppo et al., 2006, Cacioppo et al., 2014, Holt-Lunstad et al., 2010, House et al., 1988).”

    From Dorsal raphe dopamine neurons represent the experience of social isolation (2016) · cites this paper as Cacioppo et al., 2014

  • 'Loneliness' per se is difficult to directly test in mice.

    “While “loneliness” per se is difficult to directly test in mice, and consequently, the lack of animal literature on this phenomenon is noted (Cacioppo et al., 2014)”

    From Dorsal raphe dopamine neurons represent the experience of social isolation (2016) · cites this paper as Cacioppo et al., 2014

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. McKenzie A Diamond MC Greer ER Woo L Telles T 1990 6 The effects of enriched environment on neural recovery following lesioning of the forelimb area of rat cortex Paper presented at the annual meeting of the American Physical Therapy Association Annual Conference Anaheim, CA

Cited by

Sorted by citations

Related

Authors
Cacioppo, S., Capitanio, J. P., & Cacioppo, J. T.
Affiliations
  • University of Chicago (US)
  • University of California, Davis (US)
ORCID
Venue
Psychological Bulletin
Publisher
American Psychological Association (APA)
Published
2014
Volume
140
Issue
6
Pages
1464-1504
ISSN
  • 0033-2909 (ISSN-L)
  • 1939-1455
DOI
10.1037/a0037618
PMC
PMC5130107
OpenAlex
W2051094789
Semantic Scholar
7fad4e65704bc8b259f52f8421bf71a5832e4ccf
Cited by
623
References
255
Citations by year
2026: 52 · 2025: 93 · 2024: 82 · 2023: 72 · 2022: 75 · 2021: 62 · 2020: 53 · 2019: 38 · 2018: 30 · 2017: 24 · 2016: 24 · 2015: 18
FWCI
28.00
Type
journal article
Language
en
Open access
Locations
  • Psychological Bulletin (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (R01-AG033590)
Topics
  • Social Sciences › Health › Health disparities and outcomes
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
loneliness, social isolation, interpersonal relationships, brain structure and function, mortality risk, morbidity, well-being
MeSH terms
Animals, Behavior, Brain, Humans, Loneliness, Neurology, Perception, Sleep, Social Isolation, Neurogenesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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