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Cited by 176Tryptophan and brain disordersStress Responses and CortisolTreatment of Major Depression

The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation.

Open access
Dooley, Larissa N., Kuhlman, Kate R., Robles, Theodore F., Eisenberger, Naomi I., Craske, Michelle G., Bower, Julienne E.·2018·Neuroscience & Biobehavioral Reviews
DOI 10.1016/j.neubiorev.2018.09.006PMC PMC6192535
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Abstract

HighlightsExogenously‐induced inflammation leads to expression of 3 features of depression.They are neural reactivity to negative stimuli, reward processing, somatic symptoms.Little evidence for the role of inflammation in cognitive control was observed.Effects of inflammation on behavior depend on the timing and dose of the stimulus. Abstract A wealth of evidence has implicated inflammation in the development of depression. Yet, the heterogeneous nature of depression has impeded efforts to understand, prevent, and treat the disease. The purpose of this integrative review is to summarize the connections between inflammation and established core features of depression that exhibit more homogeneity than the syndrome itself: exaggerated reactivity to negative information, altered reward processing, decreased cognitive control, and somatic syndrome. For each core feature, we first provide a brief overview of its relevance to depression and neurobiological underpinnings, and then review evidence investigating a potential role of inflammation. We focus primarily on findings from experimental paradigms of exogenously‐induced inflammation. We conclude that inflammation likely plays a role in exaggerated reactivity to negative information, altered reward reactivity, and somatic symptoms. There is less evidence supporting an effect of inflammation on cognitive control as assessed by standard neuropsychological measures. Finally, we discuss implications for future research and recommendationsfor how to test the role of inflammation in the pathogenesis of heterogeneous psychiatric disorders.

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Crossref · 10.1016/j.neubiorev.2018.09.006

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  • Findingreasoning

    Increases in reactivity to the environment seem to occur only after acute inflammatory challenges.

    “For example, only acute inflammatory challenges appear to induce increases in reactivity to the environment, whereas altered reward processing appears to only be observed in studies with high doses of inflammation regardless of their acute or chronic nature.”
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  • Findingcitation

    Typhoid vaccine studies show increases in fatigue within 2-3 hours despite only mild, acute increases in inflammation.

    “This is exemplified by typhoid vaccine studies which can lead to increases in fatigue within 2–3 hours despite eliciting only mild, acute increases in inflammation (Brydon et al., 2008).”
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  • Findingcitation

    Studies using IFN-α and typhoid vaccination have found that inflammation increases are associated with subjective cognitive complaints.

    “Further, IFN-α and typhoid studies have documented links between increases in inflammation and subjective cognitive complaints (Brydon et al., 2009; Capuron et al., 2002; Harrison et al., 2009).”
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  • Findingcitation

    Endotoxin studies report that fatigue and other sickness symptoms rise and peak two hours after injection.

    “Similar results have been observed in endotoxin studies, which document elevations in fatigue and other sickness symptoms that peak 2 hours post injection (Eisenberger et al., 2010; Moieni et al., 2015).”
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  • Findingown data

    Endotoxin and IFN-α studies fairly consistently found no effects on various tasks that measure different aspects of executive function.

    “However, results from both endotoxin and IFN-α studies were fairly consistent in showing no effects across a range of tasks assessing different aspects of executive function.”
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    Findingcitation

    After an inflammatory challenge, somatic symptoms and depressed mood follow different time courses and may have separate neurobiological bases.

    “There is evidence that somatic symptoms follow a different temporal course than depressed mood following inflammatory challenge and may have distinct neurobiological underpinnings.”
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    Findingcitation

    In IFN-α studies, most patients quickly develop somatic symptoms, but only a subset later develop additional symptoms severe enough for a major depression diagnosis.

    “Support for this idea derives from IFN-α studies, which show that although the large majority of patients rapidly develop somatic symptoms (e.g., fatigue), only a subgroup go on to develop other symptoms (e.g., feelings of guilt, suicidality) severe enough to qualify for a major depression diagnosis (Capuron et al., 2002; Capuron and Miller, 2004; Musselman et al., 2001).”
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    Findingcitation

    With IFN-α therapy, most patients develop somatic symptoms within two weeks, whereas affective and cognitive symptoms appear later and in fewer patients.

