Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

Activation of the parasympathetic nervous system can modulate the activity of the immune system via alterations in vagal release of acetylcholine from T cells.

“Interestingly, evidence suggests that activation of the parasympathetic nervous system also can modulate the activity of the immune system via alterations in vagal release of acetylcholine from T cells (Tracey, 2009).”

• cites Tracey, 2009 sourceDisputed

  The ‘Anatomy of the cholinergic anti-inflammatory pathway’ section says the pathway is functionally neither parasympathetic nor sympathetic, contrary to the claim’s classification. It also describes a hypothesis in which vagus nerve signals prompt splenic nerve endings to release noradrenaline near T cells that produce acetylcholine—not vagal release of acetylcholine from T cells. The paper does support vagal modulation of immune activity, but not the mechanism stated here. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Peripheral and central concentrations of norepinephrine are augmented in individuals with PTSD at baseline.

“Peripheral and central concentrations of norepinephrine are augmented in individuals with PTSD at baseline (Delahanty et al, 2005;Geracioti et al, 2001;Southwick et al, 1999)”

• cites Delahanty et al, 2005 sourceNot checked — no full text of the source
• cites Geracioti et al, 2001 sourceNot checked — no full text of the source
• cites Southwick et al, 1999 sourceDisputed

  The Introduction’s summary says consistent elevations of plasma norepinephrine have not been reported at baseline in people with PTSD; increased noradrenergic activity is generally observed in response to stressors instead. Its baseline-catecholamine discussion notes one study with higher unstimulated plasma norepinephrine, but says at least three studies found similar levels in PTSD and controls. This contradicts the claim that peripheral and central norepinephrine concentrations are generally elevated at baseline. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

In some studies, concentrations of IL-8 and IL-4 are lower in individuals with PTSD.

“In some studies, concentrations of IL-8 (Jergovic et al, 2015;Song et al, 2007b) and IL-4 (Smith et al, 2011;von Kanel et al, 2007) are lower in individuals with PTSD.”

• cites Jergovic et al, 2015 sourceSupported
• cites Song et al, 2007b sourceNot checked — no full text of the source
• cites Smith et al, 2011 sourceSupported

Increased concentrations of CRP are seen in individuals with PTSD.

“Increased concentrations of CRP are also seen in individuals with PTSD (Bersani et al, 2016;Heath et al, 2013;Miller et al, 2001;Plantinga et al, 2013).”

• cites Bersani et al, 2016 sourceNot checked — no full text of the source
• cites Heath et al, 2013 sourceSupported
• cites Miller et al, 2001 sourceNot checked — no full text of the source

Concentrations of IL-6, IL-1β, and TNF-α are elevated with childhood maltreatment.

“Concentrations of IL-6, IL-1β, and TNF-α are elevated with childhood maltreatment (Gouin et al, 2012;Hartwell et al, 2013;Kiecolt-Glaser et al, 2011;Smith et al, 2011;Tietjen et al, 2012).”

• cites Gouin et al, 2012 sourcePartly supported

  The Results report higher IL-6 levels among adults with a childhood abuse history, particularly after multiple daily stressors. TNF-α was only marginally associated with childhood adversity, and abuse did not moderate its response to daily stressors. The Methods list IL-6, TNF-α, and CRP assays, but not IL-1β; the paper therefore does not support the claim for all three cytokines. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Hartwell et al, 2013 sourcePartly supported

  The Results (IL-6, IL1-β, and TNF-α sections; page unavailable) report positive associations between total childhood trauma and all three cytokines in healthy adults. But the claim specifies childhood maltreatment: the Discussion (page unavailable) says there was no association between emotional abuse and basal cytokine levels, and only the IL-6 association with general trauma remained significant after adjustment for multiple tests. The study therefore supports the broader childhood-adversity association, not the claim as stated for maltreatment. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Kiecolt-Glaser et al, 2011 sourcePartly supported

  The Results section ('IL-6 and TNF-α'; page unavailable) reports higher IL-6 with childhood abuse and marginally higher TNF-α overall, with significantly higher TNF-α among abused caregivers. The paper does not report elevated IL-1β, so it does not support the claim for all three cytokines. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

Increased circulating concentrations of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) are significantly associated with trauma exposure.

“Specifically, increased circulating concentrations of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and the acute phase reactant C-reactive protein (CRP) are all significantly associated with trauma exposure as shown in a recent meta-analysis (Tursich et al, 2014).”

• cites Tursich et al, 2014 sourceSupported

Parental separation in early childhood is associated with increased CRP in adulthood.

“Parental separation in early childhood is also associated with increased CRP in adulthood (Lacey et al, 2013;McDade et al, 2013).”

• cites Lacey et al, 2013 sourcePartly supported

  Section 3.2 reports higher CRP at age 44 among participants whose parents separated during childhood. The measure covered separation from birth to age 16 (Section 2.2.2), so the main finding does not specifically establish the association for early childhood. The Discussion says the association did not vary significantly across broad age bands, but cautions that this timing analysis was limited. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites McDade et al, 2013 sourcePartly supported

  The Results (§3.2; page not supplied) report that prolonged parental absence before about age 11 predicted higher CRP in young adulthood in an unadjusted model, but the association weakened after adjustment and differed by infant microbial exposure. The Methods (§2.3; page not supplied) show that parental absence was broader than separation: maternal absences also included employment-related absences and death. The paper therefore supports an association for parental absence, not an unqualified finding specifically about parental separation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Individuals exposed to childhood maltreatment show heightened levels of CRP in adulthood.

“Indeed, individuals who were exposed to childhood maltreatment, as well as those exposed to difficult family and socio-economic circumstances in childhood (Taylor et al, 2006), show heightened levels of CRP in adulthood (Bertone-Johnson et al, 2012;Danese et al, 2007;Lin et al, 2016;Matthews et al, 2014;Rooks et al, 2012;Tietjen et al, 2012).”

• cites Bertone-Johnson et al, 2012 sourcePartly supported

  The Abstract Results report higher adult CRP in women reporting adolescent sexual abuse. CRP was also elevated after childhood sexual abuse, but that result was not statistically significant; physical abuse was not consistently associated with inflammatory markers. The claim generalizes these findings to individuals exposed to childhood maltreatment broadly. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Danese et al, 2007 sourceSupported
• cites Lin et al, 2016 sourceSupported

Elevated CRP is associated with impaired inhibition of fear-potentiated startle in the presence of a safety signal.

“Furthermore, elevated CRP is also associated with impaired inhibition of fear-potentiated startle in the presence of a safety signal, a well-characterized biomarker of PTSD (Jovanovic et al, 2012).”

• cites Jovanovic et al, 2012 sourcePartly supported

  Section 1.5 (page unavailable) describes impaired safety-signal learning and fear inhibition as specific markers of PTSD symptoms, supporting the biomarker description. It presents biomarker status as a suggestion rather than an established fact. The paper does not address the sentence’s association with elevated CRP. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Immune signaling contributes to the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and other neurobiological processes that modulate affective behavior in the face of stressor exposure.

“Immune signaling contributes to the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and other neurobiological processes that modulate affective behavior in the face of stressor exposure (Haroon et al, 2012).”

• cites Haroon et al, 2012 sourceSupported

Exposure to trauma is associated with pro-inflammatory activity.

“Exposure to trauma is associated with pro- inflammatory activity (Tursich et al, 2014).”

• cites Tursich et al, 2014 sourceSupported

Gene expression of the proinflammatory cytokine IL-18 and its receptor IL-18R1 is decreased in individuals with PTSD.

“Gene expression of the proinflammatory cytokine IL-18 and its receptor IL-18R1 is decreased in individuals with PTSD (Mehta et al, 2011;Segman et al, 2005;Zieker et al, 2007).”

• cites Mehta et al, 2011 sourcePartly supported

  The Results sections on qPCR validation and replication report an association between IL18R1 expression and PTSD symptom severity that depends on FKBP5 genotype. The Comment section says IL-18 was reported as differentially expressed in patients with PTSD by Zieker et al. Neither passage establishes that expression of both IL-18 and IL18R1 is decreased in individuals with PTSD. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Segman et al, 2005 sourceNot checked — no full text of the source
• cites Zieker et al, 2007 sourceNot checked — no full text of the source

Increased methylation in the promoter region of IL-18 is associated with the development of PTSD in soldiers following military deployment.

“This decrease in IL-18 gene expression is consistent with epigenetic findings indicating that increased methylation in the promoter region of IL-18 is associated with the development of PTSD in soldiers following military deployment (Rusiecki et al, 2013).”

• cites Rusiecki et al, 2013 sourcePartly supported

  The Discussion reports a significant difference in IL18 promoter methylation changes across deployment between service members who developed PTSD and controls. However, the Results say the increase within cases and their higher post-deployment levels relative to controls were not statistically significant; the claim omits those qualifications. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Immunological aging of T-cell phenotypes has been associated with PTSD.

