The Role of Brain Structure and Function in the Association Between Inflammation and Depressive Symptoms: A Systematic Review.

SYSTEMATIC REVIEW / META-ANALYSIS

The Role of Brain Structure and Function in the Association Between Inflammation and Depressive Symptoms: A Systematic Review Michelle L. Byrne, PhD, Sarah Whittle, PhD, and Nicholas B. Allen, PhD ABSTRACT Objective: Major depressive disorder and related symptoms have been shown to be associated with inflammation, and this association is likely to be mediated through changes in brain structure and function. This article provides a systematic review of studies that have used brain imaging techniques to identify neural mechanisms linking inflammation and depressive symptoms. Methods: A systematic search of online databases identified 26 studies that fulfilled the inclusion and exclusion criteria. Results: In general, increased peripheral inflammation was associated with differences in function in several subcortical regions, as well as medial and ventral prefrontal regions—both at rest (7 studies) and during exposure to emotional stimuli (14 studies). Also, increased activation in some of these regions was associated with depression (18 studies). Too few studies have measured neuroinflammation markers (three) or brain structure (three), so generalizations about these mechanisms cannot yet be made. Conclusions: This review supports the view that peripheral inflammation is an etiological process that may influence depression via effects on brain function. Several methodological inconsistencies in the extant literature need to be addressed, most notably a lack of formal mediational testing in longitudinal designs and inconsistencies across imaging methods and inflammation induction and measurement techniques. Further work is also required to establish the mechanisms by which basal inflammation levels influence brain function and depressive symptoms in both healthy and clinical samples. Key words: depression, inflammation, brain function, brain structure, neuroimaging.

INTRODUCTION

respond to stress regardless of whether it is physical or psychosocial (12–14). There are several metabolic and behavioral changes that may occur during this acute phase, including fever, loss of appetite, lethargy, and loss of interest in social behaviors. Although these sickness behaviors, which are potentially adaptive in circumstances when an organism is suffering from illness or infection, are not identical to symptoms of MDD, they share some similarities (15,16). Furthermore, injection of cytokines can induce depressive-like behaviors in mice (17), monkeys (18), and

Overview Majordepressive disorder(MDD) isa debilitating neuropsychiatric disease, with lifetime prevalence rates estimated to be 13% to 16% in thegeneralpopulation (1,2). It is predicted tobe one of the highest global causes of disease burden by 2020 (3). MDD shows a strong association with other medical illnesses (4–6), and inflammation has been commonly hypothesized to be a key mechanism explaining this link. Indeed, recent research has shown that depressed persons display elevated levels of inflammatory markers (for reviews, see Refs. (7,8)). Stress is a strong predictor of the development of MDD (9) and a trigger for inflammatory responses, which can lead to depression (10). An acute-phase response to stress is initiated by an activation of immune cells and the release of cytokines (11), which results in a systemic reaction referred to as “inflammation,” Inflammatory processes

ACC = anterior cingulate cortex, CRP = C-reactive protein, fMRI = functional magnetic resonance imaging, IDO = indoleamine 2,3-dioxygenase, IFN = interferon, IL = interleukin, LPS = lipopolysaccharide, MDD = major depressive disorder, MRI = magnetic resonance imaging, MRS = magnetic resonance spectroscopy, OFC = orbitofrontal cortex, PFC = prefrontal cortex, PET = positron emission tomography, sACC = subgenual anterior cingulate cortex, TNF-α = tumor necrosis factor α

Supplemental Content From the Department of Psychology (Byrne, Allen), The University of Oregon, Eugene, Oregon; Melbourne Neuropsychiatry Centre (Whittle), Department of Psychiatry, The University of Melbourne & Melbourne Health, Victoria, Australia; and Melbourne School of Psychological Sciences (Allen), The University of Melbourne, Victoria, Australia. Address correspondence and reprint requests to Michelle L. Byrne, PhD, Department of Psychology 1227 University of Oregon, Eugene, OR 97403. E-mail: [email protected] Received for publication March 10, 2015; revision received November 6, 2015. DOI: 10.1097/PSY.0000000000000311 Copyright © 2016 by the American Psychosomatic Society