    “For example, IFN-α therapy resulted in the emergence of a cluster of somatic symptoms that appeared in the majority of patients within two weeks of treatment initiation (including symptoms of anorexia, fatigue, and pain), as well as cluster of affective/cognitive symptoms that emerged in a smaller proportion of patients (including symptoms of negative mood, anxiety, and cognitive dysfunction) (Cap”
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    Findingcitation

    In Hepatitis C patients given low-dose IFN-α, fatigue rises and vigor falls within four hours of the first injection, and these changes continue to increase over 8 weeks.

    “Further, patients receiving (low-dose) IFN-α treatment for Hepatitis C exhibit increases in fatigue and decreases in vigor within four hours of initial injection that continue to rise across the 8 weeks of treatment (Dowell et al., 2016).”
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    Findingreasoning

    Most studies of inflammation's impact on negative reactivity and reward processing have examined neural processes, and overall the evidence supports such an impact.

    “In general, research also supports an effect of inflammation on negative reactivity and reward processing, with most studies focusing on neural processes.”
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    Findingcitation

    Even after controlling for concurrent depressed mood, inflammation remains associated with both attentional bias and fatigue.

    “Indeed, the association between inflammation and both attentional bias and fatigue remain when accounting for concurrent depressed mood (Bower et al., 2009; Boyle et al., 2017).”
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    Findingcitation

    Among chemotherapy patients with cancer, paroxetine lowered depressed mood but did not reduce fatigue.

    “Similar findings have been observed in cancer patients, where paroxetine led to reductions in depressed mood but not fatigue in patients undergoing chemotherapy (Morrow et al., 2003).”
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    Chronic IFN-α treatment in non-human primates decreases dopamine synthesis and availability in the striatum, and these decreases correlate with reduced effort-dependent sucrose consumption.

    “Further, chronic treatment with IFN-α in non-human primates leads to decreases in the synthesis and availability of dopamine in the striatum, which are correlated with reductions in effort-dependent sucrose consumption (Felger et al., 2013).”
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    Premisenone given

    Inflammation and IDO can influence glutamate metabolism, which may play a role in depression.

    “Of note, inflammation and IDO can both influence glutamate metabolism, which may also play a role in depression”
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    Premisecitation

    Depression is highly heterogeneous, as shown by mixed symptom phenotypes and mixed treatment effectiveness.

    “However, depression is an exceedingly heterogeneous disorder as evidenced by the mixed symptom phenotypes that qualify for the disorder (Fried and Nesse, 2015; Young et al., 2014) and the mixed effectiveness of existing treatments (Biesheuvel-Leliefeld et al., 2015; Cipriani et al., 2018; Piet and Hougaard, 2011; Shea et al., 1992; Vittengl et al., 2007).”
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    Premisecitation

    Peripheral inflammation induces depressive-like behaviors in animal models, including anhedonia, reduced exploratory, novelty-seeking and social behaviors, reduced food intake, and sleep disturbance.

    “Of particular relevance for this review, peripheral inflammation has been shown to induce depressive-like behaviors in animal models, including anhedonia (e.g., reduced sucrose consumption), decreases in exploratory, novelty-seeking and social behaviors, reduced food intake; and sleep disturbance (Anisman and Matheson, 2005; De La Garza, 2005; Dunn et al., 2005; Larson and Dunn, 2001; Pecchi et al”
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    Chronically elevated glucocorticoids can stimulate neuroinflammation by activating microglia, making the process self-perpetuating.

    “This process can become self-perpetuating because chronically elevated glucocorticoids can stimulate production of neuroinflammation by activating microglia (Frank et al., 2013; Nair and Bonneau, 2006), the resident immune cells of the brain.”
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    Glutamate is released at a higher rate under stress, and excess synaptic glutamate can lead to excitotoxicity and neuronal death.

    “To summarize briefly, glutamate is released at a higher rate under conditions of stress (Goshen and Yirmiya, 2009), and excess presence of synaptic glutamate can lead to excitotoxicity and neuronal death (Ankarcrona et al., 1995).”
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    Premisecitation

    Typhoid vaccination caused greater negative mood following two stress tasks compared to placebo, driven by increases in fatigue and confusion.