“Finally, immunological aging of T-cell phenotypes has also been associated with PTSD (Aiello et al, 2016).”

• cites Aiello et al, 2016 sourceSupported

Increased spontaneous production of IL-1 and TNF-α in PBMCs is present in individuals with PTSD compared with healthy controls.

“There has also been one report that increased spontaneous production of IL-1 and TNF-α in PBMCs is present in individuals with PTSD compared with healthy controls (Gola et al, 2013).”

• cites Gola et al, 2013 sourceSupported

Levels of microRNAs involved in immune signaling pathways are dysregulated in PBMCs from individuals with PTSD.

“Furthermore, a recent analysis of microRNA expression in PBMCs from individuals with PTSD revealed that levels of microRNAs involved in immune signaling pathways are dysregulated (Zhou et al, 2014).”

• cites Zhou et al, 2014 sourceSupported

Immune-related methylation profiles are altered in PTSD.

“The changes in inflammatory gene expression that have been described in individuals with PTSD are coincident with alterations in epigenetic markers, as immune-related methylation profiles are altered in PTSD (Heinzelmann and Gill, 2013).”

• cites Heinzelmann and Gill, 2013 sourceSupported

Ex vivo administration of phytohemagglutinin (PHA) to peripheral blood mononuclear cells (PBMCs) results in heightened increases in TNF-α and IL-6 secretion in individuals with PTSD compared with traumatized and non-traumatized controls.

“Ex vivo administration of phytohemagglutinin (PHA), a potent inducer of cytokine production from T cells, to peripheral blood mononuclear cells (PBMCs) results in heightened increases in TNF-α and IL-6 secretion in individuals with PTSD compared with traumatized and non-traumatized controls (Gill et al, 2008).”

• cites Gill et al, 2008 sourcePartly supported

  The Results (Immune System Measures; page not provided) report greater stimulated TNF-α and IL-6 production in women with PTSD than in both trauma and nontrauma controls. But the Methods (Procedures; page not provided) describe diluted whole blood stimulated with PHA plus LPS, not isolated PBMCs treated with PHA alone. The claim also generalizes a finding in women to individuals with PTSD. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Expression of microRNA-125a (MiR-125a) is downregulated in PTSD.

“Specifically, expression of microRNA-125a (MiR-125a) is downregulated in PTSD (Zhou et al, 2014).”

• cites Zhou et al, 2014 sourceSupported

Methylation of mannosidase, alpha class 2C, member 1 (MAN2C1), acid phosphatase 5 (ACP5), and toll-like receptor (TLR) 8 is altered in PTSD.

“Methylation of mannosidase, alpha class 2C, member 1 (MAN2C1), acid phosphatase 5 (ACP5), and tolllike receptor (TLR) 8, which are genes involved in immune function, was found to be altered in PTSD (Smith et al, 2011;Uddin et al, 2011).”

• cites Smith et al, 2011 sourcePartly supported

  The Results section (‘Gene-Specific Changes in DNA Methylation’; page unavailable) reports increased methylation at CpG sites in ACP5 and TLR8 in subjects with PTSD compared with controls. It does not identify MAN2C1 among the genes whose CpG sites met its experiment-wide criteria, and a search for MAN2C1 and its full name found no supporting passage in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Uddin et al, 2011 sourcePartly supported

  The Abstract reports an association between MAN2C1 methylation and lifetime PTSD risk, specifically an interaction with exposure to potentially traumatic events. The Discussion says MAN2C1 was the only candidate gene with a significant interaction; our copy does not identify altered ACP5 or TLR8 methylation in PTSD. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Decreased methylation of immune-related genes TLR1 and TLR3 has been described in individuals with PTSD in a manner related to the severity and burden of the traumatic event.

“Decreased methylation of immune-related genes TLR1 and TLR3 has also been described in individuals with PTSD in a manner related to the severity and burden of the traumatic event (Uddin et al, 2010).”

• cites Uddin et al, 2010 sourcePartly supported

  The Results (page unavailable) identify TLR1 and TLR3 among genes uniquely unmethylated in the PTSD-affected group. They also link lower methylation of immune-related gene sets to a greater number of potentially traumatic events, but do not establish that this burden relationship applies specifically to TLR1 and TLR3. The analysis measures the number of events, not the severity of an event. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Alterations in the transcriptional patterns of expression for genes involved in inflammatory pathways have been associated with PTSD.

“Alterations in the transcriptional patterns of expression for genes involved in inflammatory pathways have also been associated with PTSD (Segman et al, 2005;Yehuda et al, 2009;Zieker et al, 2007).”

• cites Segman et al, 2005 sourceNot checked — no full text of the source
• cites Yehuda et al, 2009 sourcePartly supported

  The Results report genes differentially expressed between participants with and without PTSD, and the Discussion identifies immune-cell function and reduced MHC Class II expression among the findings (page not available). The paper does not characterize these changes as involving inflammatory pathways, so that specific part of the claim is not established by our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Zieker et al, 2007 sourceNot checked — no full text of the source

Expression of the gene for thioredoxin (TXNRD1) is elevated in subjects with PTSD compared with traumatized controls.

“Finally, the expression of the gene for thioredexin (TXNRD1), a protein critical for responding to oxidative stress, is elevated in subjects with PTSD compared with traumatized controls (Logue et al, 2015).”

• cites Logue et al, 2015 sourceSupported

Epigenetic variability in immune function in PTSD is associated with exaggerated immune response to a cytomegalovirus challenge.

“This epigenetic variability in immune function in PTSD is associated with exaggerated immune response to a cytomegalovirus challenge (Uddin et al, 2010).”

• cites Uddin et al, 2010 sourcePartly supported

  The Results report higher CMV-specific antibody levels in people with PTSD than in those without it, and the Discussion links this difference to immune-related epigenetic profiles. But the Methods describe measuring serum antibodies to a persistent virus, not administering a CMV challenge or measuring a response to one. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

PTSD in women is associated with an enrichment of genes involved in inflammatory pathways.

“Results from a single genome-wide association study of PTSD indicate that PTSD in women is associated with an enrichment of genes involved in inflammatory pathways (Guffanti et al, 2013).”

• cites Guffanti et al, 2013 sourceSupported

Lower circulating concentrations of anti-inflammatory cytokines such as IL-2 and IL-4 have been described in GAD patients.

“Lower circulating concentrations of anti-inflammatory cytokines such as IL-2 and IL-4 have also been described in GAD patients (Vieira et al, 2010).”

• cites Vieira et al, 2010 sourcePartly supported

  Section 3.2 reports significantly lower IL-2 and IL-4 release from activated cell cultures derived from people with GAD than from controls. Section 2.5 specifies that cytokines were measured in culture supernatants after in vitro stimulation, not as circulating concentrations in patients. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Enriched expression of genes implicated in innate immunity and INF signaling at baseline pre-deployment is associated with increased risk for PTSD development post-deployment.

“In addition, enriched expression of genes implicated in innate immunity and INF signaling at baseline (pre-deployment) is associated with increased risk for PTSD development post-deployment (Breen et al, 2015).”

• cites Breen et al, 2015 sourceSupported

Lower levels of MiR-125a in PTSD facilitate augmented IFN-γ levels.

“MiR-125a typically acts to decrease IFN-γ secretion from PBMCs, suggesting that lower levels of this microRNA in PTSD facilitate augmented IFN-γ levels.”

• cites Zhou et al, 2014 sourceSupported

Lower levels of the pro-inflammatory cytokine IFN-γ have been found in both GAD and PD patients.

“Interestingly, lower levels of the pro-inflammatory cytokine IFN-γ have been found in both GAD and PD patients (Tukel et al, 2012;Vieira et al, 2010).”

• cites Tukel et al, 2012 sourceNot checked — no full text of the source
• cites Vieira et al, 2010 sourceSupported

Prospective studies have begun to show that higher levels of inflammation prior to trauma exposure increase risk for subsequent development of PTSD following trauma exposure.

“Although no data as yet prospectively demonstrate that chronic PTSD results in augmented inflammation, prospective studies have begun to show that higher levels of inflammation prior to trauma exposure increases risk for subsequent development of PTSD following trauma exposure (Breen et al, 2015;Eraly et al, 2014;Glatt et al, 2013;Tylee et al, 2015).”

• cites Breen et al, 2015 sourceSupported
• cites Eraly et al, 2014 sourceSupported
• cites Glatt et al, 2013 sourceNot checked — no full text of the source

Higher pre-deployment concentrations of CRP increase post-deployment risk for development of PTSD.

“Indeed, higher pre-deployment concentrations of CRP increase postdeployment risk for development of PTSD (Eraly et al, 2014).”