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Copyright © 2016 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.


research directions that require further investigation. Especially, this may justify the effort involved in conducting longitudinal research to test formal mediation models whereby inflammatory processes influence brain activity and development in areas responsible for emotional processing, which may, in turn, promote risk for the development of depressive disorders. This article briefly summarizes research on brain function and structure in depression and the effects of inflammation on brain function, before providing a comprehensive, systematic review of studies that have used brain imaging techniques to identify neural mechanisms potentially linking inflammation and depressive symptoms. Our aim is to identify specific brain regions and networks that may mediate the relationship between inflammation and depressive symptoms. As such, electroencephalogram studies were not included in our review because they would not be as informative as to the specific anatomical circuits and regions involved.

humans (19). This suggests that there may be an etiological path to MDD that is cytokine induced, especially if the inflammatory response is chronic or reoccurring (20), which can be due to range of factors such as stress and life-style factors such as diet, sleep, smoking, and obesity (for review, see Ref. (21)). For example, administration of interferon-α (IFN-α) to patients with hepatitis C (19,22–25) or interleukin (IL)-2 to patients with cancer (26) is associated with increases in depressive symptoms and fatigue (27). It should be noted that one study found that patients with MDD reported improved mood the next morning after endotoxin administration (28). Nevertheless, a recent review of studies measuring cognitive performance after endotoxin administration found that the data were inconsistent (29), so increases in peripheral inflammation may not always necessarily translate to cytokineinduced depression, especially symptoms related to neurocognitive functioning. Furthermore, cytokine-induced depression may have specific neuroimmune mechanisms (30), mainly through the inflammatory, oxidative, and nitrosative stress pathways (31,32). Via nuclear factor κB, an inflammatory signaling molecule, a peripheral inflammatory response activates brain microglia to produce proinflammatory cytokines (18). This activates expression of indoleamine 2,3-dioxygenase (IDO) in the brain (33), which reduces tryptophan levels and, in turn, activates production of kynurenine (24). This process is thought to lead to depressive-like behaviors, which animal research has shown are different from sickness behaviors (17), and can sometimes contribute to reoccurring depressive illness in humans (34). Other ways that peripheral inflammation has shown to have effects on the brain include vagal activation (20) and, recently, availability of serotonin transporter in the brainstem (35). Therefore, the effect of the immune system on mood and behavioral symptoms of depression is likely to be mediated through observable changes in brain function and structure. However, the neural regions and networks that mediate this effect have not yet been fully identified. Research using neuroimaging to link inflammation and depressive symptoms is a promising approach in this regard, because differences in brain function and structure have been implicated in both depression and (to a lesser extent) inflammation. Emerging research has investigated the neural mechanisms underpinning the association between inflammation and depression, and there may be a link between inflammatory processes and differences in brain function and structure associated with MDD, schizophrenia, and Alzheimer's disease (36). However, to date, there has been no systematic review of research findings investigating the associations between brain function and structure, inflammation, and depression, specifically. A review of the existing research is timely to establish whether there are consistent depressionrelated differences in neural regions or networks that may be influenced by inflammatory processes, and will highlight Psychosomatic Medicine, V 00 • 00-00

Neural Mechanisms in Depression The past decade has seen a wealth of neuroimaging studies providing evidence for structural and functional brain changes associated with depression. A number of recent meta-analyses have been performed that elucidate the most consistent and significant neural differences associated with the disorder (37,38). These meta-analyses suggest significant reductions in gray matter in structures within a corticolimbic circuit, including the amygdala, hippocampus, striatum, dorsomedial and dorsolateral prefrontal cortex (PFC), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC), which are hypothesized to underlie some of the core cognitive, affective, and behavioral depressive symptoms. Both increased and decreased neural activities associated with emotional and cognitive processing have been found in similar areas. For example, a recent meta-analysis found evidence for opposing effects for negative and positive emotional stimuli processing in the amygdala, striatum, parahippocampus, cerebellum, fusiform, and ACC, with depressed participants displaying hyperactivation to negative stimuli, and hypoactivation to positive stimuli (39). Depression has also been associated with differences in functional connectivity in brain networks that are thought to underlie mood regulation, as well as the default mode network, a network of regions including the medial PFC, posterior cingulate, precuneus, and neighboring regions of the parietal cortex thought to underlie self-referential processing and autobiographical recall (40).