    “Typhoid vaccination caused greater negative mood following two stress tasks (a Stroop color-word task and a simulated public speaking exercise) compared to a placebo group; elevations in negative mood were driven by increases in fatigue and confusion (Brydon et al., 2009).”
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    Anhedonia is a hallmark of depression and one of the core diagnostic criteria for major depression.

    “Anhedonia, the loss of pleasure or interest in previously rewarding stimuli, is a hallmark of depression and is one of the core diagnostic criteria for major depression (American Psychiatric Association, 2013).”
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    Typhoid vaccination leads to a modest, short-term inflammatory response, with an average IL-6 increase of 0.82 pg/mL (106% increase) at 3 hours and resolution within 24 hours.

    “Typhoid vaccination leads to a modest, short-term inflammatory response; for example, an average increase of 0.82 pg/mL (a 106% increase) in IL-6 at 3 hours post-vaccination (Wright et al., 2005) and increases in inflammation resolve within 24 hours following typhoid vaccination (Paine et al., 2013).”
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    Interpretationcitation

    Inflammation may upregulate amygdala reactivity to social threats, resulting in social disconnection and withdrawal.

    “Moreover, the exaggerated amygdala response to socially threatening images was associated with increased feelings of social disconnection (Inagaki et al., 2012); thus, inflammation may upregulate amygdala reactivity to social threats, resulting in the experience of social disconnection and withdrawal.”
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    Compared to non-depressed controls, depressed individuals show more negative facial expressions to unpleasant images, greater perceived stress to laboratory stressors, and greater increases in negative affect to daily stressors.

    “For example, compared to non-depressed controls, individuals with depression exhibit more negative facial expressions in response to unpleasant images (Sloan et al., 1997), report greater perceived stress in response to a laboratory stress tasks (de Rooij et al., 2010), and display greater increases in negative affect in response to daily stressors (Myin-Germeys et al., 2003).”
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    Premisecitation

    Endotoxin did not increase self-reported affective reactivity to social stress but led to exaggerated activation of threat-related neural circuits, including greater amygdala and dACC activation.

    “For example, although endotoxin did not increase self-reported affective reactivity to social stress, endotoxin did lead to exaggerated activation of threat-related neural circuits, including greater activation of the amygdala and dACC (Muscatell et al., 2016).”
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    Premisecitation

    Endotoxin administration to healthy individuals leads to depressive symptoms including negative mood, anhedonia, cognitive impairment, fatigue, reduced food intake, altered sleep, social withdrawal, and anxiety.

    “These studies have shown that endotoxin administration leads to symptoms of depression including negative mood, anhedonia, cognitive impairment, fatigue, reduced food intake, altered sleep, and social withdrawal, as well as anxiety symptoms (DellaGioia and Hannestad, 2010; Eisenberger et al., 2010a; Reichenberg et al., 2001).”
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    Premisecitation

    The inflammation-depression pathway is bidirectional, as depressive symptoms predict increases in inflammation in some samples.

    “Yet, there is also evidence that the inflammation-depression pathway is bidirectional as depressive symptoms predict increases in inflammation in some samples (Huang et al., 2017; Matthews et al., 2010; Stewart et al., 2009).”
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    Study design and conductreasoning

    Unlike IFN-α or endotoxin, vaccines do not typically cause fever, nausea, or other physical illness symptoms, so effects on mood and cognition are not simply attributable to illness symptoms but to more direct cytokine effects on the brain.

    “Additionally, unlike IFN-α treatment or endotoxin, vaccines do not typically lead to fever, nausea, or other physical illness symptoms. Therefore, any effects on mood and cognition are not simply attributable to illness symptoms, but rather to more direct effects of cytokines on the brain.”
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    Premisecitation

    IFN-α can induce depressed mood, fatigue, sleep disturbance, loss of appetite, pain, anxiety, anhedonia, anger, hostility, cognitive impairment, and suicidal ideation.

    “Studies of patients receiving this treatment have shown that IFN-α can induce symptoms of depressed mood, fatigue, sleep disturbance, loss of appetite, pain, anxiety, anhedonia, anger, hostility, cognitive impairment, and suicidal ideation (Capuron et al., 2002; Janssen et al., 1994; Lotrich et al., 2007).”
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    Premisecitation

    Participants with larger vaccine-induced IL-6 responses exhibited elevated systolic blood pressure responses to stress tasks, as well as elevated post-stress cortisol and a marker of noradrenaline.