• cites Eraly et al, 2014 sourcePartly supported

  The Abstract Results report that higher pre-deployment CRP predicted greater odds of any post-deployment PTSD symptoms. The Comment describes this as a prospective association and a possible marker of vulnerability, not proof that CRP causes PTSD to develop; the measured outcome was symptoms rather than a PTSD diagnosis. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Prolonged exposure to stressful stimuli that elicit fear and anxiety in PTSD, GAD, PD, and phobias activates central and peripheral immune cells to release cytokines such as IL-1β.

“Prolonged exposure to stressful stimuli that elicit fear and anxiety in PTSD, GAD, PD, and phobias activate both central and peripheral immune cells to release cytokines, such as IL-1β (Koo and Duman, 2008;Maier and Watkins, 1998).”

• cites Koo and Duman, 2008 sourcePartly supported

  The paper states that animal stress exposure increases IL-1β in several brain areas (introductory text indexed under Abstract; no page supplied), and its Results link stressors to central IL-1β. It does not establish that central and peripheral immune cells release IL-1β in PTSD, GAD, panic disorder, or phobias. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Maier and Watkins, 1998 sourceNot checked — no full text of the source

Within a community sample of individuals with and without GAD, only males with GAD showed changes in immune-related gene expression compared with controls.

“Within a community sample of individuals with and without GAD, Wingo and Gibson (2015) found that only males with GAD showed changes in immune-related gene expression compared with controls (Wingo and Gibson, 2015).”

• cites Wingo and Gibson, 2015 sourcePartly supported

  The Abstract reports differential expression of 631 genes in anxious men but none significant in women, and links the altered genes to immune responses. However, Methods §2.2 defines the groups by GAD-7 symptom scores, not by confirmed GAD diagnoses; describing them as individuals with and without GAD overstates what was measured. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Exposure to the Trier Social Stress Test activates the peripheral inflammatory response via increased NFκB transcriptional activity that results in increased circulating concentrations of IL-6.

“For example, exposure to the laboratory Trier Social Stress Test activates the peripheral inflammatory response via increased NFκB transcriptional activity that results in increased circulating concentrations of IL-6 (Bierhaus et al, 2003).”

• cites Bierhaus et al, 2003 sourcePartly supported

  The Results report increased NF-κB binding activity in peripheral blood mononuclear cells after the Trier Social Stress Test. They report increased IL-6 transcription in noradrenaline-treated cultured cells and IL-6 mRNA after immobilization stress in mice, but not increased circulating IL-6 concentrations in the volunteers. No page numbers are available in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Cytokines can impair GR function by disrupting GR translocation and inhibiting downstream GR signaling, including NFκB and mitogen-activated protein kinase cascades.

“Finally, cytokines can impair GR function by disrupting GR translocation and inhibiting downstream GR signaling, including NFκB and mitogen-activated protein kinase cascades (Miller et al, 1999;Pace et al, 2007).”

• cites Miller et al, 1999 sourceNot checked — no full text of the source
• cites Pace et al, 2007 sourcePartly supported

  The Introduction (page unavailable) says cytokines can reduce GR translocation and GR signaling. It identifies NF-κB and MAPK as inflammatory pathways that can disrupt GR function, not as downstream GR-signaling cascades that cytokines inhibit. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Increased norepinephrine production in PTSD in response to stressful or threatening stimuli can induce cytokine release.

“This increased norepinephrine production in PTSD in response to stressful or threatening stimuli can induce cytokine release (Bierhaus et al, 2003).”

• cites Bierhaus et al, 2003 sourcePartly supported

  The Results report that psychosocial stress increased noradrenaline levels in healthy volunteers and that noradrenaline increased IL-6 transcription in cultured monocytes. The paper does not establish this response in people with PTSD or demonstrate cytokine release, as distinct from transcription. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

SNPs in the FKBP5 gene associated with higher FKBP5-mRNA induction upon cortisol release (rs1360780, rs9296158, rs3800373, and rs9470080) are also associated with increased PTSD symptom severity in those with high levels of child abuse.

“Importantly, SNPs in the FKBP5 gene that are associated with higher FKBP5-mRNA induction upon cortisol release (rs1360780, rs9296158, rs3800373, and rs9470080) are also associated with increased PTSD symptom severity in those with high levels of child abuse (Binder et al, 2008).”

• cites Binder et al, 2008 sourcePartly supported

  The Comment and ‘Interaction of FKBP5 Polymorphisms With Child Abuse to Predict PTSD Symptoms’ sections report that all four SNPs interacted with child abuse to predict adult PTSD symptom severity. The Comment distinguishes rs1360780 and rs3800373, which had been linked to higher FKBP5 levels or stronger cortisol-induced mRNA expression, from rs9296158 and rs9470080, which were in strong linkage disequilibrium with them. It does not establish the claimed mRNA-induction association separately for all four SNPs. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

The reciprocal association between decreased levels of FKBP5-mRNA and enhanced GR sensitivity is characteristic of PTSD in trauma survivors.

“The reciprocal association between decreased levels of FKBP5-mRNA and enhanced GR sensitivity is characteristic of PTSD in trauma survivors (Yehuda et al, 2009).”

• cites Yehuda et al, 2009 sourcePartly supported

  The Abstract and Results report reduced FKBP5 expression in participants with PTSD after exposure to the World Trade Center attacks, and describe it as consistent with enhanced GR responsiveness. The Discussion says the association *suggests* a possible link; it does not establish enhanced GR sensitivity directly or show that this pattern is characteristic of trauma survivors generally. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

The subsequent immune response occurs via NFκB-dependent and -independent mechanisms.

“The subsequent immune response occurs via NFκBdependent and -independent mechanisms (Bierhaus et al, 2003;Tan et al, 2007).”

• cites Bierhaus et al, 2003 sourcePartly supported

  The Results and Modulation of NF-B Activation sections describe a stress-related pathway involving NF-κB activation and NF-κB-regulated IL-6 transcription. Our copy does not establish an NF-κB-independent mechanism for the subsequent immune response; the searches for independent pathways found none. Page numbers were not available in the indexed passages. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Tan et al, 2007 sourceNot checked — no full text of the source

Chronic low-grade inflammation characteristic of PTSD and other fear- and anxiety-based disorders can act to further impair GR signaling.

“It is important to emphasize that this chronic lowgrade inflammation characteristic of PTSD and other fearand anxiety-based disorders can act to further impair GR signaling in a number of ways (reviewed in Pace et al (2007)).”

• cites Pace et al (2007) sourceSupported

Motor vagus nerve stimulation attenuates the activation of NFκB following an immune challenge.

“For example, motor vagus nerve stimulation attenuates the activation of NFκB following an immune challenge (Tracey, 2009).”

• cites Tracey, 2009 sourceSupported

Heightened sympathetic tone in the form of increased catecholamine secretion has been described consistently in individuals with PTSD.

“Heightened sympathetic tone in the form of increased catecholamine secretion has been described consistently in individuals with PTSD (Southwick et al, 1999).”

• cites Southwick et al, 1999 sourcePartly supported

  The Introduction’s summary reports increased noradrenergic responsiveness in people with PTSD under stress, supporting the claim’s general point. But it explicitly says consistent elevations in plasma norepinephrine have not been reported at baseline, and the baseline catecholamine section describes mixed findings. The unqualified claim of consistently increased catecholamine secretion overstates the review. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Severe sleep loss has been shown to increase circulating levels of CRP.

“Severe sleep loss has been shown to increase circulating levels of CRP (Meier-Ewert et al, 2004)”

• cites Meier-Ewert et al, 2004 sourceSupported

Hippocampal alterations, including smaller hippocampal volume, are associated with both emotional and cognitive deficits in individuals with PTSD.

“Hippocampal alterations, including smaller hippocampal volume, are associated with both emotional and cognitive deficits in individuals with PTSD (Bremner, 2006).”

• cites Bremner, 2006 sourcePartly supported

  The “Cognitive function and brain structure in PTSD” section reports smaller hippocampal volume in people with PTSD and a correlation with verbal-memory deficits. It does not establish an association between smaller hippocampal volume and emotional deficits; its discussion of emotional responsiveness instead emphasizes the amygdala and medial prefrontal cortex. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Other reports have shown decreased cortisol levels or no differences in HPA axis function in those with GAD, PD, and phobia.

“Although these data suggest that increased HPA axis functioning and GR dysregulation is present in these fear-and anxiety-based disorders, other reports have shown decreased cortisol levels or no differences in HPA axis function in those with GAD, PD, and phobia (Hek et al, 2013;van Veen et al, 2008).”

• cites Hek et al, 2013 sourcePartly supported

  The Results and Table 2 report a lower cortisol awakening response in older adults with GAD, lower total cortisol secretion in those with specific phobia, and no significant differences on several other subtype measures. The paper says there were too few panic disorder cases to assess separately, so it does not establish the claimed pattern for PD. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites van Veen et al, 2008 sourceNot checked — no full text of the source

A recent meta-analysis concluded that all these anxiety disorders are associated with reduced HRV.