Peripheral Inflammatory Effects on Brain Structure and Function Although the literature is less substantial, neuroimaging studies have also examined the effect of inflammation on brain structure and function. Many have implicated proinflammatory markers such as C-reactive protein (CRP)

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Inflammation and Depression Associations

measures in an attempt to better understand the neural mechanisms through which inflammation might be associated with depression.

(41,42), as well as ILs such as IL-6 (43,44). For example, in healthy adult men, greater CRP levels were associated with cortical thinning in several left hemisphere perisylvian regions (41). Peripheral IL-6 levels have shown to be negatively associated with gray-matter volume in the hippocampus (41). Other studies have used an experimental design by increasing levels of systemic inflammation through either injection of endotoxins or exposure to stress. These studies have found inflammation-associated changes in activity in the substantia nigra (43), and the dorsal ACC (45,46) and anterior insula (45). Patients receiving IFN-α therapy have shown increases in glucose metabolism in the basal ganglia and cerebellum and decreases in glucose metabolism in the dorsal PFC (47). Furthermore, inflammatory responses are associated with increased microglia activity across the whole brain (48,49), as well as with specific changes in activity in the amygdala (17,50,51), hypothalamus (17), and hippocampus (17,52), and damage to white matter during sensitive developmental periods (53). In particular, studies have shown associations between peripheral inflammation and activity in regions relevant to emotional processing such as the ACC and insula (54) and the subgenual ACC (sACC) and OFC (55). Overall, inflammation seems to affect brain development and functioning, especially in emotion-related brain networks, and due to the association of depression with both inflammation and changes in brain structure and function in such networks (refer to Fig. 1 for a summary of the overlapping literature), several research studies have combined these

Systematic Review—Methods The systematic review was conducted according to the PRISMA guidelines (56). Figure 2 presents a flowchart and details of the procedure.

Literature Search Online searches of the PubMed, MEDLINE, and PsycINFO databases were performed in August 2015. Abstracts were reviewed for references to magnetic resonance imaging (MRI), diffusion tensor/weighted imaging, voxelbased morphometry, functional MRI (fMRI), positron emission tomography (PET), magnetic resonance spectroscopy (MRS), inflammation, and depressive symptoms or depression. If the study was relevant, the full text was retrieved. Additional studies were retrieved through other methods, including reviewing bibliographies of articles identified through the search terms.

Inclusion and Exclusion Criteria Journal articles were included if they reported on studies that a) measured peripheral inflammation, induced an inflammatory response through cytokine or endotoxin injection, or measured another marker of inflammatory functioning (e.g., genes); b) measured brain structure using MRI or diffusion methods, brain function using fMRI or PET, or brain

FIGURE 1. Summary of the literature on associations between inflammation and brain structure/function, and depression and brain structure/function. Associations are change in activity or metabolism, except the following: *less gray matter only, **cortical thinning only, and ***increase in activity and less gray matter. CRP = C-reactive protein; IL = interleukin; OFC = orbitofrontal cortex; PFC = prefrontal cortex; ACC = anterior cingulate cortex.


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FIGURE 2. Procedure used for study selection. fMRI = functional magnetic resonance imaging.

PET and MRS Studies of Resting Brain Metabolism

metabolism using MRS; c) measured depressive illness or any discrete symptoms relevant to depressive illness such as social rejection, neurovegetation, fatigue, anhedonia, depressed mood, or grief, or was designed to elicit depressed mood; and d) examined associations between these three measures.

