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The Interplay Between Stress, Inflammation, and Emotional Attention: Relevance for Depression



Depression is among the most significant public mental health issues. A growing body of research implicates inflammation in the etiology and pathophysiology of depression. Yet, the results are somewhat inconsistent, leading to burgeoning attempts to identify associations between components of innate immune system involved in inflammation and specific symptoms of depression, including attention to emotional information. Negative attentional bias, defined as a tendency to direct attention toward negatively valenced information, is one of the core cognitive features of depression and is reliably demonstrated in depressed and vulnerable individuals. Altered attentional processing of emotional information and immunological changes are often precipitated by stressful events. Psychological stress triggers inflammatory activity and affective-cognitive changes that play a critical role in the onset, maintenance, and recurrence of depression. Using various designs, recent studies have reported a positive relationship between markers of inflammation and negative attentional bias on behavioral and neural levels, suggesting that the association between inflammation and emotional attention might represent a neurobiological pathway linking stress and depression. This mini-review summarizes current research on the reciprocal relationships between different types of stressors, emotional attention, inflammation, and depression, and discusses potential neurobiological mechanisms underlying these interactions. The integration provided aims to contribute toward understanding how biological and psychological processes interact to influence depression outcomes.
fnins-13-00384 April 19, 2019 Time: 17:29 # 1
published: 24 April 2019
doi: 10.3389/fnins.2019.00384
Edited by:
Deborah Suchecki,
Federal University of São Paulo, Brazil
Reviewed by:
Charles Barnet Nemeroff,
The University of Texas at Austin,
United States
Marisa Toups,
University of Texas Dell
Medical School, United States,
in collaboration with reviewer CBN
Bruno Bonaz,
Centre Hospitalier Universitaire
de Grenoble, France
Viktoriya Maydych
Specialty section:
This article was submitted to
Neuroendocrine Science,
a section of the journal
Frontiers in Neuroscience
Received: 10 January 2019
Accepted: 02 April 2019
Published: 24 April 2019
Maydych V (2019) The Interplay
Between Stress, Inflammation,
and Emotional Attention: Relevance
for Depression.
Front. Neurosci. 13:384.
doi: 10.3389/fnins.2019.00384
The Interplay Between Stress,
Inflammation, and Emotional
Attention: Relevance for Depression
Viktoriya Maydych*
Department Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, TU
Dortmund (IfADo), Dortmund, Germany
Depression is among the most significant public mental health issues. A growing body
of research implicates inflammation in the etiology and pathophysiology of depression.
Yet, the results are somewhat inconsistent, leading to burgeoning attempts to identify
associations between components of innate immune system involved in inflammation
and specific symptoms of depression, including attention to emotional information.
Negative attentional bias, defined as a tendency to direct attention toward negatively
valenced information, is one of the core cognitive features of depression and is reliably
demonstrated in depressed and vulnerable individuals. Altered attentional processing of
emotional information and immunological changes are often precipitated by stressful
events. Psychological stress triggers inflammatory activity and affective-cognitive
changes that play a critical role in the onset, maintenance, and recurrence of depression.
Using various designs, recent studies have reported a positive relationship between
markers of inflammation and negative attentional bias on behavioral and neural levels,
suggesting that the association between inflammation and emotional attention might
represent a neurobiological pathway linking stress and depression. This mini-review
summarizes current research on the reciprocal relationships between different types of
stressors, emotional attention, inflammation, and depression, and discusses potential
neurobiological mechanisms underlying these interactions. The integration provided
aims to contribute toward understanding how biological and psychological processes
interact to influence depression outcomes.
Keywords: inflammation, cytokines, psychological stress, emotional attention, attentional bias, negative bias,
depression, depressive disorders
Depression is a highly prevalent mood disorder in modern society and is associated with significant
impairments in the patients’ quality of life. A multitude of basic research and clinical studies have
been performed, with the aim of understanding the interaction between biological, psychological,
and environmental factors involved in the etiology of depression. There is growing evidence
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Maydych Stress, Inflammation and Emotional Attention
implicating increased levels of markers of inflammation in
the pathogenesis of depressive disorders (Raison et al., 2006).
Inflammation is a part of the innate immune system’s response
to infection or injury. The main mediators of the inflammatory
response, proinflammatory cytokines, such as interleukin (IL)-
1β, interleukin (IL)-1 receptor antagonist (RA), interleukin
(IL)- 6, tumor necrosis factor (TNF)-α, and interferon (IFN)-
γ, have been recently shown to communicate with the brain
and affect neurotransmission, neuroendocrine activity, and
brain structure and functions, thereby inducing emotional,
cognitive, and behavioral changes (Haroon et al., 2012). If the
inflammatory response remains unresolved, the chronic release
of proinflammatory cytokines can promote pathology, including
depression. Different studies using a variety of study designs and
populations have found positive associations between increased
levels of proinflammatory cytokines and symptoms of depression
(Dowlati et al., 2010;Valkanova et al., 2013). However, findings
have not been entirely consistent for all types of depression
(Rothermundt et al., 2001), raising the need for identifying
more specific links between inflammation and different somatic
and affective-cognitive symptoms, rather than merely testing
associations between increased inflammation and categorically
defined depression.
According to cognitive models of depression, one of the
key features of depressed and vulnerable individuals is biased
cognitive processing of emotional and social information.
Cognitive biases manifest themselves in a consistent shift
toward (self-referential) negative or threatening information
in all aspects of cognition, including perception, attention,
interpretation, memory, or sensitivity to feedback (Miskowiak
and Carvalho, 2014). Negatively biased processing of emotional
information is usually regarded both as a neuropsychiatric
symptom and as a lingering trait factor that confers cognitive
vulnerability to depression and may, when triggered by adverse
environmental factors (e.g., stress), initiate the development
or reoccurrence of depression (Ingram et al., 1998). The
following mini-review focuses primarily on one cognitive
domain: attention.
Heightened inflammation and negative attentional bias (AB)
are often the results of psychological stress. Acute stressful
challenges lead to increases in inflammatory activity and
other neurophysiological changes that modulate affective,
cognitive, and behavioral processes (Allen et al., 2014;
Slavich and Irwin, 2014). Chronic exposure to stressors causes
endocrine and immune system dysfunction that contributes
to sustained low-grade inflammation, which is involved in
the pathogenesis of depressive symptoms (Rohleder, 2014). In
parallel, acute stress has been shown to trigger affective and
cognitive changes similar to biased information processing
characteristic to depression (Gotlib and Joormann, 2010).
This evidence has recently led to promising attempts to
investigate interactions between emotional attention and
inflammation in the context of stress, thereby identifying
specific neurocognitive pathways that may be relevant for the
etiology of depression and development of novel treatments.