“A recent meta-analysis concluded that all these anxiety disorders are all associated with reduced HRV (Chalmers et al, 2014).”

• cites Chalmers et al, 2014 sourcePartly supported

  The Results and Discussion report reduced HRV overall and significant reductions for several specific anxiety disorders. But the Results say findings for OCD were non-significant, so the paper does not support the unqualified claim that all anxiety disorders are associated with reduced HRV. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Inflammation-induced amygdala response may contribute to the association between increased CRP levels and heightened psychophysiological hyperarousal in traumatized individuals with PTSD.

“Furthermore, this inflammation-induced amygdala response may also contribute to the association between increased CRP levels and heightened psychophysiological hyperarousal in traumatized individuals with PTSD (Michopoulos et al, 2015b).”

• cites Michopoulos et al, 2015b sourcePartly supported

  The “Biomarkers of Heightened Inflammation in PTSD” section links increased CRP to exacerbated PTSD symptoms and impaired inhibition of fear-potentiated startle, a psychophysiological measure. The “Neuroanatomical and neuroactivational biomarkers” section separately reports greater amygdala activation in PTSD. Neither section says inflammation induces that amygdala response or that it contributes to the CRP–hyperarousal association; page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

At least with PTSD, increased inflammation levels have remained significant after adjusting for BMI in multiple studies.

“However, at least with PTSD, increased inflammation levels have remained significant after adjusting for BMI in multiple studies (Heath et al, 2013;McCanlies et al, 2011;Spitzer et al, 2010).”

• cites Heath et al, 2013 sourceSupported
• cites McCanlies et al, 2011 sourceNot checked — no full text of the source
• cites Spitzer et al, 2010 sourceNot checked — no full text of the source

Smoking has been linked to a pro-inflammatory state.

“Smoking has been linked to a pro-inflammatory state (Frohlich et al, 2003;Jamal et al, 2014).”

• cites Frohlich et al, 2003 sourceNot checked — no full text of the source
• cites Jamal et al, 2014 sourceSupported

Amygdala activation in response to threatening stimuli is increased in PTSD, GAD, social anxiety disorder, specific phobia, and PD.

“Specifically, amygdala activation in response to threatening stimuli is increased in PTSD, GAD, social anxiety disorder, specific phobia, and PD (Fonzo et al, 2015;Killgore et al, 2014;Monk et al, 2008).”

• cites Fonzo et al, 2015 sourcePartly supported

  The Discussion (p. 6) reports increased amygdala activation to fearful faces in GAD, social anxiety disorder and panic disorder. The paper does not report a finding for specific phobia; it says its finding may not generalise to PTSD, although findings for PTSD generally suggest a similar abnormality (p. 8). (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Killgore et al, 2014 sourcePartly supported

  The Results (page not provided) report greater amygdala activation to masked fearful versus neutral faces for the three anxiety disorders combined, with a significant individual comparison for PTSD. The Discussion describes prior evidence for social anxiety disorder, specific phobia, and panic disorder, but says GAD was not included and discusses it only speculatively. The paper therefore does not establish the claim for every disorder listed. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Monk et al, 2008 sourcePartly supported

  The Comment section (page not provided) reports greater amygdala activation to briefly displayed, masked angry faces in youth with GAD than in comparison subjects. The paper also reports prior findings in PTSD and discusses social phobia, but the passages do not establish the claim for specific phobia or PD. Its own finding is limited to pediatric GAD under a particular threat-presentation condition. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

A proinflammatory state may serve as an underlying biological mechanism by which PTSD and other fear- and anxiety-based disorders are highly co-morbid with CVD and metabolic syndrome, as well as other physical illnesses.

“A proinflammatory state may serve as an underlying biological mechanism by which PTSD and other fear-and anxietybased disorders are highly co-morbid with CVD (Boscarino and Chang, 1999a) and metabolic syndrome (Weiss et al, 2011), as well as other physical illnesses (Boscarino, 2004).”

• cites Boscarino and Chang, 1999a sourceNot checked — no full text of the source
• cites Weiss et al, 2011 sourcePartly supported

  The Discussion (page unavailable) reports an association between current PTSD and metabolic syndrome, supporting the part of the sentence attached to Weiss et al. It proposes stress-response and HPA-axis pathways, but does not identify a proinflammatory state as the underlying mechanism or establish the association for other fear- and anxiety-based disorders. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Boscarino, 2004 sourceNot checked — no full text of the source

Heightened amygdala response to stress is associated with increased IL-6 production.

“This heightened amygdala response to stress is associated with increased IL-6 production (Inagaki et al, 2012;Muscatell et al, 2015).”

• cites Inagaki et al, 2012 sourcePartly supported

  The Results (Behavioral Analyses; page unavailable) report increased IL-6 after endotoxin, and the Results (Effect of Condition and Stimulus Type on Amygdala Activity; page unavailable) report heightened amygdala responses to socially threatening images in the endotoxin group. The paper does not establish that individuals with greater amygdala responses produced more IL-6, or that a stress response increased IL-6; its reported amygdala correlation is with feelings of social disconnection. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Muscatell et al, 2015 sourceSupported

Low-grade inflammation may also facilitate the expression of behavioral co-morbidities, such as depression, that are characterized by alterations in stress pathways and neurotransmitter systems.

“Furthermore, low-grade inflammation may also facilitate the expression of behavioral co-morbidities, such as depression, that are characterized by alterations in stress pathways and neurotransmitter systems (Haroon et al, 2012).”

• cites Haroon et al, 2012 sourceSupported

Administration of IFN-α for the treatment of hepatitis C increases glutamate to creatinine levels in the dACC that correlate with anhedonia and fatigue.

“For instance, administration of IFN-α for the treatment of hepatitis C increases glutamate to creatinine levels in the dACC that correlate with anhedonia and fatigue (Haroon et al, 2014).”

• cites Haroon et al, 2014 sourcePartly supported

  The Abstract reports that IFN-α treatment in patients with hepatitis C increased glutamate normalized to creatine (Glu/Cr) in the dACC. The Correlations section reports an association between dACC Glu/Cr changes and overall depression severity across treated patients and controls, but not within either group alone; it reports no significant association with fatigue subscales and does not establish a dACC association with anhedonia. (LLM, conf=0.92)

  Experimental — accuracy not yet measured

Activation of the ventral mPFC (including the sgACC and the orbitofrontal cortex) due to a grief-elicitation task in women undergoing bereavement stress is associated with increased IL-1β and TNF receptor II.

“Activation of the ventral mPFC (including the sgACC and the orbitofrontal cortex) due to a grief-elicitation task in women undergoing bereavement stress is associated with increased IL-1β and TNF receptor II (TNF-II; O'Connor et al, 2009).”

• cites O'Connor et al, 2009 sourceSupported

Increased CRP and IL-6 is associated with decreased functional connectivity between the ventral mPFC and the striatum.

“Similarly, increased CRP and IL-6 is associated with decreased functional connectivity between the ventral mPFC and the striatum (Felger et al, 2015).”

• cites Felger et al, 2015 sourceSupported

Functional connectivity between the sgACC and the amygdala and mPFC is reduced upon typhoid vaccination in a manner that was associated with vaccine-induced increases in IL-6.

“Functional connectivity between the sgACC and the amygdala and mPFC is also reduced upon typhoid vaccination in a manner that was associated with vaccine-induced increases in IL-6 (Harrison et al, 2009a).”

• cites Harrison et al, 2009a sourceSupported

Typhoid vaccination results in heightened activation of the dACC that is concurrent with increased blood flow during a Stroop task.

“Typhoid vaccination also results in heightened activation of the dACC that is concurrent with increased blood floor during a Stroop task (Eisenberger and Lieberman, 2004;Harrison et al, 2009b).”

• cites Eisenberger and Lieberman, 2004 sourceNot checked — no full text of the source
• cites Harrison et al, 2009b sourcePartly supported

  The Results section, “Maintenance of Cognitive Performance Under Inflammation Recruits an Extended Frontal Cortical Network” (page unavailable), reports greater recruitment of midcingulate cortex during demanding Stroop trials after typhoid vaccination than after placebo; it does not identify that vaccine-related activation specifically as dACC. A separate Results section reports increased mean arterial blood pressure, not increased blood flow during the task. Thus the vaccination-related cingulate activation is supported, but the anatomical specificity and concurrent blood-flow claim are not. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Women with PTSD due to interpersonal trauma show increased dACC activity in response to viewing threatening faces.

“Women with PTSD due to interpersonal trauma also show increased dACC activity in response to viewing threatening facing (Eisenberger et al, 2005).”