Four studies used MRS techniques (57–60) and six used PET (47,61–65). Increased inflammation, whether induced or measured peripherally, was associated with differences in function in several regions at rest, including alterations in dopaminergic function in the caudate, putamen, and ventral striatum (63), and higher glucose metabolism in the insula (64), putamen, and nucleus accumbens (47), although one study found decreased metabolism in the dorsolateral PFC (47). These neural changes were, in turn, associated with depressive symptoms. Three studies measured the neuroinflammation marker translocator protein

Systematic Review—Results Information from each study is presented in Table S1, Supplemental Digital Content 1, http://links.lww.com/PSYMED/A272. Twenty-six studies were identified as relevant and are reviewed later. Results are categorized based on study protocol. Psychosomatic Medicine, V 00 • 00-00

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in the amygdala (66,75), ACC (46,75), sACC (55,66), dorsal ACC (45,72), basal ganglia, thalamus, hypothalamus (75), anterior insula (45,72), OFC (55), and substantia nigra (43). Some studies also measured associations between depression and neural activity. In general, increased depressive symptoms were associated with increased activity in the medial PFC, hippocampus, posterior cingulate cortex (66), and substantia nigra (43), and depressed patients had more μ-opioid activation associated with inflammation (75). Furthermore, in some studies, inflammation was also associated with depression or depressive symptoms (43,46,75), but not in all (66,72). However, one study reported an association between inflammation and depressed mood in females only (72), and this association was mediated by brain activity.

18 kDa (TSPO) using PET—one study did not find any difference between depressed and control participants (62); however, one study measured TSPO density and found elevated levels in depressed patients in the PFC, ACC, and insula compared with controls (61), and another found that within patients with chronic fatigue syndrome, peak TSPO in the thalamus, midbrain, and amygdala was associated with cognitive impairment (65). MRS studies in patients with hepatitis C showed that treatment with proinflammatory cytokines increased glutaminergic metabolism in the dorsal ACC, pregenual ACC, and left basal ganglia, which were, in turn, associated with increased depressive symptoms (60) and reduced motivation (59). Older age was also associated with a greater increase in glutaminergic metabolism in the left basal ganglia, which was also associated with increased peripheral inflammation and depressive symptoms (57). Another MRS study of breast cancer survivors found that fatigue was associated with higher levels of peripheral inflammation and changes in brain metabolic function in the posterior insula, but there were no associations between inflammation and measures of brain metabolites (58).

Other Methods Three studies measured brain structure. One found that patients with depression had smaller hippocampal volumes and increased inflammation compared with controls (76). Another used quantitative magnetization transfer to measure microstructure and found that inflammation induced changes in the ventral striatum which were, in turn, associated with increases in fatigue (77). Finally, one study found that inflammatory genes were associated with volume of the sACC, hippocampus, and caudate, but not with depression (67).

fMRI and PET Studies of Task-Related Activity All studies involving tasks to measure activity used fMRI techniques (43,45,46,55,63,66–74), except one, which used PET to measure μ-opioid receptor activity during a sadness induction task (75). Tasks included exposure to emotional stimuli, reward processing, and emotion or stress induction. During exposure to emotional (particularly negative) stimuli, increased inflammation was associated with activation in a number of brain regions including the amygdala (67,69), ventromedial PFC (66), hippocampus (67), inferior OFC (68), ACC (73,74), and insula (74). Increased activation in some of these regions was associated with depression, either by an effect only in depressed patients (67) or by an increase in depressive symptoms (46,68,69,72–74). One study showed that inflammation was associated with increases in both depressed mood and brain activation while viewing aversive pictures, but did not analyze explicit associations between brain function and mood (68). Only one study found inflammation (measured by a genetic variant associated with increased inflammation) to be associated with decreased brain activity in depression during negative emotional stimuli (70). Two studies used reward tasks to elicit brain activity and showed that inflammation was associated with less activation of the ventral striatum in relation to anticipating the reward (71) and actual receipt of the reward (63). In turn, decreased activity during reward processing was associated with depressive symptoms. Finally, seven studies used tasks that were designed to elicit stress, sadness, or other negative feelings such as social exclusion. In these studies, increases in inflammation were associated with increased activity during these tasks Psychosomatic Medicine, V 00 • 00-00

