Anterior Cingulate Activation and Error Processing During Interferon-Alpha Treatment

Capuron, Lucile; Pagnoni, Giuseppe; Demetrashvili, Marina F; Woolwine, Bobbi J.; Nemeroff, Charles B.; Berns, Gregory S.; Miller, Andrew H.

doi:10.1016/j.biopsych.2005.03.033

Cited by 206 publications

(140 citation statements)

References 49 publications

(51 reference statements)

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“…In patients receiving IFN-α for the treatment of hepatitis C, the fatigue and impaired concentration that are induced by the treatment were not associated with changes in activity of parietal and occipital brain regions, as assessed by functional magnetic resonance imaging 73 . However, IFN-α-treated patients showed a greater activation of the anterior cingulate cortex during a high-demand visuo-spatial attention task 74 . This hyperactivity was highly correlated with the number of task-related errors in IFN-α-treated patients despite the lack of any effect of IFN-α on the number of errors.…”

Section: Neuroanatomy Of Cytokine-induced Depressionmentioning

confidence: 88%

From inflammation to sickness and depression: when the immune system subjugates the brain

et al. 2008

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In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.Anyone who has experienced a viral or bacterial infection knows what it means to feel sick. The behaviour of sick people changes dramatically; they often feel feverish and nauseated, ignore food and beverages, and lose interest in their physical and social environments. They tire easily and their sleep is often fragmented. In addition, they feel depressed and irritable, and can experience mild cognitive disorders ranging from impaired attention to difficulties in remembering recent events. Despite their negative impact on well-being, these symptoms of sickness are usually ignored. They are viewed as uncomfortable but banal components of infections 1 .Sickness is a normal response to infection, just as fear is normal in the face of a predator. It is characterized by endocrine, autonomic and behavioural changes and is triggered by soluble mediators that are produced at the site of infection by activated accessory immune cells. These mediators are known as pro-inflammatory cytokines, and include interleukin-1α and β (IL-1α and IL-1β), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). They coordinate the local and systemic inflammatory response to microbial pathogens. However, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript these peripherally produced cytokines also act on the brain to cause the aforementioned behavioural symptoms of sickness. Recently, it has been suggested that 'sickness behaviour' 2, 3, a term used to describe the drastic changes in subjective experience and behaviour that occur in physically ill patients and animals, is an expression of a previously unrecognized motivational state. It is responsible for re-organizing perceptions and actions to enable ill individuals to cope better with an infection4.During the last five years, it has been established that pro-inflammatory cytokines induce not only symptoms of sickness, but also true major depressive disorders in physically ill patients with no previous history of mental disorders. Some of the mechanisms that might be responsible for inflammation-mediated sickness and depression have now been elucidated. These findings suggest that the brain-cytokine system, which is in essence a diffuse system, is the unsuspected conductor of the ensemble of neuronal circuits and neurotransmitters that organize physiologi...

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Section: Neuroanatomy Of Cytokine-induced Depressionmentioning

confidence: 88%

From inflammation to sickness and depression: when the immune system subjugates the brain

et al. 2008

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“…Relevant to this issue is a growing body of research suggesting that the ACC and anterior insula function as an integrated circuit (32,33), forming a key node in the visceromotor network (34). Both regions appear to be involved in high-level representation of visceral states (35), which may include neural encoding of peripheral inflammation (36)(37)(38), and they are connected to the periphery in several ways that give these paralimbic structures the ability to modulate inflammatory activity. For example, both the ACC and the anterior insula have extensive efferent connections to the hypothalamus (39), enabling them to influence inflammatory activity via endocrine pathways.…”

Section: Discussionmentioning

confidence: 99%

Neural sensitivity to social rejection is associated with inflammatory responses to social stress

Slavich

Way

Eisenberger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

331

163

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Although stress-induced increases in inflammation have been implicated in several major disorders, including cardiovascular disease and depression, the neurocognitive pathways that underlie inflammatory responses to stress remain largely unknown. To examine these processes, we recruited 124 healthy young adult participants to complete a laboratory-based social stressor while markers of inflammatory activity were obtained from oral fluids. A subset of participants (n = 31) later completed an fMRI session in which their neural responses to social rejection were assessed. As predicted, exposure to the laboratory-based social stressor was associated with significant increases in two markers of inflammatory activity, namely a soluble receptor for tumor necrosis factor-α (sTNFαRII) and interleukin-6 (IL-6). In the neuroimaging subsample, greater increases in sTNFαRII (but not IL-6) were associated with greater activity in the dorsal anterior cingulate cortex and anterior insula, brain regions that have previously been associated with processing rejectionrelated distress and negative affect. These data thus elucidate a neurocognitive pathway that may be involved in potentiated inflammatory responses to acute social stress. As such, they have implications for understanding how social stressors may promote susceptibility to diseases with an inflammatory component.P sychological stress is intimately related to human health and well-being. It increases susceptibility to the common cold (1), elevates risk for several major diseases (2), and is a strong, independent predictor of morbidity and mortality. In a recent epidemiological study, for example, males experiencing high levels of stress were 32% more likely to die during a 22-y assessment period than were those experiencing low levels of stress (3).

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“…Another brain region that has been consistently associated with the effects of inflammation on behavior is the dACC, a brain region that has been referred to as a 'neural alarm system' based on its role in threat detection and activation of downstream arousal pathways. Early studies in IFN-α-treated patients demonstrated increased activation of the dACC during a visuospatial attention task using fMRI that highly correlated with the number of errors made on the task (Capuron et al, 2005). Activation of the dACC during a social rejection task has also been correlated with the degree of stress-induced activation of oral sTNFR2 during a public speaking stressor (Slavich et al, 2010).…”

Section: Inflammation Effects On Neurocircuitrymentioning

confidence: 99%

“…For example, stress-induced activation of inflammation and administration of inflammatory cytokines have been found to activate neural circuits relative to the processing of threatening stimuli including the dACC, amygdala, and insula (Capuron et al, 2005;Slavich et al, 2010;Muscatell et al, 2015). Moreover, in patient populations such as women with breast cancer, increased peripheral blood inflammatory markers (eg, CRP) have been correlated with increased activation of the amygdala during a threat sensitivity task (Muscatell et al, 2016).…”

Section: Symptom Specificity For Outcome Variablesmentioning

confidence: 99%

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

Neuropsychopharmacol

119

124

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A wealth of data has been amassed that details a complex, yet accessible, series of pathways by which the immune system, notably inflammation, can influence the brain and behavior. These data have opened the window to a diverse array of novel targets whose potential efficacy is tied to specific neurotransmitters and neurocircuits as well as specific behaviors. What is clear is that the impact of inflammation on the brain cuts across psychiatric disorders and engages dopaminergic and glutamatergic pathways that regulate motivation and motor activity as well as the sensitivity to threat. Given the ability to identify patient populations with increased inflammation, the precision of interventions can be further tuned, in conjunction with the ability to establish target engagement in the brain through the use of multiple neuroimaging strategies. After a brief overview of the mechanisms by which inflammation affects the brain and behavior, this review examines the extant literature on the efficacy of anti-inflammatory treatments, while forging guidelines for future intelligent clinical trial design. An examination of the most promising therapeutic strategies is also provided, along with some of the most exciting clinical trials that are currently being planned or underway.

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Anterior Cingulate Activation and Error Processing During Interferon-Alpha Treatment

Cited by 206 publications

References 49 publications

From inflammation to sickness and depression: when the immune system subjugates the brain

From inflammation to sickness and depression: when the immune system subjugates the brain

Neural sensitivity to social rejection is associated with inflammatory responses to social stress

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

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