    “Additionally, participants with larger vaccine-induced IL-6 responses exhibited elevated systolic blood pressure responses to stress tasks, as well as elevated post-stress cortisol and a marker of noradrenaline (Brydon et al., 2009).”
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    Premisecitation

    Alterations in reward processing precede and potentially contribute to the etiology of depression in at-risk groups.

    “Importantly, these alterations in reward processing precede and potentially contribute to the etiology of depression in at-risk groups (Gotlib et al., 2010), and number of prospective studies have shown that self-reported anhedonia (less frequent and intense positive affect) is a strong predictor of subsequent increases in depression severity (Morris et al., 2009).”
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    Interpretationcitation

    Inflammation may impact both consummatory and anticipatory reward processes, potentially leading to behavioral manifestations of depressed mood.

    “Thus, inflammation may impact not only consummatory but also anticipatory reward processes, potentially leading to behavioral manifestations of depressed mood.”
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    Impaired cognitive control is heritable.

    “Impaired cognitive control is heritable”
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    Interpretationcitation

    Much of the induced inflammation work has found reduced reward-related neural activity after an inflammatory stimulus, generally consistent with preclinical research.

    “Much of this work has shown attenuated reward-related neural activity following an inflammatory stimulus, which is generally consistent with preclinical research on inflammation and reward (See Swardfager et al., 2016 for review).”
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    Anhedonia is often conceptualized as the behavioral manifestation of altered reward processing in depressed patients.

    “Anhedonia is often conceptualized as the behavioral manifestation of altered reward processing in depressed patients (Beck, 2004; Nutt et al., 2007; Webb et al., 2016; Winer and Salem, 2015), and may underlie many of the profound social impairments that are central to depression (Kupferberg et al., 2016).”
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    Anhedonia is estimated to be 46% heritable in studies of monozygotic twins.

    “Anhedonia is a broad construct that includes deficits in anticipation of, motivation toward, and responsiveness to reward, as well as deficits in reward learning (ability to recall and make decisions based on past rewarding experiences) (Treadway and Zald, 2011) and is estimated to be 46% heritable in studies of monozygotic twins (Bogdan and Pizzagalli, 2009).”
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    Several studies of IFN-α treated hepatitis C patients found no significant deficits on the Trail Making Test part B, the Wisconsin Card Sorting task, or the Intradimensional/Extradimensional Shift task.

    “However, several other studies of IFN-α treated hepatitis C patients have found no significant performance deficits on the Trail Making Test part B (Amodio et al., 2005; Drozdz et al., 2008; Fontana et al., 2007), the Wisconsin Card Sorting task (Fontana et al., 2007), or on the Intradimensional/Extradimensional Shift task (Majer et al., 2008).”
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    In the placebo condition, functional connectivity between the substantia nigra and hippocampus during novelty was increased, while in the typhoid vaccine condition it was attenuated.

    “substantia nigra-hippocampus connectivity to novelty was increased in the placebo condition and attenuated in the vaccine condition (Harrison et al., 2015)”
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    Interpretationreasoning

    Lower substantia nigra responsiveness to novel stimuli is relevant to the reduced motivational and approach behavior observed in depression.

    “which is relevant to reductions in motivational and approach behavior seen in depression”
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    Premisecitation

    Anhedonia includes deficits in anticipation, motivation, responsiveness to reward, and reward learning.

    “Anhedonia is a broad construct that includes deficits in anticipation of, motivation toward, and responsiveness to reward, as well as deficits in reward learning (ability to recall and make decisions based on past rewarding experiences) (Treadway and Zald, 2011) and is estimated to be 46% heritable in studies of monozygotic twins (Bogdan and Pizzagalli, 2009).”
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    Interpretationreasoning

    The review concludes that inflammation likely plays a role in exaggerated reactivity to negative information, altered reward reactivity, and somatic symptoms.

    “We conclude that inflammation likely plays a role in exaggerated reactivity to negative information, altered reward reactivity, and somatic symptoms.”
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    Premisecitation

    In a study asking participants to sustain positive mood after positive stimuli, depressed individuals failed to sustain NAc activation over time compared with controls, and this reduced capacity was associated with lower self-reported positive affect.