• cites Eisenberger et al, 2005 sourceCould not verify

  The Neuroimaging Data section (p. 6) reports a correlation between neuroticism and dACC activity during an oddball task, not a response to threatening faces. Searches for PTSD, interpersonal trauma, and threatening faces found no passage addressing the claimed finding in women. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Endotoxin administration in healthy controls results in augmented social pain-related neural activity in the dACC that is associated with increases in IL-6 of females but not males.

“Similarly, endotoxin administration in healthy controls results in augmented social pain-related neural activity in the dACC that is associated with increases in IL-6 of females but not males (Eisenberger et al, 2005)”

• cites Eisenberger et al, 2005 sourceCould not verify

  The Neuroimaging Data section (p. 6) examines dACC responses to oddball trials in relation to neuroticism, not social pain after endotoxin administration. Searches for endotoxin, IL-6, social pain, and sex differences found no passage addressing the attributed finding. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Exposure to a laboratory stressor that increases IL-6 concentrations peripherally was associated with increased functional connectivity between the dorsomedial PFC and the amygdala in a manner that was correlated with IL-6.

“Finally, exposure to a laboratory stressor that increases IL-6 concentrations peripherally was associated with increased functional connectivity between the dorsomedial PFC and the amygdala in a manner that was correlated with IL-6 (Muscatell et al, 2015).”

• cites Muscatell et al, 2015 sourceSupported

Endotoxin administration also augmented glucose metabolism in the insula as determined by positron emission tomography neuroimaging.

“Endotoxin administration also augmented glucose metabolism in the insula as determined by positron emission tomography neuroimaging (Hannestad et al, 2012).”

• cites Hannestad et al, 2012 sourceSupported

Activation of the sgACC in response to typhoid vaccination is increased concurrently with mood deterioration.

“Similarly, activation of the sgACC in response to typhoid vaccination is increased concurrently with mood deterioration (Harrison et al, 2009a).”

• cites Harrison et al, 2009a sourceSupported

Increased CRP in depression is also associated with heightened glutamate levels within the basal ganglia.

“Increased CRP in depression is also associated with heightened glutamate levels within the basal ganglia (Haroon et al, 2016).”

• cites Haroon et al, 2016 sourceSupported

A meta-analysis indicates that reduced volume of the ventral ACC and the inferior frontal gyrus is common to anxiety disorders (social anxiety, GAD, PD, agoraphobia, and specific phobia).

“A meta-analysis indicates that reduced volume of the ventral ACC and the inferior frontal gyrus is common to anxiety disorders (social anxiety, GAD, PD, agoraphobia, and specific phobia; Shang et al, 2014).”

• cites Shang et al, 2014 sourcePartly supported

  The Discussion reports reduced gray-matter volume in the right ventral ACC and left inferior frontal gyrus across the anxiety subgroups analyzed. However, the Methodology (Enrollment of Studies) says no voxel-based morphometry research on specific phobias had been reported, so the finding does not establish that the reduction is common to specific phobia. (LLM, conf=0.93)

  Experimental — accuracy not yet measured

Individuals with neuroticism and high trait anxiety show increased dACC activation.

“Individuals with neuroticism (Eisenberger et al, 2005) and high trait anxiety (Paulus et al, 2004) also show increased dACC activation.”

• cites Eisenberger et al, 2005 sourceSupported
• cites Paulus et al, 2004 sourceNot checked — no full text of the source

Women with PTSD show decreased activation of the insula in response to shifts in interoceptive responses.

“For instance, women with PTSD show decreased activation of the insula in response to shifts in interceptive responses (Simmons et al, 2009)”

• cites Simmons et al, 2009 sourceSupported

Endotoxin-induced increases in IL-6 and TNF-α are correlated with greater feelings of depressed mood and social disconnection only in women.

“endotoxin-induced increases IL-6 and TNF-α are correlated with greater feelings of depressed mood and social disconnection only in women (Moieni et al, 2015)”

• cites Moieni et al, 2015 sourcePartly supported

  The “Relationships between Cytokines and Affective and Social Responses” section reports that increases in both IL-6 and TNF-α correlated with greater social disconnection in women but not men. It also states that neither cytokine’s increase was significantly correlated with depressed mood in either sex, so the depressed-mood part of the claim is unsupported. (LLM, conf=0.92)

  Experimental — accuracy not yet measured

Overactivity of the SNS and decreased activity of the parasympathetic nervous system in fear-and anxiety-based disorders increases the release of pro-inflammatory cytokines.

“The overactivity of the SNS and decreased activity of the parasympathetic nervous system in fear-and anxiety-based disorders increases the release of pro-inflammatory cytokines.”

• cites Felger et al (2016) sourceCould not verify

  The Introduction and Discussion describe how inflammation and cytokines relate to reward circuitry in depression, not how autonomic activity affects cytokine release. Searches for sympathetic and parasympathetic activity, fear- or anxiety-based disorders, and autonomic mechanisms found no passage addressing the claimed pathway. Page numbers were not available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

C-reactive protein is increased in generalized anxiety disorder (GAD).

“| C-reactive protein | Increased in GAD | Bankier et al (2008),Copeland et al (2012), and Wagner et al (2015) |”

• cites Bankier et al (2008) sourceNot checked — no full text of the source
• cites Copeland et al (2012) sourceSupported
• cites Wagner et al (2015) sourcePartly supported

  The Introduction says that small clinical studies suggest increased inflammatory activity in GAD, but it does not identify C-reactive protein as the increased marker. Its cited GAD study concerns C-reactive protein in patients with stable coronary heart disease, while this paper’s own Results report increased C-reactive protein for agoraphobia, not GAD. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Other forms of behavioral interventions that have been used for the treatment of fear- and anxiety-based disorder, such as community-based educational intervention, exercise, yoga, and meditation, have also been associated with decreases in inflammation.

“Other forms of behavioral interventions that have been used for the treatment of fear-and anxiety-based disorder, such as community-based educational intervention, exercise, yoga, and mediation, have also been associated with decreases in inflammation (Bower and Irwin, 2016;Pace et al, 2009;Villablanca et al, 2015).”

• cites Bower and Irwin, 2016 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites Pace et al, 2009 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites Villablanca et al, 2015 sourceNot checked — no full text of the source

Interleukin-2 is decreased in generalized anxiety disorder (GAD).

“| Interleukin-2 | Decreased in GAD | Koh and Lee (2004),Rapaport and Stein (1994), and Vieira et al (2010) |”

• cites Koh and Lee (2004) sourceNot checked — no full text of the source
• cites Rapaport and Stein (1994) sourceNot checked — no full text of the source
• cites Vieira et al (2010) sourceSupported

Suppressed ability of glucocorticoids to inhibit inflammatory processes in chronic stress states contributes to a pro-inflammatory state that can influence neurotransmitter systems, neurocircuitry, and affective behavior.

“Suppressed ability of glucocorticoids to inhibit inflammatory processes in these chronic stress states also contributes to a pro-inflammatory state that can influence neurotransmitter systems, neurocircuitry, and finally, affective behavior.”

• cites Felger et al (2016) sourcePartly supported

  The Introduction and Discussion (pages unavailable) link inflammation to altered reward circuitry, reduced dopamine release, and anhedonia. Our copy does not support the claim that chronic stress suppresses glucocorticoids’ ability to inhibit inflammation; searches for glucocorticoids and chronic stress found no passage addressing that mechanism. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

There is a clear sex difference in the prevalence of PTSD and other fear-and anxiety-based disorders.

“there is a clear sex difference in the prevalence of PTSD and other fear-and anxiety-based disorders (Kessler et al, 1995;McLean et al, 2011)”

• cites Kessler et al, 1995 sourceNot checked — no full text of the source
• cites McLean et al, 2011 sourceSupported

Exposure to trauma and acute stressors in individuals with fear-and anxiety-based disorders may facilitate increased immune activity in both the periphery and the central nervous system (CNS) via stress and trauma effects on neuroendocrine systems and the sympathetic nervous system (SNS).

“Exposure to trauma and acute stressors in individuals with fear-and anxiety-based may facilitate increased immune activity in both the periphery and the central nervous system (CNS) via stress and trauma effects on neuroendocrine systems and the sympathetic nervous system (SNS).”

• cites Felger et al (2016) sourceCould not verify

  Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

ACE-I/ARBs are capable of reducing neuroinflammation.

“However, these agents are also capable of reducing neuroinflammation (Benicky et al, 2011;Welty et al, 2015)”

• cites Benicky et al, 2011 sourcePartly supported

  The Discussion reports that ARBs reduced inflammatory responses in the brains of normotensive rats, supporting the ARB portion of the claim. The paper does not establish that ACE inhibitors reduce neuroinflammation; its findings concern AT1 receptor blockers. No page numbers are available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Welty et al, 2015 sourcePartly supported

  The Hypertension section on ACE inhibitors and ARBs says these agents inhibit inflammatory cytokine formation and describes anti-inflammatory effects involving T cells and monocytes (page not provided). It does not establish that they reduce neuroinflammation specifically. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Tumor necrosis factor-α increases over time in agoraphobia.