DISCUSSION Summary Overall, this review suggests that inflammation is associated with changes in brain function and depression, and although not explicitly tested, findings to date provide some preliminary support for a model by which inflammatory effects on brain function might mediate the effects of inflammation on depressive symptoms. As such, this review provides grounds to encourage future research to formally test the hypothesis that inflammation is one of the etiological processes that influences depressed mood and depressive disorders via effects on brain function. Although methodologies differed, inflammation was consistently associated with differences in function in several subcortical, and medial and ventral prefrontal regions, both during rest and in response to aversive and positive/reward stimuli. Below, the extant literature is discussed with respect to four emergent issues: a) the specific brain regions that are emerging as most critical/promising, b) imaging methods, c) inflammation methods, and d) assessment of depression and depressive symptoms.

Brain Regions Subcortical Regions Our review of the literature suggests that at rest, inflammation is associated with differences in dopaminergic function

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and a recent study has also found that experimentally induced inflammation changes the subjective value of rewards versus punishments, as well as reducing the encoding of reward prediction errors within the ventral striatum (80). Interestingly, another recent study showed that endotoxin administration and the associated increase in inflammation increased activity in the ventral striatum while viewing a personally identified support figure (81), suggesting that inflammation may not uniformly change all types of reward behavior. Overall, this review found that the current literature, albeit limited, suggests that reward processing networks may be involved in the etiology of cytokine-induced depression, and also may play a specific role in IDO pathways. The subcortical brain regions that were identified as having both immune- and depression-related increases in activation in response to emotional stimuli included the amygdala, ventral pallidum, hypothalamus, and hippocampus. Many of these regions are consistently identified as being hyperactive in response to negative emotional stimuli in depressive disorder (82). This review showed that emotionally valenced human faces were particularly salient stimuli that were associated with increased inflammation and depression, suggesting that these regions are part of an important network attending to social cues that may be affected by inflammatory states.

(suggestive of impaired dopamine release or increased dopamine reuptake) in the caudate, putamen, and ventral striatum (e.g., Ref (62)). Although experimentally induced inflammation was associated with significant increases in dopamine uptake in striatal areas, decreased dopamine uptake in these areas at baseline was associated with development of neuropsychiatric symptoms in the context of experimentally induced inflammation. Lower dopamine uptake in the striatum has consistently been implicated in depression (78), suggesting that dopaminergic tone may serve as an important vulnerability factor mediating the impact of cytokines on depression. As noted earlier, IFN-α has been associated with decreased dopamine levels (63). As such, decreased availability of dopamine may indirectly lead to an overactivation of glutamatergic projections to the striatum and basal ganglia output nuclei. Glutamate concentrations (57,59) and metabolic activity (47) were also increased in the basal ganglia (especially striatal areas) in patients treated with cytokine injections, which, in turn, were associated with increased depressive symptoms, and activity in the substantia nigra was associated with peripheral inflammation and depressive symptoms (43) (refer to Fig. 3 for a summary of all brain regions). Two studies found that the ventral striatum was less active in response to inflammation during reward tasks, whether anticipation or actual receipt of reward (63,71). Another found that inflammation was associated with changes in the microstructure of the ventral striatum at rest, which also predicted an increase in fatigue (77). Reduced ventral striatum activation in response to reward is also a well-established finding in the depression literature (79),

Cortical Regions Both at rest and in studies of processing emotional stimuli, activity in the medial PFC (especially ventral region), inferior OFC, and ACC (dorsal and subgenual regions) was associated with increased inflammation and depression.

FIGURE 3. Brain regions identified from systematic review. vmPFC = ventromedial prefrontal cortex; OFC = orbitofrontal cortex; PFC = prefrontal cortex.


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of guiding future research, is summarized in Figure 3. However, several other methodological issues need to be addressed to advance the field to enable stronger conclusions about these relationships.