    “In a study in which participants were explicitly asked to sustain their positive mood following the presentation of positive stimuli, depressed individuals failed to sustain NAc activation over time compared with controls; moreover, this reduced capacity was associated with lower self-reported positive affect (Heller et al., 2009).”
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    Cognitive control deficits are among the most frequent complaints in depression.

    “Deficits in cognitive control are among the most frequent complaints for individuals with depression (Simons et al., 2009).”
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    Moderate inflammation facilitated updating speed on the n-back task, shown by faster reaction times compared with placebo and comparable accuracy.

    “the only published study examining the role of inflammation in performance on behavioral tasks of updating found that moderate inflammation facilitated (rather than slowed) updating speed (Grigoleit et al., 2011)”
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      “the moderate-dose endotoxin group exhibited significantly faster reaction times on the n-back task compared to the placebo condition (with comparable levels of accuracy across the two groups) (Grigoleit et al., 2011)”
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    A meta-analysis of 113 studies found significant executive functioning deficits in depressed individuals versus non-depressed controls, including updating, shifting, inhibition, working memory, planning, and verbal fluency, with effect sizes from d = 0.32 to 0.97.

    “A meta-analysis of 113 studies found significant deficits in executive functioning among depressed individuals compared to non-depressed controls, including deficits in updating, shifting, inhibition, working memory, planning, and verbal fluency, with effect sizes ranging from d = 0.32 – 0.97 (Snyder, 2014).”
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    Novel stimuli have high intrinsic reward value and motivate adaptive behaviors like exploration and social approach.

    “Novel stimuli are high in intrinsic reward value, thereby motivating adaptive behaviors such as exploration and social approach (Kakade and Dayan, 2002).”
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    The role of inflammation in shifting ability impairments is mixed, with most studies finding no effect.

    “Thus, a role of inflammation in shifting ability impairments is mixed, with the majority of studies finding no effect of inflammation on shifting ability.”
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    A large epidemiological study of more than 1800 depressed patients found that 73% reported feeling tired.

    “A large epidemiological study of more than 1800 depressed patients found that 73% reported feeling tired, and that this was the second most commonly endorsed symptom, after low mood (Tylee et al., 1999).”
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    Interpretationcitation

    Inflammation did not impair inhibitory control but instead led to overall psychomotor slowing and/or decreased motivation.

    “Thus, inflammation did not impair inhibitory control, but rather led to an overall psychomotor slowing and/or decrease in motivation (Brydon et al., 2008).”
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    Fatigue is a prevalent presenting symptom of major depressive disorder.

    “Fatigue is a prevalent presenting symptom of major depressive disorder (Demyttenaere et al., 2005).”
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    In that study, feeling tired was the second most commonly endorsed symptom, after low mood.

    “A large epidemiological study of more than 1800 depressed patients found that 73% reported feeling tired, and that this was the second most commonly endorsed symptom, after low mood (Tylee et al., 1999).”
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    In IFN-α models, fatigue is the most commonly reported symptom, affecting an estimated 80% of patients.

    “In IFN-α models, fatigue is the most commonly reported symptom, affecting an estimated 80% of patients (Capuron et al., 2002).”
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    Persistent fatigue can lead to substantial impairment in fulfilling social, familial, and work roles.

    “Persistent fatigue can lead to substantial impairment in fulfilling social, familial, and work roles, and patients with residual fatigue are more likely to experience depression recurrence despite continued prophylactic treatment (Targum and Fava, 2011).”
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    The basal ganglia and frontal lobes have been implicated in diseases such as chronic fatigue syndrome.

    “In addition, conceptual models have suggested a role for the anterior insula and the dorsal ACC in fatigue, particularly in the context of inflammation (Dantzer et al., 2014; Karshikoff et al., 2017), while the basal ganglia and frontal lobes have been implicated in diseases such chronic fatigue syndrome (DeLuca et al., 2009).”
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    Psychomotor retardation is a common symptom of depression.

    “Psychomotor retardation, defined as a slowing of motor activity and difficulty responding quickly and spontaneously to environmental cues, is a common symptom of depression (Taylor et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor et al., 2006 source

      Not checked in the free run.

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

    Premisenone given

    Common sleep alterations in depression include frequent nocturnal awakenings.