“| Tumor necrosis factor-α | Increased in GAD and PD | Hoge et al (2009),Vieira et al (2010), and Wagner et al (2015) |”

• Also stated in: § Treatment Implications and Future Directions · plain

  “| | Increases over time in agoraphobia | |”

• cites Hoge et al (2009) sourceNot checked — no full text of the source
• cites Vieira et al (2010) sourcePartly supported

  The Discussion reports higher TNF-α release from activated cell cultures of individuals with generalized anxiety disorder. It does not report that TNF-α increases over time in agoraphobia, nor does it establish the citing table’s panic-disorder finding. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Wagner et al (2015) sourceSupported

Cytokines may contribute to the maintenance of fear-and anxiety-based symptoms by affecting the activity and connections of brain regions implicated in the etiology of these disorders, including the amygdala, hippocampus, insula, medial prefrontal cortex (mPFC), and the anterior cingulate (ACC).

“Cytokines may contribute to the maintenance of fear-and anxiety-based symptoms by affecting the activity and connections of regions of the brain implicated in the etiology of these disorders, including the amygdala, hippocampus, insula, medial prefrontal cortex (mPFC), and the anterior cingulate (ACC).”

• cites Felger et al (2016) sourcePartly supported

  The Discussion reports an association between inflammatory markers and decreased connectivity between the striatum and ventromedial prefrontal cortex in depressed patients. It links that connectivity to anhedonia and psychomotor slowing, not to maintenance of fear- or anxiety-based symptoms. The cited passages do not establish the claimed effects across the amygdala, hippocampus, insula, and anterior cingulate. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Interleukin-2 is increased in panic disorder (PD).

“| Interleukin-2 | Decreased in GAD | Koh and Lee (2004),Rapaport and Stein (1994), and Vieira et al (2010) |”

• Also stated in: § Treatment Implications and Future Directions · plain

  “| | Increased in PD | |”

• cites Koh and Lee (2004) sourceNot checked — no full text of the source
• cites Rapaport and Stein (1994) sourceNot checked — no full text of the source
• cites Vieira et al (2010) sourceSupported

Dietary intake and the microbiome are potent modulators of inflammatory pathways.

“Finally, it is important to note that dietary intake and the microbiome are potent modulators of inflammatory pathways (Kiecolt-Glaser, 2010;Petra et al, 2015)”

• cites Kiecolt-Glaser, 2010 sourcePartly supported

  The Abstract and ‘Diet and Inflammation’ section state that dietary components and dietary patterns influence inflammatory pathways. The discussion of bacterial endotoxins after high-fat meals does not establish that the microbiome itself modulates those pathways; the microbiome part of the claim is not supported by this paper. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Petra et al, 2015 sourceSupported

Only one study has been conducted on immune-related gene expression in GAD.

“To our knowledge, only one study has been conducted on immune-related gene expression in GAD.”

Findings have been equivocal with regard to peripheral cytokine levels in anxiety disorders.

“Findings have also been equivocal with regard to peripheral cytokine levels.”

Studies of potential genetic and epigenetic alterations of immune function in relation to anxiety disorders are scarce.

“Similarly, studies of potential genetic and epigenetic alterations of immune function in relation to anxiety disorders are scarce.”

No data as yet prospectively demonstrate that chronic PTSD results in augmented inflammation.

“Although no data as yet prospectively demonstrate that chronic PTSD results in augmented inflammation, prospective studies have begun to show that higher levels of inflammation prior to trauma exposure increases risk for subsequent development of PTSD following trauma exposure (Breen et al, 2015;Eraly et al, 2014;Glatt et al, 2013;Tylee et al, 2015).”

Evidence with regard to immune function or genetic mechanisms in relation to anxiety disorders remains unclear.

“Looking beyond inflammatory marker levels, evidence with regard to immune function or genetic mechanisms in relation to anxiety disorders remains unclear.”

Our review of the literature did not identify any studies examining associations between social phobia or specific phobias and inflammation.

“Our review of the literature did not identify any studies examining associations between social phobia or specific phobias and inflammation.”

There are reports of increased concentrations of IL-4, IL-8, and IL-10 in those with PTSD.

“However, there are also reports of increased concentrations of IL-4, IL-8, and IL-10 in those with PTSD (Guo et al, 2012).”

• cites Guo et al, 2012 sourceNot checked — no full text of the source

Exposure to trauma in childhood is associated with increased risk for developing PTSD and other psychiatric conditions.

“Importantly, exposure to trauma in childhood is associated with increased risk for developing PTSD and other psychiatric conditions (Edwards et al, 2003).”

• cites Edwards et al, 2003 sourceNot checked — no full text of the source

Central levels of IL-6 in cerebrospinal fluid are elevated in PTSD.

“Central levels of IL-6 in cerebrospinal fluid have also been found to be elevated in PTSD (Baker et al, 2001).”

• cites Baker et al, 2001 sourceNot checked — no full text of the source

There are data suggesting no relationship between PTSD and heightened inflammation.

“Although these data together collectively indicate that PTSD is associated with increases in pro-inflammatory markers, there are also data suggesting that there is no relationship between PTSD and heightened inflammation.”

• Also stated in: § Immune gene transcription, expression, and methylation changes in PTSD. · plain

  “However, not all studies addressing this relationship have reported a positive association between increased inflammation and PTSD (McCanlies et al, 2011;Sondergaard et al, 2004;von Kanel et al, 2007).”

• cites McCanlies et al, 2011 sourceNot checked — no full text of the source
• cites Sondergaard et al, 2004 sourceNot checked — no full text of the source
• cites von Kanel et al, 2007 sourceNot checked — no full text of the source

Combining concentrations of IL-1β, IL-6, TNF-α, IFN-γ, and CRP into a single pro-inflammatory score indicates that inflammation is elevated in PTSD.

“Combining concentrations of IL-1β, IL-6, TNF-α, IFN-γ, and CRP into a single pro-inflammatory score also indicated that inflammation is elevated in PTSD (Lindqvist et al, 2014b).”

• cites Lindqvist et al, 2014b sourceNot checked — no full text of the source

IL-4 concentrations have been correlated negatively with total hyperarousal symptoms.

“IL-4 concentrations have also been correlated negatively with total hyperarousal symptoms (von Kanel et al, 2007).”

• cites von Kanel et al, 2007 sourceNot checked — no full text of the source

Elevated concentrations of pro-inflammatory markers have been observed in individuals with PTSD.

“Elevated concentrations of pro-inflammatory markers have been observed in individuals with PTSD (Guo et al, 2012;Hoge et al, 2009;Table 1, A).”

• Also stated in: § Immune gene transcription, expression, and methylation changes in PTSD. · plain

  “Peripheral levels of cytokines and CRP are elevated in individuals with PTSD.”

• cites Guo et al, 2012 sourceNot checked — no full text of the source
• cites Hoge et al, 2009 sourceNot checked — no full text of the source
• cites Table 1, ANot matched

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

Endotoxin-induced increases in IL-6 are heightened in individuals with PTSD.

“More specifically, endotoxin-induced increases in IL-6 are heightened in individuals with PTSD (Rohleder et al, 2004).”

• cites Rohleder et al, 2004 sourceNot checked — no full text of the source

Production of anti-inflammatory IL-4 and the antiviral IFN-γ in blood following PHA stimulation in men with PTSD is attenuated compared with matched controls without PTSD.

“In contrast, production of anti-inflammatory IL-4 and the antiviral IFN-γ in blood following PHA stimulation in men with PTSD is attenuated compared with matched controls without PTSD (Kawamura et al, 2001).”

• cites Kawamura et al, 2001 sourceNot checked — no full text of the source

Duration of illness was associated positively with pro-inflammatory markers in PTSD.

“Analyses also revealed that the duration of illness was associated positively with pro-inflammatory markers (Passos et al, 2015).”

• cites Passos et al, 2015 sourceNot checked — no full text of the source

Cell-mediated immunity, as assessed with a delayed-type hypersensitivity in vivo skin test, is enhanced in individuals with PTSD.

“Finally, cell-mediated immunity, as assessed with a delayed-type hypersensitivity in vivo skin test, has also been shown to be enhanced in individuals with PTSD (Altemus et al, 2003;Masoudzadeh et al, 2012).”

• cites Altemus et al, 2003 sourceNot checked — no full text of the source
• cites Masoudzadeh et al, 2012Not matched

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

Cross-sectional genetic and epigenetic studies indicate that higher inflammation is associated with increased PTSD severity.

“Overall, the discussed cross-sectional genetic and epigenetic studies indicate that higher inflammation is associated with increased PTSD severity.”

The association between PTSD and inflammation is impacted by other adverse mental and physical health outcomes, including depression and cardiovascular disease.