Again, activity in response to negative stimuli in these regions is implicated in depression (82). Furthermore, neural models of depression posit that changes in function within a network that comprises these regions (along with the subcortical regions discussed above, such as the amygdala, ventral pallidum, hypothalamus, hippocampus, and insula), known as the “extended medial network,” underlie the differences in emotional behavior and cognition that characterize depressive disorder (79). Because this network is understood to exert forebrain modulation over visceral responses mediated via the hypothalamus and brainstem, dysfunction within this circuit may account for the differences in autonomic (83,84) and neuroendocrine (85) function that have been associated with depression. The reviewed research suggests that this network is also relevant in inflammatory pathways that may lead to depression, and that areas within this network may be particularly susceptible to inflammation through the IDO and tryptophan/kynurenine pathways. Of relevance is that the sACC was identified in four independent emotion/stress elicitation studies (55,66,73,75). This region has been one of the most consistently implicated regions in depression (86). Therefore, future research should continue to examine the role of inflammation as a moderator of activity in this region. Two studies (59,60) found that IFN-α treatment was associated with an increase in glutamine or Glu/Cr levels in the ACC, which, in turn, was associated with increased depressive symptoms. However it is of note that, generally, in patients with current unipolar depression, MRS levels of total glutamate and glutamine are reported to be lower than controls, whereas elevated levels have been associated with bipolar depression (87). It is thus possible that the neurochemical changes in the ACC produced by IFN-α as measured by MRS may be associated with risk for bipolar as opposed to unipolar depression, although this is yet to be explicitly tested. It should also be noted that a few studies found decreases in activity in the dorsolateral PFC (47), ACC, and amygdala (70) associated with depression and inflammation, suggesting that more research examining these brain regions is needed to establish which pattern of findings is valid. Furthermore, inflammation and depressive symptoms were associated with greater neuronal activity in the insula (45,58,64,72,74). Interestingly, in one study (64), increased activity in the insula was associated with increased social interest and lower peak cytokine levels. It was suggested that in those with higher activity in the insula, serum cytokine levels may have been lower because of an active inhibition of the systemic inflammatory response. Lower cytokine levels may, in turn, have caused less reduction in social interest. In sum, patterns are beginning to emerge in the literature showing changes in activity in certain brain regions and networks, especially the extended medial network. This pattern of findings, which will clearly be important in terms Psychosomatic Medicine, V 00 • 00-00

Imaging Techniques Six of the reviewed studies used PET imaging techniques (47,61,62,64,66,75), 4 used MRS (57–60), 13 examined brain activity with fMRI (43,45,46,55,66–74), and 1 study used both PET and fMRI techniques (63). Although all measure brain function, the nature of the function that is assayed and its interpretation differ significantly between techniques. As such, fMRI, PET, and MRS studies are not directly comparable. Two studies measured neuroinflammation markers but did not measure peripheral inflammation (61,62), or did not make direct comparisons between peripheral inflammation and depressive symptoms or brain activity (65). Only two studies examined brain structure using MRI (76,77), so clearly more research is needed before generalizations can be made about the relationships between inflammation, brain structure, and depression. Furthermore, studies differed in their analytical approach, especially with regard to whole brain versus region of interest approaches, and the statistical thresholds used. A more formal meta-analytic approach will be extremely useful once there are a greater number of published studies. Finally, studies that used tasks to elicit emotion did so in different ways. For example, there may be differences in neural processing of a sadness-induction task compared with a stress-induction task, or task designed to elicit social rejection, or simply viewing emotionally expressive faces. A greater number of studies that use each of these kinds of tasks are needed before strong conclusions can be made about neural mechanisms involved in this kind of processing.

