Neural mechanisms of the cognitive model of depression

Disner, Seth G.; Beevers, Christopher G.; Haigh, Emily A. P.; Beck, Aaron T.

doi:10.1038/nrn3027

Cited by 1,339 publications

(1,236 citation statements)

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“…In various psychiatric disorders, psychosocial stress is a major aetiological factor and excessive fear is a major psychopathology (Cuthbert and Insel, 2013;Disner et al, 2011;Kendler et al, 2003;Kessler, 1997). Mouse CSD resulted in excessive fear learning and memory of an aversive CS-US association, indicating that psychosocial stress induced generalized hyper-reactivity to aversion.…”

Section: A Valid Mouse Model For Psychosocial Stress-induced Hyperactmentioning

confidence: 99%

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Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

116

125

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Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immuneinflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-, IFN-, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, higher KYN and 3-HK in amygdala and hippocampus. However, CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders. ABSTRACTPsychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyperactivity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.3

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Section: A Valid Mouse Model For Psychosocial Stress-induced Hyperactmentioning

confidence: 99%

“…Negative valence is a major proposed domain (Cuthbert and Insel, 2013), and includes the excessive fearfulness that is common in MDD and GAD (Disner et al, 2011;Eshel and Roiser, 2010). Importantly, these domains can be studied in humans and other species.…”

Section: Introductionmentioning

confidence: 99%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

116

125

View full text Add to dashboard Cite

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“…For instance, it has been found that upon encountering negative material the increased activation in limbic regions (e.g., amygdala, hippocampus) is related to a reduced activity in specific regions in the prefrontal cortex (e.g., dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex) with these latter structures being crucial to implement cognitive control over processing of affective material (Davidson et al, 2002;Whittle, Allen, Lubman, & Yucel, 2006). The emerging integrative (gene-by-environment) views on depression allow further exploration of the interplay among genes, neuroendocrine, and stress in relation to multiple cognitive biases (Disner, Beevers, Haigh, & Beck, 2011).…”

Section: Predicting Depressionmentioning

confidence: 99%

The combined cognitive bias hypothesis in depression

Everaert

Koster

Derakshan

2012

Clinical Psychology Review

270

179

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Drawing from substantial evidence demonstrating cognitive biases in depression at various stages of information processing (i.e., attention, interpretation, memory, cognitive control), we argue for an approach that considers the interplay among these processes. This paper attempts to apply the combined cognitive bias hypothesis (Hirsch, Mathews, & Clark, 2006) to depression research and reviews competing theoretical frameworks that have guided research in this area. We draw on current findings from behavioral studies on the interplay between depression-related processing biases. These data indicate that various cognitive biases are associated. However, it is not clear whether single or multiple biases are most predictive of depressive symptoms. We conclude this article with theoretical and clinical implications of the current state of research in this field and propose a number of ways in which research on the combined cognitive bias hypothesis can be advanced. A State-of-the-art Major depression is a prevalent psychiatric disorder that is associated with debilitating symptomatic suffering, functional impairments, and high societal costs (Kessler & Wang, 2009). Notwithstanding a range of well-established psychological and pharmacological interventions, relapse and recurrence rates of depression remain high (Vittengl, Clark, Dunn, & Jarrett, 2007) indicating that current therapies do not sufficiently address vulnerability factors for this burdensome disorder. Moreover, with each successive depressive episode the risk for recurrence increases (Boland & Keller, 2009), which points to an expanding vulnerability with multiple episodes. Hence, profound insight into the mechanisms involved in the etiology and maintenance of major depression seems essential in improving contemporary treatment options and the prevention of depression.In the past three decades, research inspired by cognitive accounts of depression has been successful in identifying vulnerability factors for this disorder. Apart from substantial research examining depressive cognitive content as a vulnerability factor (e.g., negative thoughts), a promising line of research highlights the role of cognitive biases in the development, maintenance, and relapse/recurrence of depression (for reviews see Mathews & MacLeod, 2005). Research efforts in this particular area of interest have typically focused on abnormalities in attention, interpretation, and memory processes, which are considered to be instrumental in the understanding of the processes involved in these cognitive biases. More recently, there is growing interest into cognitive and neural mechanisms underlying cognitive control impairments, which may operate across a variety of cognitive biases. Indeed a substantial number of studies on emotional information processing in depressed samples provide evidence that depression is characterized by attention, interpretation, and memory biases, especially for negative information (see below). COMBINED COGNITIVE BIAS HYPOTHESIS IN DEPRESSION 4This resea...

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“…These observations have been rationalized in terms of altered neurocircuitry proposed to underlie specific depression psychopathologies, e.g. the amygdala -sgACC -PFC circuit for hyper-processing of negative stimuli (Disner et al, 2011). Imaging studies related to specific tasks have been complemented by restingstate (rs) fMRI, which provides information on the synchronicity of spontaneous activity thereby enabling the study of functional connectivity (FC) within and between networks.…”

Section: Introductionmentioning

confidence: 99%

Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

et al. 2016

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Human depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward. Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a post-treatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in between-network FC, including amygdala -prefrontal cortex and amygdala -cingulate cortex. MRS identified metabolic alterations in CPS mice as increased inositol levels in amygdala and increased glycerophosphorylcholine levels in prefrontal cortex. Diffusion-weighted MRI detected increased fractional anisotropic values in the cingulum. This study demonstrates that chronic psychosocial stress induces FC states in the mouse brain analogous to those observed in depression, as well as cerebral metabolism and white matter pathway alterations that contribute to understanding of pathological processes. It also demonstrates the importance of brain imaging to the establishment of valid animal models in translational psychiatry. AbstractHuman depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward.Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a posttreatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in b...

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Neural mechanisms of the cognitive model of depression

Cited by 1,339 publications

References 118 publications

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

The combined cognitive bias hypothesis in depression

Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

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