The aim of this mini-review is to summarize independent lines
of inquiry focusing on the effects of stress (1) on inflammation
and (2) emotional attention as well as the potential link
between stress-inflammation and stress-cognition pathways
(3), and depression.
A considerable body of evidence suggests that individuals
with diagnosed depression exhibit significantly higher
levels of IL-1, IL-6, TNF-α, and C-reactive protein (CRP)
compared to non-depressed counterparts (Howren et al., 2009;
Dowlati et al., 2010). Concurrently, depressive symptoms
are more frequent in patients with conditions involving
inflammation (e.g., autoimmune diseases) and can be reversed
through the use of anti-inflammatory drugs (Kojima et al.,
2009;Köhler et al., 2014). Notably, increased inflammatory
activity has been documented only in some patients with
depression. This indicates that the depression-inflammation
link may be modulated by further vulnerability factors,
such as genes or cognitive vulnerability. Alternatively,
since depression is a heterogeneous disorder, it is also
plausible that the association between cytokine-mediated
inflammatory processes and depression is more nuanced
in terms of the groups of depressive symptoms (somatic
vs. affective-cognitive). In support of this notion, a large
data set has documented mechanistic links between somatic
symptoms of depression and increased inflammation in animals
and humans (DellaGioia and Hannestad, 2010); however,
studies are lacking in affective-cognitive changes related to
inflammatory activity. There is some evidence that inflammatory
processes may have differential effects on somatic and affective-
cognitive depressive symptoms that are based on distinct
neurophysiological mechanisms. For example, studies examining
the development of depressive symptoms during the course
of IFN-αtherapy found that all patients developed somatic
symptoms, including fatigue, altered sleep and appetite, motor
slowing, during the first weeks of therapy (Capuron and
Miller, 2004). In contrast, only 30–50% of patients developed
affective-cognitive symptoms such as negative mood, anhedonia,
or cognitive impairment during the later stages of therapy.
Strikingly, the development of this group of symptoms could
be prevented by prophylactic antidepressant administration
(Musselman et al., 2001).
There is considerable evidence that psychological stress can
activate the inflammatory response. Different types of stressors
are capable of eliciting increases in inflammatory activity in
a manner that may promote depressive symptoms (Slavich
and Irwin, 2014). Moreover, the link between stressor-evoked
increases in CRP and proinflammatory cytokines and depression
appears to be bidirectional, as chronic stressors and current
depressive symptoms, both associated with neurophysiological
changes (e.g., glucocorticoid resistance), were found to increase
stress reactivity, including cytokine changes in response to
stressful challenges.
One of the most robust predictors of increased levels of
proinflammatory cytokines is early life adversity (ELA). Usually
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indicated by parental maltreatment and low socioeconomic
status during childhood, ELA is considered as a chronic and
severe stressor causing long-lasting psychological and biological
abnormalities that considerably increase the risk of depression
(Hostinar et al., 2018). Psychological alterations are manifested
in exaggerated reactivity to negative information and stress;
biological abnormalities include HPA axis activity dysregulation
(in most cases hyperactivity leading to glucocorticoid resistance),
low parasympathetic activity, and frontolimbic circuit alterations
that promote reactivity to threatening stimuli (Callaghan
and Tottenham, 2016). For example, individuals exposed to
ELA showed stronger increases in proinflammatory cytokines
in response to laboratory stress than those who were not
(Pace et al., 2006). Moreover, exposure to ELA was prospectively
and retrospectively associated with an increased inflammation
in later life (Danese et al., 2008;Kiecolt-Glaser et al., 2011;
Coelho et al., 2014).
The causal role of stress in inflammatory activity was also
examined in laboratory settings that enable the assessment of
temporal patterns of cytokine responses and use of standardized
stress induction procedures such as the Trier Social Stress Test
(TSST) (Kirschbaum et al., 1993;Slavich and Irwin, 2014).
Laboratory studies showed that acute stress was associated
with significant increases in IL-1β(Yamakawa et al., 2009),
IL-1RA and IL-6 (Goebel et al., 2000;O’Donnell et al.,
2008;Hackett et al., 2012), and TNF-α(O’Donnell et al.,
2008), with IL-β, IL-6, and TNF-αdemonstrating the most
robust increases (Marsland et al., 2017). At the same time,
higher cytokine levels were reported to be associated with
increases in negative mood and anxiety in some studies
(Yamakawa et al., 2009;Moons et al., 2010;Carroll et al.,
2011). The notion that increases in inflammatory activity
can lead to negative emotional states was also supported
by studies that induced low-grade inflammation through
the injection of bacterial endotoxin (i.e., lipopolysaccharide,
LPS) or vaccines (i.e., flu, typhoid). Stimulated increases in
proinflammatory cytokines were associated with symptoms such
as fatigue, negative mood, anhedonia, cognitive impairment,
social withdrawal, motor slowing – a variety of symptoms
collectively referred to as sickness behavior and resembling
those of affective-cognitive and somatic symptoms of depression
(Dantzer et al., 2008;Eisenberger et al., 2010). Moreover,
the associations between inflammatory activity and sickness
behavior were not restricted to the laboratory, but also
predicted depressive symptoms and cognitive impairment 1 week
later (Kuhlman et al., 2018). Similarly, increases in IL-1β
in response to TSST predicted the increase of depressive
symptoms 1 year later (Aschbacher et al., 2012). Individuals
with diagnosed depression have demonstrated stronger increases
in proinflammatory cytokines in response to laboratory stress
than non-depressed individuals (Weinstein et al., 2010;Fagundes
et al., 2013), indicating an increased inflammatory stress
responsiveness in depression. Although the aforementioned
studies provide interesting findings, the ecological validity of
most results is limited due to laboratory settings and mainly
samples of healthy young adults. Future research could seek
to examine whether naturalistic stressor-induced increases in
proinflammatory cytokines are prospectively associated with
depressive symptoms.
Cognitive symptoms of depression include attentional biases
(AB) toward negative information (Mathews and MacLeod,
2005). A number of studies using different attention allocation
tasks (MacLeod et al., 1986) demonstrated that compared
to non-depressed counterparts, depressed individuals exhibit
increased difficulty in disengaging their attention from negative
stimuli than from positive or neutral stimuli, especially when
negative material is related to depression (e.g., feelings of
worthlessness, guilt) (Gotlib et al., 2004a,b;Koster et al., 2005;
Caseras et al., 2007). Negative AB has been also documented in
patients with remitted depression and in individuals exposed to
ELA (Luecken and Appelhans, 2005;Joormann and Gotlib, 2007;
Raymond et al., 2018).