    “Common sleep alterations in depression include difficulty initiating sleep, frequent nocturnal awakenings, and early morning awakenings.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Sleep deprivation appears to cause alterations to neural processes that underlie a wide range of cognitive tasks, including attentional control, memory, reward processing, and emotion discrimination.

    “Sleep deprivation appears to cause alterations to neural processes that underlie a wide range of cognitive tasks, including attentional control, memory, reward processing, and emotion discrimination which involve multiple brain regions and the connectivity between them (Krause et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Krause et al., 2017 source

      Not checked in the free run.

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

    Premisecitation

    Hypersomnia can also accompany depression, though it is somewhat less common.

    “Hypersomnia can also accompany depression, though it is somewhat less common (Garvey et al., 1984; Tsuno et al., 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Garvey et al., 1984 source

      Not checked in the free run.

    • cites Tsuno et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increases in IL-6 and decreases in motor speed were both associated with altered activation patterns (enhanced activation) in the substantia nigra.

    “Notably, increases in IL-6 and decreases in motor speed were both associated with altered activation patterns (enhanced activation) in the substantia nigra (Brydon et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brydon et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Psychomotor slowing involves disruptions in dopamine functioning and the basal ganglia circuit.

    “Psychomotor slowing involves disruptions in dopamine functioning and the basal ganglia circuit; dopaminergic abnormalities underlie the psychomotor slowing seen in depression as they do in Parkinson’s disease (Rogers et al., 1987).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rogers et al., 1987 source

      Not checked in the free run.

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

    Premisenone given

    Common sleep alterations in depression include early morning awakenings.

    “Common sleep alterations in depression include difficulty initiating sleep, frequent nocturnal awakenings, and early morning awakenings.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    An estimated 50-90% of individuals with diagnosed depression complain of poor sleep quality.

    “An estimated 50–90% of individuals with diagnosed depression complain of poor sleep quality (Casper et al., 1985; Hetta et al., 1985; Kupfer et al., 1969; Riemann et al., 2001).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Casper et al., 1985 source

      Not checked in the free run.

    • cites Hetta et al., 1985

      Not checked in the free run.

    • cites Kupfer et al., 1969 source

      Not checked in the free run.

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

    Premisenone given

    Common sleep alterations in depression include difficulty initiating sleep.

    “Common sleep alterations in depression include difficulty initiating sleep, frequent nocturnal awakenings, and early morning awakenings.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Fatigue is a classic example of adaptive sickness behavior that can promote recovery by driving rest and allowing energy to be devoted to healing.

    “The classic example of these adaptive behavioral changes is fatigue, which can promote recovery by driving the organism to rest and thereby allow the body to devote its energy to healing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Social rewards may be an exception to reduced reward responsiveness, because having close others nearby likely aids caretaking.

    “Blunted responsivity to rewards may be similarly adaptive, minimizing an organism’s pursuit of rewards in favor of rest; the exception to this blunted reward responsivity could be social rewards, due to the likely benefits of having close others nearby for caretaking purposes (Eisenberger et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Eisenberger et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Taken together, results suggest that inflammation can disrupt sleep in ways that mirror the sleep disruptions observed in depression, including reductions in sleep quality, increases in NREM sleep, and decreases in REM sleep latency following IFN-α and moderate doses of endotoxin.

    “Taken together, results suggest that inflammation can disrupt sleep in ways that mirror the sleep disruptions observed in depression, including reductions in sleep quality, increases in NREM sleep, and decreases in REM sleep latency following IFN-α and moderate doses of endotoxin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These adaptations are beneficial in the short term, but if they persist they may cause harm over the long term.

    “In the short-term, these adaptations serve a clear benefit to the individual, but if sustained (such as through ongoing stress or immune dysregulation) could be iatrogenic in the long-term.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Prior work indicates that inflammatory processes regulate learning and memory.

    “In some ways, this is puzzling given that inflammatory processes have been shown to regulate learning and memory (e.g., Yirmiya and Goshen, 2011) and that correlational studies have identified associations between mild elevations in inflammatory markers and both self-reported (Davis et al., 2018; Kuhlman et al., 2018) and objective (Marsland et al., 2015) measures of cognitive function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yirmiya and Goshen, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low-level immune activation decreases or has no effect on REM sleep.