“The association between PTSD and inflammation is also impacted by other adverse mental and physical health outcomes, including depression (Gill et al, 2010;Maes et al, 1999) and cardiovascular disease (Spitzer et al, 2010;von Kanel et al, 2007), indicating that taking these co-morbid conditions into account when studying the relationship between PTSD and inflammation is critical in future studies.”

• cites Gill et al, 2010 sourceNot checked — no full text of the source
• cites Maes et al, 1999 sourceNot checked — no full text of the source
• cites Spitzer et al, 2010 sourceNot checked — no full text of the source

Heightened baseline inflammatory markers due to genetic variability may serve as a biomarker of PTSD vulnerability.

“However, these genomic findings suggest that heightened baseline inflammatory markers due to genetic variability may serve as a biomarker of PTSD vulnerability.”

Existing findings indicate that PTSD is associated with a pro-inflammatory state.

“Overall, existing findings indicate that PTSD is associated with a pro-inflammatory state.”

Elevated IL-6 concentrations immediately following exposure to motor vehicle collision in child trauma survivors are predictive of elevated risk for PTSD development.

“Elevated IL-6 concentrations immediately following exposure to motor vehicle collision in child trauma survivors are also predictive of elevated risk for PTSD development (Pervanidou et al, 2007).”

• cites Pervanidou et al, 2007 sourceNot checked — no full text of the source

Two studies examining immune function using circulating lymphocyte phenotypic markers in PD patients found evidence that individuals with PD may show alterations in circulating lymphocyte profiles or diminished cell activation.

“Two studies examining immune function using circulating lymphocyte phenotypic markers in PD patients found evidence that individuals with PD may show alterations in circulating lymphocyte profiles or diminished cell activation (Manfro et al, 2000;Rapaport, 1998).”

• cites Manfro et al, 2000Not checked yet

  Not checked in the free run.

• cites Rapaport, 1998 sourceNot checked — no full text of the source

HPA axis activation and subsequent secretion of glucocorticoids in response to stressor exposure typically acts to prevent pro-inflammatory activity via inhibition of NFκB.

“HPA axis activation and subsequent secretion of glucocorticoids in response to stressor exposure typically acts to prevent pro-inflammatory activity via inhibition of NFκB (Rhen and Cidlowski, 2005).”

• cites Rhen and Cidlowski, 2005 sourceNot checked — no full text of the source

Increased inflammation in fear- and anxiety-based disorders is most parsimoniously explained by activation of the stress response.

“The most parsimonious explanation of increased inflammation in fear-and anxiety-based disorders is via the activation of the stress response (Figure 1).”

High IL-8 and low transforming growth factor-β have been shown to be predictors of PTSD in the acute aftermath of trauma.

“High IL-8 and low transforming growth factor-β (TFG-β, normally involved in immunosuppression) have also been shown to be predictors of PTSD in the acute aftermath of trauma (Cohen et al, 2011).”

• cites Cohen et al, 2011 sourceNot checked — no full text of the source

Elevated glucocorticoid receptor (GR) expression levels in lymphocytes occur in tandem with enhanced glucocorticoid sensitivity in PTSD.

“Heightened levels of peripheral and central corticotropin-releasing hormone (CRH; Baker et al, 2005;de Kloet et al, 2008) and elevated glucocorticoid receptor (GR) expression levels in lymphocytes (Matic et al, 2013) occur in tandem with enhanced glucocorticoid sensitivity in PTSD.”

• cites Matic et al, 2013 sourceNot checked — no full text of the source

Higher cortisol awakening response has been described in individuals with PD with agoraphobia.

“Higher cortisol awaking response has been described in individuals with PD with agoraphobia (Vreeburg et al, 2010)”

• cites Vreeburg et al, 2010 sourceNot checked — no full text of the source

Similar studies assessing cytosolic radioligand assays find GR expression to be decreased upon treatment with these same pro-inflammatory signals.

“Similar studies assessing cytosolic radioligand assays find GR expression to be decreased upon treatment with these same pro-inflammatory signals (Miller et al, 1999).”

• cites Miller et al, 1999 sourceNot checked — no full text of the source

Any chronic condition that results in diminished actions of glucocorticoids, and increased sympathetic and decreased parasympathetic activity should occur in tandem with increased inflammation.

“Taken together, these data suggest that any chronic condition that results in the diminished actions of glucocorticoids, and increased sympathetic and decreased parasympathetic activity should occur in tandem with increased inflammation.”

Decreased urinary free cortisol has been described in individuals with PTSD.

“Decreased basal levels of circulating (Yehuda et al, 2005) and urinary free cortisol (Mason et al, 1986) have been described in individuals with PTSD.”

• cites Mason et al, 1986 sourceNot checked — no full text of the source

Increased salivary cortisol concentrations have been associated with late-life GAD.

“and increased salivary cortisol concentrations have been associated with late-life GAD (Mantella et al, 2008).”

• cites Mantella et al, 2008 sourceNot checked — no full text of the source

Expression of GR is increased in whole-cell radioligand binding in vitro studies in response to challenge with pro-inflammatory cytokines (IL-6, TNF-α, and IFN-α).

“First, expression of GR is increased in whole-cell radioligand binding in vitro studies in response to challenge with pro-inflammatory cytokines (IL-6, TNF-α, and IFN-α;Miller et al, 1999).”

• cites Miller et al, 1999 sourceNot checked — no full text of the source

FKBP5 negatively regulates the GR complex by inhibiting ligand binding and nuclear translocation of GR.

“One critical modulator of HPA axis responsivity and glucocorticoid function is FKBP5, a heat-shock protein 90 co-chaperone that functions to negatively regulate the GR complex by inhibiting ligand binding and nuclear translocation of GR ( reviewed in Binder (2009)).”

• cites Binder (2009) sourceNot checked — no full text of the source

Increased expression of FKBP5 following GR activation leads to subsequent reduction in GR sensitivity.

“such that increased expression of FKBP5 following GR activation leads to the subsequent reduction in GR sensitivity (Binder, 2009).”

• cites Binder, 2009 sourceNot checked — no full text of the source

Increased expression and function of adrenergic-β2 receptors described in individuals with PTSD can contribute to increased inflammation in those with the disorder.

“Thus, the increased expression and function of adrenergic-β2 receptors that has been described in individuals with PTSD (Gurguis et al, 1999) can also contribute to increased inflammation in those with the disorder (Table 1).”

• cites Gurguis et al, 1999 sourceNot checked — no full text of the source

Peripheral and central concentrations of norepinephrine are augmented in individuals with PTSD following exposure to threatening stimuli.

“and following exposure to threatening stimuli (Blanchard et al, 1991;Geracioti et al, 2008).”

• cites Blanchard et al, 1991 sourceNot checked — no full text of the source
• cites Geracioti et al, 2008 sourceNot checked — no full text of the source

Hair cortisol levels are elevated in individuals with GAD and PD.

“Hair cortisol levels are elevated in individuals with GAD and PD (Staufenbiel et al, 2013)”

• cites Staufenbiel et al, 2013 sourceNot checked — no full text of the source

HPA axis dysregulation in PTSD facilitates a proinflammatory state.

“HPA axis dysregulation in PTSD facilitates a proinflammatory state.”

Sympathetic activation of the innate immune system acts via nerve fibers that innervate lymphoid organs that coordinate innate immune responses to threat via alterations in adrenergic signaling.

“This sympathetic activation of the innate immune system acts via nerve fibers that innervate lymphoid organs that coordinate the innate immune responses to threat via alterations in adrenergic signaling (Nance and Sanders, 2007;Tan et al, 2007).”

• cites Nance and Sanders, 2007 sourceNot checked — no full text of the source
• cites Tan et al, 2007 sourceNot checked — no full text of the source

PTSD is associated with enhanced glucocorticoid negative-feedback inhibition of the HPA axis as evidenced by increased suppression of cortisol levels following a dexamethasone-suppression test.

“more consistent are the findings that PTSD is associated with enhanced glucocorticoid negative-feedback inhibition of the HPA axis as evidenced by increased suppression of cortisol levels following a dexamethasone-suppression test (Yehuda et al, 1995).”

• cites Yehuda et al, 1995 sourceNot checked — no full text of the source

The proportion of hGRα (active) and hGRβ directly influences the ability of glucocorticoids to activate GR-dependent genes by contributing to glucocorticoid resistance.

“The proportion of hGRα (active) and hGRβ directly influences the ability of glucocorticoids to activate GRdependent genes by contributing to glucocorticoid resistance (Lewis-Tuffin and Cidlowski, 2006).”

• cites Lewis-Tuffin and Cidlowski, 2006 sourceNot checked — no full text of the source

Decreased basal levels of circulating cortisol have been described in individuals with PTSD.

“Decreased basal levels of circulating (Yehuda et al, 2005) and urinary free cortisol (Mason et al, 1986) have been described in individuals with PTSD.”