The common assumption of cognitive stress-diathesis models
is that depression is a result of the interaction between cognitive
vulnerability and stressful life events (Ingram et al., 1998).
Therefore, given cognitive vulnerability, experiencing stressful
events can initiate a depressive episode. Although the causal
role of stress and cognitive biases that jointly increase the
subsequent depression risk is theoretically now well-established,
surprisingly few studies have examined this etiological pathway
with assessments of stressful events and attention measures
that do not rely on the participants’ self-report. A number
of laboratory-based studies have examined whether laboratory
stress would increase negative AB and whether attention shift
would be associated with mood change. Indeed, AB toward
negative vs. neutral material has been shown to be increased
after a stressful challenge (Ellenbogen et al., 2002;Tsumura
and Shimada, 2012). Moreover, attention shift toward negative
information was associated with mood lowering (Ellenbogen
et al., 2002, 2006) cortisol responses (Ellenbogen et al., 2010;
Roelofs et al., 2007) in healthy participants and slower stress
recovery in a depressed cohort (Sanchez et al., 2017). Although
these results suggest a causal link between stressor-evoked AB
and negative mood, the main limitation of this work is that
stress effects on AB and mood change reflect short-term prime
effects rather than providing ecologically valid evidence of the
stress-diathesis hypothesis. To examine the long-term effects,
several studies examined whether baseline or stressor-related
negative AB shifts would prospectively predict depressive
symptoms. These studies reported that AB shift following
induction of negative mood interacted with subsequent stressful
events in predicting increases in dysphoria 7 weeks later
in dysphoric students (Beevers and Carver, 2003). Similarly,
negative AB was predictive of the exacerbation of depressive
symptoms in adults with subclinical depression after 5 weeks
(Disner et al., 2017). Finally, a significant interaction effect
of stressful life events and dysfunctional attitudes on clinical
depression incidence after 12 months has been reported
(Lewinsohn et al., 2001).
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As outlined in previous sections, distinct lines of research
show that different stressors can trigger inflammatory activity
and increase the attentional processing of negative information.
Both inflammatory processes and cognitive stressor-evoked
changes were associated with mood lowering and an increase in
anxiety and depressive symptoms. Stressor-evoked elevations in
proinflammatory cytokines and attention shift toward negative
information can represent stress responses at multiple levels that
independently contribute to depressive symptoms. Alternatively,
inflammatory and cognitive stress responses may act together,
potentiating one another’s impact on promoting depression. The
following section provides a summary of studies that examined
the relationship between AB and markers of inflammation.
To analyze an association between negative AB and increased
inflammatory activity, several cross-sectional and clinical studies
examined performance in attention tasks using emotional
material and tested for relationships with inflammatory markers.
Levels of CRP were reported to positively correlate with increased
AB toward sad vs. happy and angry faces in breast cancer
survivors (Boyle et al., 2017). In addition, hepatitis C patients
showed an AB away from positive vs. neutral and fearful faces
and an increase in symptoms of depression, anxiety, and fatigue
6–7 weeks after commencing IFN-αtherapy (Cooper et al., 2018).
Concurrently, a greater increase in AB toward self-referential
positive vs. negative words and improvement of affective-
cognitive and somatic depressive symptoms was observed after
completion of anti-TNF-αtherapy in patients with inflammatory
bowel disease (Gray et al., 2018). This preliminary evidence
suggests that affective processing and depressive symptoms may,
at least, be partially driven by inflammatory activity. The pattern
of AB toward negative and away from positive information is
consistent with AB usually observed in depression. However,
the influence of disease or environmental confounding factors
cannot be ruled out in these studies.
To examine whether a causal relationship exists between
stressor-evoked inflammatory response and AB, a number of
experimental studies investigated the effects of acute stress or
mood induction on cytokine levels and emotional attention
in healthy and depressed individuals; however, the findings
have been mixed. Significant increases in both pro- and
anti-inflammatory cytokines following laboratory stress were
reported by some studies (Boyle, 2018;Maydych et al., 2018).
Elevations of cytokine levels were, in turn, positively associated
with increased AB toward negative and decreased AB toward
positive information. While these findings provide support for
the notion that stressor-evoked cytokine increases may drive,
at least, short-term changes in attention processing with these
effects depending on the valence of emotional material, other
studies could not confirm this hypothesis (Benson et al., 2017;
Niemegeers et al., 2019). The inconsistency of the findings may
stem from methodological and design issues, especially from
differences in stress/mood induction procedures, the timing
of cytokine assessments, and types of attention tasks. It is
also plausible that endogenous concentrations of cytokines, in
particular in healthy samples, even after a stressful challenge,
may be too low to map on behavioral attention measures.
Alternatively, attention tasks may not be sensitive enough to the
cognitive changes produced by cytokines.
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). As outlined earlier, depressed individuals and those
exposed to ELA exhibit higher increases in proinflammatory
cytokines in response to acute stress. Thus, it is possible that
exogenously induced inflammation prior to stress manipulation
would increase stress reactivity and drive even stronger changes
in emotional processing than individual treatments. Increases in
IL-6 levels have been demonstrated to be positively associated
with negative AB only in response to typhoid vaccine in women
with partially remitted depression, but not in response to
laboratory stress or both treatments (Niemegeers et al., 2019).
In another study, slower processing of negative information was
observed in response to LPS treatment and at a trend level in
combined LPS and negative mood induction condition in healthy
males (Benson et al., 2017).
In summary, the findings from various behavioral studies
indicate that stressor-related or endotoxin-induced increases in
inflammatory activity may affect emotional attention similar to
AB in depression. Yet, there were some inconsistent results and
null results, which can reflect methodological differences between
studies. In addition, the results obtained in laboratory studies
do not allow for conclusions on long-term causal relationships
between immune and cognitive processes. Future studies should
determine whether increased inflammation can prospectively
predict alterations in emotional attention.
Although the literature is rather sparse at present, the effects
of inflammation on neural activity and functional connectivity
during the processing of emotional stimuli have also been
the subject of investigation. The experimental designs of these
studies induced increased inflammation through either LPS,
vaccines, or laboratory stress and measured neural activity
and connectivity during exposure to emotional stimuli or
receiving social feedback. LPS-induced inflammation was shown
to increase amygdala activity while viewing negative facial
expression images (Inagaki et al., 2012). Furthermore, peripheral
levels of IL-6 were associated with increased activation of
the amygdala and increased functional connectivity between
the amygdala and dorsomedial prefrontal cortex (dmPFC) in
response to negative social feedback (Muscatell et al., 2015).