    “Specifically, low-level immune activation leads to increased non-rapid eye movement (NREM) sleep, while decreasing or having no effect on REM sleep; in contrast, more robust immune activation decreased both NREM and REM sleep (Mullington et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mullington et al., 2000 source

      Not checked in the free run.

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

    Interpretationreasoning

    Being more reactive to negative stimuli may help when a threat exists, but not when the organism feels safe.

    “For example, heightened reactivity to negative stimuli may be beneficial when the threat is present, but not when an organism perceives safety.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Inflammation may be relevant only for some depressed individuals and for specific aspects of depression rather than others.

    “Inflammation may only be relevant for some individuals with depression, while also being relevant to specific aspects of depression and not others.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent findings indicate inflammation can lead to heightened ventral striatum reactivity specifically to social rewards.

    “and the recent findings indicating that inflammation can lead to heightened VS reactivity specifically to social rewards (Inagaki et al., 2015; Muscatell et al., 2016)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Inagaki et al., 2015 source

      Not checked in the free run.

    • cites Muscatell et al., 2016 source

      Not checked in the free run.

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

    Premisecitation

    Genetic influences combine with psychological, environmental, and other biological influences and act at several points across the course of disorders.

    “Genetic factors interact with psychological, environmental, and other biological factors and exert their influences at multiple points throughout the course of disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Miller and Rockstroh, 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early life immune activation and chronic stress alter microglial density and morphology, especially in emotion-related brain regions.

    “For example, early life exposure to immune activation and exposure to chronic stress alter the density and morphology of microglia, particularly in regions of the brain involved in emotion and emotion regulation (Bilbo and Schwarz, 2012; Tynan et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bilbo and Schwarz, 2012

      Not checked in the free run.

    • cites Tynan et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These factors help explain why some depressed individuals lack elevated peripheral inflammation markers while some non-depressed individuals have them.

    “Taken together, these factors provide insight into how some individuals with depression do not exhibit elevated peripheral markers of inflammation while some individuals without depression do.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Inflammation's effects on mood and behavior are mediated by brain inflammatory signaling (neuroinflammation), and peripheral markers only approximate this.

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

    Premisecitation

    Women have a higher prevalence of depression than men.

    “Despite the fact that depression is more prevalent among women than men (Kuehner, 2003; Nolen-Hoeksema, 2001, 1987)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kuehner, 2003 source

      Not checked in the free run.

    • cites Nolen-Hoeksema, 2001, 1987

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In females but not males, endotoxin-induced increases in IL-6 are associated with increased activation of threat-related neural regions (dACC, anterior insula), which mediate the relationship between IL-6 and depressed mood.

    “Additionally, among females but not males, endotoxin-induced increases in IL-6 have been associated with increased activation of threat-related neural regions (dACC, anterior insula), which mediate the relationship between IL-6 levels and depressed mood (Eisenberger et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Eisenberger et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Based on their review, the authors expect anti-inflammatory treatments to benefit patients with exaggerated negative-information reactivity, altered reward processes, or somatic symptoms, but not necessarily those with primarily cognitive-control difficulties.

    “Based on our review of the causal role of inflammation on core features of depression, we would expect anti-inflammatory treatments to benefit patients presenting with exaggerated reactivity to negative information, altered reward processes, and somatic symptoms but not necessarily those presenting primarily with difficulties in cognitive control.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Depressed individuals attend selectively to negative information.

    “Depressed individuals attend selectively to negative information (Gotlib and Joormann, 2010; Joormann and Quinn, 2014)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gotlib and Joormann, 2010

      Not checked in the free run.

    • cites Joormann and Quinn, 2014

      Not checked in the free run.

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

    Interpretationnone given

    Much of the work on negative-information reactivity has focused on endotoxin-induced inflammation's impact on reactivity to social threats and sensitivity to social rewards.

    “Much of the work on reactivity to negative information has focused on the impact of endotoxin-induced inflammation on negative reactivity to social threats (social evaluation, social exclusion, images of fearful faces) and sensitivity to social rewards.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Animal work indicates that males possess more microglia early in life, whereas females have more primed or activated microglia in adolescence and adulthood.