• cites Yehuda et al, 2005 sourceNot checked — no full text of the source

Chronic problems with sleep, which are characteristic of PTSD and GAD, could contribute to a pro-inflammatory state.

“suggesting that chronic problems with sleep, which is characteristic of PTSD and GAD, could contribute to a pro-inflammatory state.”

CRH levels in GAD and PD are not different from controls.

“For instance, CRH levels in GAD and PD are not different from controls (Fossey et al, 1996;Jolkkonen et al, 1993).”

• cites Fossey et al, 1996 sourceNot checked — no full text of the source
• cites Jolkkonen et al, 1993 sourceNot checked — no full text of the source

Disruptions in regular sleep patterns can have a very detrimental effect on the immune system.

“For example, disruptions in regular sleep patterns can have a very detrimental effect on the immune system (Bryant et al, 2004)”

• cites Bryant et al, 2004 sourceNot checked — no full text of the source

Cortisol nonsuppression in response to dexamethasone occurs in those with agoraphobia and PD.

“and cortisol nonsuppression in response to dexamethasone in those with agoraphobia and PD (Coryell et al, 1989).”

• cites Coryell et al, 1989 sourceNot checked — no full text of the source

Individuals with PTSD and anxiety disorders are more likely to smoke.

“Indeed, individuals with PTSD and anxiety disorders are more likely to smoke (Fu et al, 2007;Morissette et al, 2007).”

• cites Fu et al, 2007Not matched

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

• cites Morissette et al, 2007 sourceNot checked — no full text of the source

Severe sleep loss has been shown to increase circulating levels of IL-6.

“and IL-6 (Vgontzas et al, 1999).”

• cites Vgontzas et al, 1999 sourceNot checked — no full text of the source

Obesity and high BMI are associated with increased concentrations of inflammatory markers, such as CRP and IL-6.

“Obesity and high BMI are also associated with increased concentrations of inflammatory markers, such as CRP and IL-6 (Khaodhiar et al, 2004).”

• cites Khaodhiar et al, 2004 sourceNot checked — no full text of the source

Even mild reductions in sleep quantity can increase inflammation levels.

“Even mild reductions in sleep quantity can increase inflammation levels (Vgontzas et al, 2004)”

• cites Vgontzas et al, 2004 sourceNot checked — no full text of the source

Many behavioral symptoms contribute to inflammatory response and functioning that often co-occur with PTSD and other fear- and anxiety-based disorders.

“It is critical to keep in mind that there are many behavioral symptoms that also contribute to inflammatory response and functioning that often co-occur with PTSD and other fear-and anxiety-based disorders.”

Inflammatory processes within the dACC may serve as a potent mechanism by which behavioral alterations may occur in individuals with fear- and anxiety-based disorders.

“Overall these data indicate that inflammatory processes within the dACC may serve as a potent mechanism by which behavioral alterations may occur in individuals with fear-and anxiety-based disorders.”

Cytokines can also lead to excitotoxicity by altering the function of indoleamine 2,3 dioxygenase, the enzyme that acts to convert tryptophan into kynurenine.

“Cytokines can also lead to excitotoxicity by altering the function of indoleamine 2,3 dioxygenase, the enzyme that acts to convert tryptophan into kynurenine (Schwarcz, 2004).”

• cites Schwarcz, 2004 sourceNot checked — no full text of the source

Peripheral inflammatory stimuli are capable of increasing the activity of the insula.

“Importantly, peripheral inflammatory stimuli are capable of increasing the activity of the insula.”

One biological mechanism by which inflammation influences neural networks critical for the regulation of emotional behavior and fear processes is by altering central neurotransmitter systems.

“One biological mechanism by which inflammation influences neural networks critical for the regulation of emotional behavior and fear processes is by altering central neurotransmitter systems (reviewed in Dunn et al (1999)).”

• cites Dunn et al (1999) sourceNot checked — no full text of the source

The dACC in the etiology of PD is suggested by data that indicate that surgery damage to the dACC can induce panic attacks.

“Finally, the dACC in the etiology of PD is suggested by data that indicate that surgery damage to the dACC can induce panic attacks (Shinoura et al, 2011).”

• cites Shinoura et al, 2011 sourceNot checked — no full text of the source

Increased activity of the insula has also been associated with other anxiety-based disorders.

“Increased activity of the insula has also been associated with other anxiety-based disorders (Paulus and Stein, 2006).”

• cites Paulus and Stein, 2006 sourceNot checked — no full text of the source

Anxiety-prone individuals show heightened insula activity in anticipation of aversive visual stimuli.

“and anxietyprone individuals show heightened insula activity in anticipation of aversive visual stimuli (Simmons et al, 2006).”

• cites Simmons et al, 2006 sourceNot checked — no full text of the source

Injections of TNF-α and IL-6 in the amygdala results in glutamate toxicity that is associated with impaired auditory fear conditioning in rodents.

“However, injections of TNF-α and IL-6 in the amygdala results in glutamate toxicity that is associated with impaired auditory fear conditioning in rodents (Hao et al, 2014;Jing et al, 2015).”

• cites Hao et al, 2014 sourceNot checked — no full text of the source
• cites Jing et al, 2015 sourceNot checked — no full text of the source

Neuroimaging studies in hepatitis C patients indicate that treatment with INF-α results in increased dACC activity that is correlated with visual-spatial-attention errors.

“Neuroimaging studies in hepatitis C patients indicate that treatment with INF-α results in increased dACC activity that is correlated with visual-spatial-attention errors (Capuron et al, 2005).”

• cites Capuron et al, 2005 sourceNot checked — no full text of the source

Inflammatory processes influence neurobiological substrates underlying behavior and emotion characteristic of fear- and anxiety-based disorders.

“It is clear that inflammatory processes influence neurobiological substrates underlying behavior and emotion characteristic of fear-and anxiety-based disorders (Figure 1).”

The lack of specificity in the era of the Research Domain Criteria suggests that inflammation may better serve as a biomarker of specific sub-domains of dysfunction (ie, negative- and positive-valence systems).

“The lack of specificity in the era of the Research Domain Criteria marshaled in by the National Institutes of Mental Health (Cuthbert, 2014) suggests that inflammation may better serve as a biomarker of specific sub-domains of dysfunction (ie, negative-and positivevalence systems).”

• cites Cuthbert, 2014 sourceNot checked — no full text of the source

Reductions in GABA signaling can contribute to glutamate excitotoxicity via inflammatory pathways.

“and reductions in GABA signaling can contribute to glutamate excitotoxicity via inflammatory pathways (Crowley et al, 2016).”

• cites Crowley et al, 2016 sourceNot checked — no full text of the source

Levels of other neurotransmitters are altered in PTSD and other fear- and anxiety-based disorders that may be related to inflammation-induced excitotoxicity.

“It is also important to note that levels of other neurotransmitters are altered in PTSD and other fear-and anxiety-based disorders that maybe related to inflammationinduced exicitotoxicity (Crowley et al, 2016).”

• cites Crowley et al, 2016 sourceNot checked — no full text of the source

Angiotensin-II activity increases CRP and IL-6 release.

“as angiotensin-II activity increases CRP and IL-6 release (Sano et al, 2001;Zhao et al, 2013).”

• cites Sano et al, 2001 sourceNot checked — no full text of the source
• cites Zhao et al, 2013 sourceNot checked — no full text of the source

Increased inflammation is not specific to these disorders, as other mental health problems, such as depression, are also associated with a pro-inflammatory state.

“increased inflammation is not specific to these disorders, as other mental health problems, such as depression, are also associated with a pro-inflammatory state (Dowlati et al, 2010).”

• cites Dowlati et al, 2010 sourceNot checked — no full text of the source

Interleukin-1β is increased in panic disorder (PD).

“| Interleukin-1β | Increased in PD | Brambilla et al (1994) and Hoge et al (2009) |”

• cites Brambilla et al (1994) sourceNot checked — no full text of the source
• cites Hoge et al (2009) sourceNot checked — no full text of the source

Interleukin-6 is increased in panic disorder (PD).

“| Interleukin-6 | Increased in PD | Hoge et al (2009) |”

• cites Hoge et al (2009) sourceNot checked — no full text of the source

Heightened inflammation and increased cytokine production in the face of HPA axis and autonomic nervous system dysregulation is characteristic of fear- and anxiety-based disorders.

“In sum, heightened inflammation and increased cytokine production in the face of HPA axis and autonomic nervous system dysregulation is characteristic of fear-and anxietybased disorders.”

The available data indicate a clear role for inflammation in the etiology and maintenance of fear- and anxiety-based disorders.

“The available data indicate a clear role for inflammation in the etiology and maintenance of fear-and anxietybased disorders”

• AssumptionRests on an assumption: The observed associations between inflammation and fear- and anxiety-based disorders reflect a causal role of inflammation in their etiology and maintenance.