Laboratory stressor-evoked increases in the soluble TNF-α
receptor (sTNFαRII) have been shown to be positively correlated
with increased activation in dorsal anterior cingulate cortex
(dACC) and anterior insula (AI) in response to social rejection
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Maydych Stress, Inflammation and Emotional Attention
(Slavich et al., 2010;Muscatell et al., 2016). Comparatively, the
LPS-stimulated increase in IL-6 was positively associated with
increased activation of the bilateral amygdala, dACC, and dorsal
prefrontal cortex (dPFC) in response to negative feedback from
the confederate based on a 10-min interview previously provided
by participants (Muscatell et al., 2016). Other studies reported on
the enhanced activity of right inferior orbitofrontal cortex (iOFC)
(Kullmann et al., 2013) and subgenual ACC (Harrison et al., 2009)
in response to viewing emotional pictures and faces, respectively.
Although the data is not yet sufficient to draw generalized
conclusions, the majority of studies have documented the
increased activity of amygdala and dACC in response to increases
in inflammatory activity and negative social stimuli/feedback.
This is consistent with the literature on AB in depressive or at-risk
individuals (e.g., those exposed to ELA) that found enhanced and
long-lasting activity of amygdala in response to negative material
(Disner et al., 2011). A simultaneous activation increase in of PFC
and ACC was attributed to cortical insufficiency and abnormal
frontolimbic circuit function (Wagner et al., 2006;Matsuo et al.,
2007). Along with amygdala and AI, dACC was suggested to
constitute a so-called “neural alarm system,” which is responsible
for the detection of environmental threats and the regulation of
responses to danger including SNS system and HPA axis response
(Muscatell and Eisenberger, 2012).
Peripherally released cytokines communicate with the brain and
are capable of eliciting changes in emotional processing that
mimic affective-cognitive symptoms of depression. Research has
identified several pathways by which cytokine signals can access
the brain (Haroon et al., 2012). Briefly, cytokines can enter the
brain through leaky regions in the blood-brain barrier (e.g.,
circumventricular organs) or activated monocytes/macrophages
recruited to the brain. In addition, cytokine release can be
stimulated through brain blood vessel cells (e.g., endothelial
cells). Furthermore, afferent vagus nerve fibers can be stimulated
to transduce cytokine signals from the periphery into the brain,
where the cytokine signals activate cytokine-producing glia cells.
One of the most important molecular mechanisms
linking inflammation to emotional cognition is the cytokine
effect on the serotonergic system (Capuron and Castanon,
2016). Proinflammatory cytokines activate indoleamine-2,3-
dioxygenase (IDO), an enzyme involved in the synthesis of
kynurenine from dietary tryptophan. Central and peripheral
activation of IDO causes increased catabolism of tryptophan, an
important precursor of serotonin, leading to serotonin deficiency
(O’connor J. et al., 2009;O’Connor J.C. et al., 2009). Furthermore,
the products of kynurenine metabolism, such as quinolinic acid,
stimulate the N-methyl-D-aspartate (NMDA) receptor, thereby
unfolding neurotoxic effects leading to neuronal damage
(Campbell et al., 2014).
Another mechanism linking inflammation with cognition
is the effect of cytokines on the HPA axis. Cytokines can
act on glucocorticoid receptors and indirectly upregulate
the synthesis of corticotrophin-releasing hormone (CRH),
adrenocorticotropic hormone (ACTH), and cortisol (Raison
and Miller, 2003). The extent to which cytokines induce
the release of ACTH and cortisol is predictive of the
development of affective-cognitive but not of somatic symptoms
of depression (Capuron et al., 2003). This implies that HPA axis
sensitivity to inflammatory stimulation is particularly relevant for
the development of affective-cognitive symptoms of depression.
Finally, the parasympathetic nervous system has been
suggested to modulate affective-cognitive and immune processes
involved in stress cascade and depression (Thayer and Sternberg,
2006;Ondicova et al., 2010). Lower activity of the vagus nerve
is predictive of higher levels of cortisol and cytokine acute
stress response (Hamer and Steptoe, 2007;Smeets, 2010;Woody
et al., 2017) as well as slower stress recovery (Weber et al.,
2010). In addition, the vagal tone has been implicated in the
detection and (down-) regulation of inflammatory processes.
The anti-inflammatory effects are mediated by the vagal release
of acetylcholine, which activates a7 nicotinic Ach receptors in
macrophages, thereby inhibiting the release of proinflammatory
cytokines from these lymphocytes (the mechanism referred to
as “cholinergic anti-inflammatory reflex”) (Rosas-Ballina and
Tracey, 2009). It has been also suggested that reduced activity of
the vagus nerve is associated with disturbed emotion regulation
and further affective-cognitive symptoms that stem from the
impaired inhibitory control of the prefrontal cortex over the
limbic system (Thayer and Sternberg, 2006;Thayer et al., 2012)
as well as deficiency in monoamines (Dorr and Debonnel, 2006).
In summary, preliminary evidence suggests that acute and
chronic stress is associated with increased inflammatory activity
and enhanced attentional processing of negative information.
Both are predictive of negative mood and depression symptoms
that, in turn, increase inflammatory and cognitive stress
reactivity. Increased inflammation was associated with a pattern
of attentional changes characteristic to depression, whereas
affective-cognitive states were predictive of inflammatory stress
responses. These findings indicate that immune and affective-
cognitive processes are interconnected and may potentiate
one another’s impact on depression onset, maintenance or
recurrence. An improved understanding of the interplay between
inflammatory activity and emotional cognition in the context of
stress may help to optimize treatment strategies for depression.
VM has conceptualized and written the manuscript.
The author thanks Dr. Thomas Kleinsorge for proofreading of the
first version of the manuscript. The publication of this article was
funded by the Open Access Fund of the Leibniz Association.
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... Por el contrario, si las amenazas continúan y las habilidades de afrontamiento dejan de ser eficaces para reducir o terminar los eventos estresantes, se produce una hiperactividad del eje HHS potenciada por una pérdida de la retroalimentación negativa debido a la baja en la cantidad y la eficiencia de los receptores de GC (Popoli et al., 2011). Producto del estrés crónico, por tanto, los organismos progresivamente transitan de un estado de hipervigilancia y sobreactivación hacia uno de indefensión y pasividad, acompañado de sentimientos de desesperanza y desmotivación (Duman et al., 2016;Maydych, 2019). Al lado de estos síntomas, la fatiga, las alteraciones en la ingesta alimenticia y el peso, los problemas de atención y concentración y las ideaciones negativistas son resultado no solo de la hipercortisolemia, sino también de la deficiencia en la neurotransmisión monoaminérgica en la corteza prefrontal y el sistema límbicoestriatal (e. g., amígdala y núcleo accumbens) responsables de la cognición y de la regulación emocional (Popoli et al., 2011;Liuet al., 2018). ...