    “Early exploration of these pathways in preclinical models suggests that males have more microglia in early life and females have more activated or primed microglia during adolescence and adulthood (Schwarz et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schwarz et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Evidence to date suggests that inflammation is often causally related to changes in central affective and cognitive processes, such as anhedonia and negative reactivity bias, and in the neural circuits tied to depression's origins and treatment.

    “The current body of evidence indicates that inflammation is linked, in many cases causally, to alterations in core affective and cognitive processes (e.g., anhedonia; negative reactivity bias) and their neural circuits that are strongly implicated in current models of the etiology and treatment of depression.”
    Quote in the paperSubstantial claim
76 of 76

  • The paper relies on this without support.

    The four selected core features are largely transdiagnostic.

    “It should be noted that while these core features were identified from studies aimed specifically at identifying endophenotypes for depression, each of these constructs is largely transdiagnostic.”

  • The paper relies on this without support.

    The three inflammatory challenge paradigms can test a causal role of inflammation in psychological constructs.

    “The strength of limiting our review to studies using these three paradigms is that such studies can test a causal role of inflammation in each psychological construct.”

  • The paper relies on this without support.

    The IFN-α paradigm models chronic exposure to moderate inflammation, while endotoxin and typhoid vaccination model acute exposure at high and low levels, respectively.

    “While the IFN-α paradigm models the effects of chronic exposure to moderate levels of inflammation, endotoxin and typhoid vaccination model the short-term effects of acute exposure at high and low levels, respectively.”

  • The authors state this as an assumption.

    The network perspective treats symptoms as causally influencing each other over time, not as arising from one common cause.

    “A network perspective of psychopathology assumes that symptoms causally influence one another over time, rather than emerge from a singular, common cause (Borkulo et al., 2015; Borsboom and Cramer, 2013).”

  • The paper relies on this without support.

    Inflammation's effects on mood and behavior are mediated by brain inflammatory signaling (neuroinflammation), and peripheral markers only approximate this.

    “However, the impact of inflammation on mood and behavior occurs through inflammatory signaling in the brain or neuroinflammation, for which peripheral markers are only a proxy.”

  • The paper relies on this without support.

    Even with chronic inflammation, only some people develop depressive symptoms.

    “Given that depressive symptoms only arise in a subset of individuals even under chronic inflammatory conditions, inflammation must interact with pre-existing host factors to determine mood outcomes.”
6 of 6

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?

  • Increased inflammatory activity appears to be associated with attentional bias toward negative information and has been suggested to increase stress reactivity.

    “Increased inflammatory activity appears not only to be associated with AB toward negative information but has also been suggested to increase stress reactivity (Dooley et al., 2018).”

    From The interplay between stress, inflammation, and emotional attention: relevance for depression (2019) · cites this paper as Dooley et al., 2018

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • REM-latency direction reverses in the sleep summary

    Minor

    The sleep section reports that IFN-α treatment increased REM latency, but its summary describes decreased REM latency following IFN-α.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Weinstein, 2010, Acute mental stress in depression, Russell J. Bertrand Russell Arch., 84, 228

Cited by

Sorted by citations

Related

Authors
Dooley, L. N., Kuhlman, K. R., Robles, T. F., Eisenberger, N. I., Craske, M. G., & Bower, J. E.
Affiliations
University of California, Los Angeles (US)
Corresponding author
Kuhlman, Kate R.
ORCID
Venue
Neuroscience & Biobehavioral Reviews
Publisher
Elsevier BV
Published
2018-11
Volume
94
Pages
219-237
ISSN
0149-7634 (ISSN-L)
DOI
10.1016/j.neubiorev.2018.09.006
PMC
PMC6192535
OpenAlex
W2889889361
Semantic Scholar
b0a653586c48d1fb17957155194dd65a01ec6a99
Cited by
176
References
254
Citations by year
2026: 20 · 2025: 21 · 2024: 19 · 2023: 24 · 2022: 23 · 2021: 28 · 2020: 21 · 2019: 19 · 2018: 1
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroscience & Biobehavioral Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institute of Mental Health (K08MH112773)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
depression, inflammation, reward processing, cognitive control, somatic symptoms, neuroinflammation, depression pathogenesis, depression heterogeneity
MeSH terms
Animals, Depression, Depressive Disorder, Humans, Inflammation

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

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