are involved in the generation of sickness behavior, which shares some overlap with the symptoms of depression. neurotransmitters hypothesized to be affected include dopamine and serotonin, which are common targets for antidepressant drugs. induction of indolamine-2,3 dioxygenease by cytokines has been proposed as a mechanism by which immune dysfunction causes depression. one review found normalization of cytokine levels after successful treatment of depression. a meta analysis published in 2014 found the use of anti-inflammatory drugs such as nsaids and investigational cytokine inhibitors reduced depressive symptoms. exercise can act as a stressor, decreasing the levels of il-6 and tnf-a and increasing those of il-10, an anti-inflammatory cytokine. inflammation is also intimately linked with metabolic processes in humans. for example, low levels of vitamin d have been associated with greater risk for depression. the role of metabolic biomarkers in depression is an active research area. recent work has explored the potential relationship between plasma sterols and depressive symptom severity. oxidative stress a marker of dna oxidation, 8-oxo-2'-deoxyguanosine, has been found to be increased in both the plasma and urine of people with mdd. this along with the finding of increased f2-isoprostanes levels found in blood, urine and cerebrospinal fluid indicate increased damage to lipids and dna in people with mdd. studies with 8-oxo-2' deoxyguanosine varied by methods of measurement and type of depression, but f2-isoprostane level was consistent across depression types. authors suggested lifestyle factors, dysregulation of the hpa axis, immune system and autonomics nervous system as possible causes. another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity. oxidative dna damage may play a role in mdd. mitochondrial dysfunction: increased markers of oxidative stress relative to controls have been found in people with mdd. these markers include high levels of rns and ros which have been shown to influence chronic inflammation, damaging the electron transport chain and biochemical cascades in mitochondria. this lowers the activity of enzymes in the respiratory chain resulting in mitochondrial dysfunction. the brain is a highly energy-consuming and has little capacity to store glucose as glycogen and so depends greatly on mitochondria. mitochondrial dysfunction has been linked to the dampened neuroplasticity observed in depressed brains. large-scale brain network theory instead of studying one brain region, studying large scale brain networks is another approach to understanding psychiatric and neurological disorders, supported by recent research that has shown that multiple brain regions are involved in these disorders. understanding the disruptions in these networks may provide important insights into interventions for treating these disorders. recent work suggests that at least three large-scale brain networks are important in psychopathology: central executive network the central executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal cortex. this network is involved in high level cognitive functions such as maintaining and using information in working memory, problem solving, and decision making. deficiencies in this network are common in most major psychiatric and neurological disorders, including depression. because this network is crucial for everyday life activities, those who are depressed can show impairment in basic activities like test taking and being decisive. default mode network the default mode network includes hubs in the prefrontal cortex and posterior cingulate, with other prominent regions of the network in the medial temporal lobe and angular gyrus. the default mode network is usually active during mind-wandering and thinking about social situations. in contrast, during specific tasks probed in cognitive science (for example, simple attention tasks), the default network is often deactivated. research has shown that regions in the default mode network (including medial prefrontal cortex and posterior cingulate) show greater activity when depressed participants ruminate (that is, when they engage in repetitive self-focused thinking) than when typical, healthy participants ruminate. people with mdd also show increased connectivity between the default mode network and the subgenual cingulate and the adjoining ventromedial prefrontal cortex in comparison to healthy individuals, individuals with dementia or with autism. numerous studies suggest that the subgenual cingulate plays an important role in the dysfunction that characterizes major depression. the increased activation in the default mode network during rumination and the atypical connectivity between core default mode regions and the subgenual cingulate may underlie the tendency for depressed individual to get "stuck" in the negative, self-focused thoughts that often characterize depression. however, further research is needed to gain a precise understanding of how these network interactions map to specific symptoms of depression. salience network the salience network is a cingulate-frontal operculum network that includes core nodes in the anterior cingulate and anterior insula. a salience network is a large-scale brain network involved in detecting and orienting the most pertinent of the external stimuli and internal events being presented. individuals who have a tendency to experience negative emotional states (scoring high on measures of neuroticism) show an increase in the right anterior insula during decision-making, even if the decision has already been made. this atypically high activity in the right anterior insula is thought to contribute to the experience of negative and worrisome feelings. in major depressive disorder, anxiety is often a part of the emotional state that characterizes depression.