... De forma interesante, los antidepresivos pueden normalizar la tasa de neurogénesis, cuyo aumento está relacionado con la reversión de los síntomas (Hanson et al., 2011;Micheli et al., 2018). Este último aspecto vincularía recíprocamente al estrés crónico con la progresiva hiperactividad del eje HHS, la falla en los mecanismos de retrocontrol negativo, la depleción de monoaminas, la disminución en los niveles de BDNF, el aumento en la señalización glutamatérgica, la reducción en la tasa de neurogénesis y las alteraciones micro y macroanatómicas implicadas con la depresión (Felger y Lotrich, 2013 El papel iniciador y perpetuador de la cognición en la depresión ha sido ampliamente reconocido (Levine, 2000;Maydych, 2019;Kandola et al., 2019). El menoscabo de la plasticidad y la actividad de la corteza prefrontal observado en la depresión explica la dificultad para ejercer control ejecutivo sobre la amígdala y así inhibir las emociones adversas y las cogniciones depresogénicas asociadas. ...
... El menoscabo de la plasticidad y la actividad de la corteza prefrontal observado en la depresión explica la dificultad para ejercer control ejecutivo sobre la amígdala y así inhibir las emociones adversas y las cogniciones depresogénicas asociadas. Los mediadores de la respuesta inflamatoria, llamados citocinas proinflamatorias, inducen los comúnmente llamados síntomas de enfermedad (e. g., tristeza, anhedonia, fatiga, retraso psicomotor, pérdida de apetito y alteraciones del sueño), prácticamente indiferenciables de los de la depresión (Felger y Lotrich, 2013;Maydych, 2019;Slavich y Irwin, 2014). Esa reacción biológica altamente conservada es fundamental para afrontar la adversidad por lesión o enfermedad aguda al detener los efectos de la noxa y reparar los daños causados (inflamación resolutiva) (Nathan y Ding, 2010). ...
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Introduction: Major depression is one of the most common mental illnesses and one of the principal causes of disability worldwide, with an increasing prevalence in recent decades. The aim of this essay is to present epidemiological data, as well as to briefly review the psychobiological mechanisms of depression related to the exposure to chronic stress. Finally, we will also discuss some strategies for the prevention and/or treatment of the disease. Proposal: Alternative treatments complementing medication and psychotherapy could be much more effective in preventing and mitigating the effects of chronic stress and the risk of depression than these treatments alone. Arguments for discussion: Chronic stress can precipitate a depressive episode due to hyperactivity of the amygdala and hypothalamic-pituitary-adrenal (HPA) axis, failure of the HPA negative feedback, monoamine depletion, decreased levels of neurotrophins, increased glutamatergic excitotoxicity, reduced hippocampal neurogenesis, prefrontal cortex dysfunction, and excessive inflammatory response. Conclusions:The chronic accumulation of uncontrollable psychosocial stressors plus a sedentary lifestyle, a poor diet, and limited time or places for recreational activities underlie the high depresogenic potential of our current lifestyles. In contrast, activities that include exercise, meaningful social interactions, recreational activities, exposure to natural environments, a balanced diet, and healthy routines would represent a highly effective strategy for managing depression and improving overall health.
... (1,2) En cualquiera de las dos vías, el estrés afecta la homeostasia del organismo y altera los mecanismos psicológicos, neuronales y endocrinos de regulación interna que contrarrestan los cambios inducidos por el estrés, de tal forma que al superar la capacidad de adaptación y defensa del organismo, se generan procesos patológicos asociados a la alteración de la respuesta inmunológica, (3) la cual incluye, entre otras, la producción de citoquinas proinflamatorias que elevan los niveles de proteínas de fase aguda como la proteína Creactiva. (4) De esta forma, una vez alterado el sistema inmune, se pueden presentar dos situaciones: 1. Si el estrés es agudo la respuesta implica un proceso adaptativo que procura mantener la homeostasia y prepara al organismo para la supervivencia (lucha o huida); y 2. Si el estrés es crónico la respuesta procura mantener la alostasia o estabilidad a través de adaptaciones fisiológicas de los sistemas nervioso, endocrino e inmune, las cuales sostenidas en el tiempo se constituyen en una carga alostática y por supuesto en un factor de riesgo para la salud dentro del espectro de las enfermedades crónicas no transmisibles, (5) incluido el síndrome metabólico que consiste en la aparición simultánea o secuencial de un conjunto de factores de riesgo que corresponden a alteraciones metabólicas e inflamatorias tales como la obesidad abdominal, la resistencia a la insulina, el perfil lipídico aterogénico y la hipertensión, variables que han sido asociadas a la aparición de enfermedades cardiovasculares y de diabetes mellitus tipo 2. (6) En el caso del estrés académico, la reacción adaptativa del organismo ante las demandas del medio será la misma, lo que cambia será el contexto (medio universitario) y los agentes estresores. Uno de los mayores agentes relacionados con estrés académico es la sobrecarga académica, la cual depende del contexto educativo y de otros factores como el proceso de enseñanza-aprendizaje, el manejo del tiempo, las estrategias pedagógicas y el rendimiento académico. ...
... 1. Clasificación de la AHA (American Heart Association) para la presión arterial hipotensivo (<120/<80), normal (<120/<80), pre-hipertensivo (120-139/80-89), hipertensión en estadio 1 (140-159/90-99) e hipertensión en estadio 2 (160/100); 2. Clasificación de la Organización Mundial de la Salud (OMS) para perímetro abdominal normal (1<80, 2<94); riesgo alto en estadio 1 (80-88), riesgo alto en estadio 2 (94-102), riesgo muy alto en estadio 1 (>88) riesgo muy alto en estadio (>102); 3. Clasificación adaptada de la OMS para índice de masa corporal por debajo del peso (<18,5), saludable (18,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)9), sobrepeso (25,9), obeso (30,0-39,9) y obesidad extrema (>40); 4. Estrés académico agrupado por ponderados en las categorías muy bajo, bajo, medio, alto y muy alto; 5. Proteína C-reactiva de acuerdo a los valores de la OMS en bajo riesgo (>1,0 mg/L), riesgo medio (1,0-3,0 mg/L) y alto riesgo (>3,0 mg/L); 6. Para determinar el riesgo a desarrollar síndrome metabólico se tuvieron en cuenta la presión arterial (>130/85), el índice de masa corporal (>25) y el perímetro abdominal (>88 centímetros en la mujer y >102 para hombres) de acuerdo a lo estipulado por la OMS, se diagnosticó dos factores de riesgo elevados. Para este estudio se tuvieron en cuenta los dos primeros factores. ...