Inflammation Techniques and Measurements Peripheral inflammation was measured in many of the studies reviewed, but in a variety of ways. Although IL-6 was the most commonly examined cytokine, inflammatory markers including IFN-α, TNF-α, IL-1ra, IL-1β, IL-6, IL-10, IL-18, and CRP were all variably measured across studies. Three studies examined expression and variants of inflammatory genes (67,70,76). The results from one of these studies (70) were contrary to expectation, suggesting that the effect of inflammatory genes may need to be examined separately from basal levels of circulating cytokines. Relatedly, studies differed in their experimental technique. Some studies induced an inflammatory response through stress (45,66), or injection of lipopolysaccharide (LPS) (68), whereas others used endotoxins (64,69,71,72), vaccines (43,73,74), injected cytokines as part of a treatment (46,47,57,59,60,63,77), or measured basal levels of inflammatory markers (55,58,75,76). Administration of LPS produces a stronger immune response than a typhoid

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patients with the former report more psychomotor disturbances and less feelings of guilt (90). Whether this suggests that depressive conditions with a more directly endogenous etiology might have a greater emphasis on vegetative symptoms, and less on cognitive and affective symptoms, than do those that are associated with psychosocial stress is a hypothesis that may require investigation of the common and distinctive neural basis of these putative etiological paths. Future neuroimaging research may be able to play a particularly important role in understanding whether there are specific neural and inflammatory processes that distinguish types of depressive disorder. Furthermore, it will also be important to measure discrete dimensions of depressive symptoms that may be specific to inflammation and differentiate between functional and emotional aspects of depression.

vaccine, and even a small dose of LPS at 0.8 ng/kg can affect memory performance (for review, see Ref. (29)). Typhoid vaccine (43) activates only a low-grade inflammatory response and avoids the confounding effects of fever triggered by LPS administration, but still shows increases in negative mood (88). Clear identification of mechanisms in depression is not possible until more research is conducted with similar inflammation inductions and measurement methods. For example, one study measured inflammation at baseline and after a stress test and found that baseline inflammation levels were not associated with brain activity, whereas levels of inflammation in response to stress were (45), suggesting that different mechanisms might be associated with each of these measures. Finally, three studies (61,62,65) measured neuroinflammation (binding to TSPO). Results from these studies were conflicting in that one found that TSPO was elevated in the PFC, ACC, and insula in patients with depression (61), but another found no differences between patients and controls (62). Another used a sample of patients with chronic fatigue syndrome and found that peak TSPO was associated with cognitive impairment in the thalamus and amygdala (65). It should be noted that within the two studies of patients with depression, the study that found significant results had twice the sample size of the earlier study, suggesting that greater power may be required to observe these effects. Further research with adequate sample sizes, therefore, is needed to determine mechanisms of neuroinflammation in depression.

Limitations of the Extant Literature Several methodological discrepancies across the studies limit our ability to draw firm conclusions. As of yet, there are few studies that conduct formal statistical tests of mediation to determine if brain activity mediates the association between inflammation and depression. This type of analysis would be especially beneficial in longitudinal research. Only one longitudinal study has been conducted, which found that patients receiving IFN-α treatment for 4 to 6 weeks had increased 18F-DOPA uptake and less 18F-Dopa turnover compared with baseline, and this was associated with increased depressive symptoms (63). Further longitudinal research examining naturally occurring levels of cytokines within individuals over longer periods is justified to elucidate the temporal sequence and potential causal relationships between inflammation, neural biomarkers, and the emergence of depression. Another issue to be considered is the possibility of publication bias, where studies that found significant associations between inflammation, brain function, and depression have been more likely to be published. However, it should be noted that some null findings have been reviewed here, including a study showing no differences in TSPO binding between people with depression and controls (62). Finally, causal mechanisms relevant to depressive disorders cannot yet be inferred from these data. Although some studies used an experimental design by injecting participants with cytokines, these studies did so in healthy adults, not persons diagnosed as having a depressive disorder. As discussed earlier, the pathophysiology of cytokine-induced depression may differ to depressed mood in healthy persons (90).