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Introducción: El estrés académico resulta de la confrontación de un individuo con las demandas del medio universitario, lo cual puede producir cambios a nivel neuro-endocrino-inmunológico y generar un estado de inflamación crónica en donde los niveles de proteína C-reactiva aumentan. Objetivo: Determinar los niveles de estrés académico y proteína C-reactiva en estudiantes de medicina y su posible asociación con síndrome metabólico. Métodos: Se realizó un estudio observacional descriptivo de corte longitudinal que determinó el estrés académico en 68 estudiantes de medicina (41 mujeres y 27 hombres). Se obtuvo información sociodemográfica y clínica de cada estudiante. Se aplicó un cuestionario para la evaluación del estrés académico y se obtuvieron dos muestras de sangre para realizar dos pruebas de proteína C-reactiva de alta sensibilidad en dos tiempos diferentes. Resultados: Pese a que se observaron niveles altos de estrés académico y proteína C-reactiva, no hubo una asociación directa; sin embargo, se encontraron relaciones significativas entre proteína C-reactiva y las variables clínicas, además de un riesgo alto de desarrollar síndrome metabólico. Conclusiones: Se observaron altos niveles de estrés académico asociado a las demandas y exigencias de un programa de medicina con acreditación de alta calidad. Los altos niveles de proteína C-reactiva fueron asociados a los altos niveles de obesidad abdominal, lo que hace que un número significativo de estudiantes se encuentre en riesgo de desarrollar enfermedades cardiovasculares y diabetes mellitus tipo 2, sobre todo aquellos en los que se detectó prehipertensión. No se encontró una relación significativa entre el estrés académico y los niveles de proteína C-reactiva.
... Additional factors seem to contribute, such as diabetes, obesity, hypertension, peripheral or carotid vascular disease (as in these patients), as well as an impaired synaptogenesis and neuroplasticity, which would start early in the in mid-life but would aggravate during aging [91]. Each of these stressors seems to trigger maladaptive responses, eventually leading to cerebral network diseases and different neuropsychiatric disorders [92]. ...
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Background: Although the antidepressant potential of repetitive transcranial magnetic stimulation (rTMS), the pleiotropic effects in geriatric depression (GD) are poorly investigated. We tested rTMS on depression, cognitive performance, growth/neurotrophic factors, cerebral blood flow (CBF) to transcranial Doppler sonography (TCD), and motor-evoked potentials (MEPs) to TMS in GD. Methods: In this case series study, six drug-resistant subjects (median age 68.0 years) underwent MEPs at baseline and after 3 weeks of 10 Hz rTMS on the left dorsolateral prefrontal cortex. The percentage change of serum nerve growth factor, vascular endothelial growth factor, brain-derived growth factor, insulin-like growth factor-1, and angiogenin was obtained. Assessments were performed at baseline, and at the end of rTMS; psychocognitive tests were also repeated after 1, 3, and 6 months. Results: Chronic cerebrovascular disease was evident in five patients. No adverse/undesirable effect was reported. An improvement in mood was observed after rTMS but not at follow-up. Electrophysiological data to TMS remained unchanged, except for an increase in the right median MEP amplitude. TCD and neurotrophic/growth factors did not change. Conclusions: We were unable to detect a relevant impact of high-frequency rTMS on mood, cognition, cortical microcircuits, neurotrophic/growth factors, and CBF. Cerebrovascular disease and exposure to multiple pharmacological treatments might have contributed.
... The interplay of stress and infection in the pathogenesis of CFS (Blomberg et al. 2018). Not only infection but physical and psychological stress can also result in immune dysregulation partly through alteration in the production of proinflammatory cytokines (Maydych 2019). Many CFS patients have consistently observed impaired immune responses (Mensah et al. 2017). ...
... This triggers an inflammatory response through cytokine release (Picard and McEwen, 2018a;Zampino et al., 2020). Prolonged inflammation, when unresolved, can lead to damage to cells and tissues and has been associated with a number of chronic diseases, including cardiovascular diseases (Lopez-Candales et al., 2017), depression (Maydych, 2019), and neurodegeneration (Missiroli et al., 2020). Our study shows that low mtDNAcn is associated with higher levels of Neuroticism and facets of Neuroticism, including depression. ...
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Background Mitochondrial DNA copy number (mtDNAcn) in tissues and blood can be altered in conditions like diabetes and major depression and may play a role in aging and longevity. However, little is known about the association between mtDNAcn and personality traits linked to emotional states, metabolic health, and longevity. This study tests the hypothesis that blood mtDNAcn is related to personality traits and mediates the association between personality and mortality. Methods We assessed the big five personality domains and facets using the Revised NEO Personality Inventory (NEO-PI-R), assessed depressive symptoms with the Center for Epidemiologic Studies Depression Scale (CES-D), estimated mtDNAcn levels from whole-genome sequencing, and tracked mortality in participants from the Baltimore Longitudinal Study of Aging. Results were replicated in the SardiNIA Project. Results We found that mtDNAcn was negatively associated with the Neuroticism domain and its facets and positively associated with facets from the other four domains. The direction and size of the effects were replicated in the SardiNIA cohort and were robust to adjustment for potential confounders in both samples. Consistent with the Neuroticism finding, higher depressive symptoms were associated with lower mtDNAcn. Finally, mtDNAcn mediated the association between personality and mortality risk. Conclusions To our knowledge, this is the first study to show a replicable association between mtDNAcn and personality. Furthermore, the results support our hypothesis that mtDNAcn is a biomarker of the biological process that explains part of the association between personality and mortality. Funding Support for this work was provided by the Intramural Research Program of the National Institute on Aging (Z01-AG000693, Z01-AG000970, and Z01-AG000949) and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. AT was also supported by the National Institute on Aging of the National Institutes of Health Grant R01AG068093.
... Stress is identified by the brain, with different types of stressors being possible sources (e.g., physical and psychological) (Haykin and Rolls, 2021). Systemic and low-grade inflammation can increase stress sensitivity (Maydych, 2019). There is evidence that the ACC connects the limbic system and the prefrontal cortex (Mohanty et al., 2007) and that this connection is responsible for stress-mediated reactions (Jeon et al., 2010). ...
Social interaction difficulties are a hallmark of psychotic disorders, which in some cases can be definitely traced back to autoimmunological causes. Interestingly, systemic and intrathecal inflammation have been shown to significantly influence social processing by increasing sensitivity to threatening social stimuli, which bears some resemblance to psychosis. In this article, we review evidence for the involvement of systemic and intrathecal inflammatory processes in psychotic disorders and how this might help to explain some of the social impairments associated with this group of disorders. Vice versa, we also discuss evidence for the immunomodulatory function of social interactions and their potential role for therapeutic interventions in psychotic disorders.