Assessment of Depressive Disorders and Symptoms Studies also differed in their measurement of depression. Although some included samples of patients with MDD, others only measured symptoms, which may not have reached levels of clinical significance. Some studies measured changes in depressed mood in healthy participants. Although research should be careful not to conflate these results without examining them separately, elevated levels of depressive symptoms do predict the emergence of MDD later (89), so this can shed some light on the pathophysiology of cytokine-induced depression. This systematic review reveals an emerging pattern showing that, with some exceptions, when brain activity and/or increased inflammation is associated with depression, the relationship is observed regardless of whether depression is measured by a clinical diagnosis or an increase in subclinical symptoms. A critical question that arises from this review is whether increased inflammation is one of many etiological processes that contribute to the neural differences in persons with depression, or whether increased inflammation represents a pathway leading to a specific type of neurological change and depression. There is some support for the latter view. For example, symptoms of cytokine-induced depression seem to differ from idiopathic major depression in that Psychosomatic Medicine, V 00 • 00-00

Conclusions and Future Directions This review highlights the small but growing number of research studies showing associations between increased inflammation, brain activity, and measures of depression. It seems that specific neural mechanisms are likely to be implicated in the immune-depression relationship, including

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basal dopaminergic functioning, activity in the extended medial network (especially the sACC) while processing negative affective stimuli, and inhibited activity of the ventral striatum during reward tasks. However, further neuroimaging research is needed to determine if cytokineinduced depression has a separate etiological pathway that is different from idiopathic MDD. Importantly, several methodological inconsistencies need to be addressed, most notably a lack of formal mediational testing in longitudinal designs. Furthermore, more studies that use the same inflammation induction techniques, especially stress induction, are required to make generalizations across the type of inflammatory response. Finally, studies that use PET techniques to measure neuroinflammation should also measure peripheral inflammation to enhance our understanding of the relationships between these types of processes and markers. Ultimately, identification of these causal mechanisms will assist treatment, early intervention, and preventative efforts aimed at reducing the burden of depression and its psychosomatic correlates. Source of Funding and Conflicts of Interest: Sarah Whittle was supported by a National Health and Medial Council Career Development Fellowship (ID: 1007716). The authors declare no conflicts of interest.

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12

Month 2016


The association between body composition and foot structure and function: a systematic review.

The association between depressive symptoms in the community, non-psychiatric hospital admission and hospital outcomes: a systematic review.

Association between pain, neuropsychiatric symptoms, and physical function in dementia: a systematic review and meta-analysis.

The relationship between physical activity and depressive symptoms in adolescents: a systematic review.

The association between workplace bullying and depressive symptoms: the role of the perpetrator.

Association between higher BMI and depressive symptoms in Icelandic adolescents: the mediational function of body image.

The Effectiveness of Aromatherapy for Depressive Symptoms: A Systematic Review.

The Association Between Lifestyle Activities and Late-Life Depressive Symptoms.

Rumination mediates the association between cyber-victimization and depressive symptoms.

Executive function moderates the relation between coping and depressive symptoms.

A systematic review of the association between pleural plaques and changes in lung function.

The association between vasomotor symptoms and depression during perimenopause: a systematic review.

The association between cognitive function and subsequent depression: a systematic review and meta-analysis.

Association between signs and symptoms of bruxism and presence of tori: a systematic review.

Emotion regulation mediates the association between ADHD and depressive symptoms in a community sample of youth.

The association between discrimination and depressive symptoms among older African Americans: the role of psychological and social factors.

The association between community environment and cognitive function: a systematic review.

The Association Between Olfaction and Depression: A Systematic Review.

Can pharmacological and psychological treatment change brain structure and function in PTSD? A systematic review.

The association between immune activation and manic symptoms in patients with a depressive disorder.

The Association Between Depressive Symptoms and Age in Cancer Patients: A Multicenter Cross-Sectional Study.

Associations Between Maternal Depressive Symptoms and Nonresponsive Feeding Styles and Practices in Mothers of Young Children: A Systematic Review.

Association between Work-Family Conflict and Depressive Symptoms among Chinese Female Nurses: The Mediating and Moderating Role of Psychological Capital.

The mediating role of depressive symptoms in the relationship between adverse childhood experiences and smoking.