... Stress is closely related to a decrease in immune status, a self-defence response against viruses. Nakata (2012) and Maydych (2019) added that stress affects the inflammatory response, characterized by increased levels of C-Reactive Protein (CRP). Shivpuri et al. (2012) reported that interpersonal stress is greater in women than men are. ...
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Background: Psychosocial stress and depressive disorder have been associated with cancer as putative contributors to worse prognosis. On the other hand, cancer diagnosis is a recognised life event that can contribute to distress and depressive states. Humoral and cellular inflammation can promote depressive disorder by means of decreased monoamine synthesis, glutamate neurotoxicity, neurogenesis and neuroplasticity, dysregulated hypothalamic-pituitary-adrenal axis, and glucocorticoid resistance. This protocol objectives are to observe the interactions between psychosocial variables and biochemical and immunological biomarkers in a longitudinal, prospective design; to identify inflammation-related depression endophenotypes in breast cancer patients and to understand if early diagnosed and treated depression in this population will translate in better inflammation status and better global prognosis. Methods: Prospective observational cohort, composed by 100 consecutive premenopausal patients, diagnosed with non-distant metastatic breast carcinoma and with no history of major psychopathology or other organic illness. The participants will have an in-person assessment in three different moments, along illness treatment and follow-up, with respect to cytometric, immunologic, and psychosocial parameters and will be tested for depression vulnerability and resilience inflammation-related functional genetic polymorphisms. Additionally, at years 5 and 10 post enrollment, patients`medical records will be assessed. As a control cohort, all patients excluded due to psychiatric history or past psychiatric treatments will have their clinical records assessed at years 5 and 10 after admission. All the data will be managed with the SPSS® software. Discussion and conclusion: This study is an original longitudinal cohort of breast cancer premenopausal patients, with a comprehensive approach to psychosocial, clinical, inflammatory, and genetic variables. It expects to provide evidence regarding the links between genetic, cytometric, immunologic, and psychosocial factors, their potential contribution to the pathophysiology of depressive disorder, breast cancer course, progression, and prognosis. It may further contribute with data to better efficacy of the psycho-oncological interventions. Trial registration: National Commission of Data Protection (CNPD) 13413/2017; Ethics Committee of IPOP project code CI-IPOP81/2017.
All humans deal with acute psychological stress periodically. Some individuals are affected by needle phobia in which a heightened sense of arousal is precipitated by venepuncture. Acute psychological stress invokes a range of physiological changes including activation of the sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal axes. In this review article, we first examine the human response to acute stress. We then provide an overview of how psychological stress in a subject is likely to be a source of pre-analytical variability for certain measurands, and the major biochemical markers that have been studied in research aiming to quantify stress. As such, we highlight how stress can be a hindrance to the accurate interpretation of certain laboratory results (particularly cortisol, prolactin, metanephrines and growth hormone), and point out the role that biochemical analysis might play in future studies looking at the effects of stress on human behaviour.
Mu-Opioid Receptors (MORs) are well-known for participating in analgesia, sedation, drug addiction, and other physiological functions. Although MORs have been related to neuroinflammation their biological mechanism remains unclear. It is suggested that MORs work alongside Toll-Like Receptors to enhance the release of pro-inflammatory mediators and cytokines during pathological conditions. Some cytokines, including TNF-α, IL-1β and IL-6, have been postulated to regulate MORs levels by both avoiding MOR recycling and enhancing its production. In addition, Neurokinin‐1 Receptor, also affected during neuroinflammation, could be regulating MOR trafficking. Therefore, inflammation in the central nervous system seems to be associated with altered/increased MORs expression, which might regulate harmful processes, such as drug addiction and pain. Here, we provide a critical evaluation on MORs’ role during neuroinflammation and its implication for these conditions. Understanding MORs’ functioning, their regulation and implications on drug addiction and pain may help elucidate their potential therapeutic use against these pathological conditions and associated disorders.
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Background: Major Depressive Disorder (MDD) covers a wide spectrum of symptoms, including cognitive dysfunction, which can persist during remission. Both inflammatory states and psychosocial stress play a role in MDD pathogenesis. Methods: The effects of inflammatory (i.e., Salmonella typhi vaccine) and psychosocial stressor (i.e., Trier Social Stress Test), as well as their combination were investigated on cognition in women (aged 25–45 years, n = 21) with (partially) remitted MDD and healthy controls (n = 18) in a single-blind placebo-controlled study. In a crossover design, patients received on the first day one of the aforementioned interventions and on the other day a placebo, or vice versa, with a washout period of 7–14 days. Short-term and verbal memory, working memory, attention, verbal fluency, information processing speed, psychomotor function, and measures of attentional bias to emotions were measured. Exploratory analyses were performed to assess the correlation between biomarkers of inflammation and the Hypothalamic–Pituitary–Adrenal axis and cognitive functioning. Results: In patients, inflammatory stress decreased information processing speed and verbal memory, and increased working memory; after psychosocial stress, there was an increase in attention. There was also an increased negative attentional bias in patients after inflammatory stress. Neither stressor had any effect in controls. Limitiations: Limitations are the relatively small sample size and antidepressant use by a part of the participants. The effects of the stressors were also measured a relatively short period after administration. Conculsion: Patients were sensitive to the cognitive effects of inflammation and psychosocial stress on cognition, while controls were not.
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This study aimed to investigate the impact of mental stress on salivary cytokines and attention to emotional stimuli, as well as associations between stress-induced changes of immune and cognitive parameters. In a randomized order a total of 60 young adults were assigned to one of two stress conditions with varying stress intensity. High stress was induced by a socially evaluated Paced Auditory Serial Addition Test (PASAT). As a low stress task a paper-and-pencil version of PASAT was administered. Salivary cytokines were measured before, 5 min after, and 45 min after completion of the stress task, and were assayed for pro-and anti-inflammatory cytokines. Three distinct types of attention-alerting, orienting, and executive control-were measured by the modified Emotional Attention Network Test Integration (E-ANTI). IL-1β and IL-6 increased only in the high-stress group. Significant increases in IFN-α, IFN-γ, TNF-α, and IL-10 at 45 min after stress induction (all p's < 0.05) were observed in both the high-stress and the low-stress group. Alerting attention was positively related to more pronounced increases in IFN-α and TNF-α in both groups. Further, better orienting attention after presentation of negative cues was associated with higher increases in IFN-α, TNF-α, IL-2, IL-5, and IL-10 in both groups, and higher overall levels of IFN-α, IFN-γ, and IL-12p70 in the high-stress group. There were no systematic gender differences in cytokine responses. We conclude that attention processes modulate the increases of salivary cytokines after stress exposure, and that these effects depend on stress level, particular attention network, and stimulus valence.
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Background In inflammatory bowel disease (IBD), immune activation with increased circulating TNF-α is linked to the intensity of gastrointestinal symptoms and depression or anxiety. A central feature of depression is cognitive biases linked to negative attributions about self, the world and the future. We aimed to assess the effects of anti-TNFα therapy on the central processing of self-attribution biases and visceral afferent information in patients with Crohn’s disease. Methods We examined 9 patients with Crohn’s disease (age 26.1±10.6. yrs, 5 female, 5 ileocolonic, 2 colonic and 2 ileal disease) during chronic anti-TNFα therapy (5 adalimumab, 4 infliximab). Patients were studied twice in randomized order before and after anti-TNFα administration. On each occasion patients underwent functional magnetic resonance imaging (fMRI) of the brain during a test of implicit attribution biases regarding sickness/health and undertook a standardized nutrient challenge. Results Following anti-TNFα treatment, ratings of ‘fullness’ following nutrient challenge reduced compared to pre-treatment ratings (p<0.05). Reaction times revealed improved processing of self-related and positive health words, consistent with improved implicit sense of wellbeing that correlated with improvements in sensory function after treatment (r = 0.67, p<0.05). Treatment-associated improvements in implicit processing were mirrored by alterations of prefrontal, amygdala, posterior cingulate and visual regions. Between patients, the degree of functional amygdala change was additionally explained by individual differences in attention regulation and body awareness rankings. Conclusion In patients with Crohn’s disease, anti-TNFα administration reduces visceral sensitivity and improves implicit cognitive-affective biases linked to alterations in limbic (amygdala) function.
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Experimental endotoxemia is a translational model to study inflammatory mechanisms involved in the pathophysiology of mood disorders including depression. Disturbed affective cognition constitutes a core aspect in depression, but has never been studied in the context of inflammation. We combined experimental endotoxemia with an established experimental mood induction procedure to assess the interaction between acute inflammation and sad mood and their effects on affective cognition. In this randomized cross-over study, N = 15 healthy males received endotoxin (0.8 ng/kg lipopolysaccharide iv) on one study day and placebo an otherwise identical study day. The affective Go/Nogo task was conducted after experimental induction of neutral and sad mood. Inflammatory markers were assessed hourly. Endotoxin application induced a transient systemic inflammation, characterized by increased leukocyte counts, TNF-alpha and interleukin-6 plasma concentrations (all p < 0.01, interaction effects). Mood induction led to greater sadness ratings, with highest ratings when sad mood was induced during inflammation (p < 0.05, interaction effect). Based on a 2 (endotoxin vs. placebo) × 2 (sad vs. neutral mood) × 2 (sad vs. happy Go/Nogo target words) factorial design, we observed a significant target × endotoxin condition interaction (p < 0.01) reflecting slower responses to sad targets during endotoxemia. Additionally, we found a valence × mood interaction (p < 0.05), reflecting slower reaction times to sad targets in sad mood. In summary, acute inflammation and sad mood are risk factors for disturbed affective cognition. The results may reflect a mood-congruency effect, with prolonged and sustained processing of mood-congruent information during acute inflammation, which may contribute to depression risk.
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Background Treatment of medical patients with the inflammatory cytokine, interferon- α (IFN- α ), is frequently associated with the development of clinical depressive symptomatology. Several important biological correlates of the effect of IFN- α on mood have been described, but the neuropsychological changes associated with IFN- α treatment are largely unexplored. The aim of the present preliminary study was to assess the effect of IFN- α on measures of emotional processing. Method We measured changes in emotional processing over 6–8 weeks in 17 patients receiving IFN- α as part of their treatment for hepatitis C virus infection. Emotional processing tasks included those which have previously been shown to be sensitive to the effects of depression and antidepressant treatment, namely facial expression recognition, emotional categorisation and the dot probe attentional task. Results Following IFN- α , patients were more accurate at detecting facial expressions of disgust; they also showed diminished attentional vigilance to happy faces. IFN- α produced the expected increases in scores on depression rating scales, but there was no correlation between these scores and the changes in emotional processing. Conclusions Our preliminary findings suggest that IFN- α treatment produces negative biases in emotional processing, and this effect is not simply a consequence of depression. It is possible that increased recognition of disgust may represent a neuropsychological marker of depressive disorders related to inflammation.
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 recommendations for how to test the role of inflammation in the pathogenesis of heterogeneous psychiatric disorders.
Background: Inflammation plays a role in mood and behavior that may be relevant to identifying risk factors and treatment for depression and other stress-related illnesses. The purpose of this study was to examine whether fluctuations in inflammation following a mild immune stimulus were associated with changes in daily reported features of depression for up to a week in a healthy sample of young adults. Methods: Forty one undergraduate students completed daily diaries of mood, feelings of social disconnection, sleep, and physical symptoms for one week before and after receiving the seasonal influenza vaccine. Circulating plasma interleukin-6 (IL-6) was measured via blood samples taken immediately before and one day after vaccination. Results: There was a significant increase in circulating IL-6 from pre- to post-intervention (p = .008), and there was significant variability in the magnitude of IL-6 change. Greater increases in IL-6 were associated with greater mood disturbance on post-vaccine days, specifically depressed mood and cognitive symptoms. Conclusions: Minor increases in inflammation were associated with corresponding increases in features of depression, and these associations occurred in the absence of any physical symptoms. The influenza vaccine could be used to probe causal relationships with a high degree of ecological validity, even in high-risk and vulnerable populations, to better understand the role of inflammation in the pathogenesis of depression.
The finding that inflammatory markers are elevated in various neuropsychiatric disorders raises the need of identifying the precise research domain criteria driven by inflammation. Based on the model of inflammation-induced depression it has been possible to identify distinct pathophysiological pathways leading to alterations in neurotransmitter metabolism with specific relevance for the development of symptom constellations that are common to various neuropsychiatric and neurodegenerative conditions. Moreover, converging data indicate that these pathways interact with relevant vulnerability factors and modulatory systems to ultimately impact the presentation of inflammation-driven neuropsychiatric symptoms. Altogether, these findings make inflammation a key pivotal factor in psychopathology. Developing treatments that target inflammation and modulate the pathways and systems by which inflammatory processes selectively affect brain function will be of particular relevance for the treatment of specific neurobehavioral symptom domains.