Altered temporal variance and functional connectivity of BOLD signal is associated with state anxiety during acute systemic inflammation

Systemic inflammation is accompanied by complex behavioral changes and disturbed emotion regulation that have been related to the pathophysiology of mood disorders including depression and anxiety. However, the causal role of systemic inflammation on mood disorders is still unclear. We herein investigated neural resting state patterns of temporal variance of the amygdala and functional connectivity within the salience network underlying changes in state anxiety during experimentally-induced systemic inflammation. In this randomized, double-blind study, N = 43 healthy men received an intravenous injection of either low-dose lipopolysaccharide (LPS, 0.4 ng/kg body weight) or saline. Resting state functional magnetic resonance imaging was assessed before and 3.5 h after injection. State anxiety, assessed with a standardized questionnaire, and plasma cytokine concentrations were repeatedly measured. LPS administration induced a transient systemic inflammatory response reflected in increases in plasma Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α concentration. Compared to placebo, state anxiety and temporal variance in the amygdala significantly increased while functional connectivity in the salience network decreased during LPS-induced systemic inflammation. Together, these data indicate that acute systemic inflammation alters temporal variance of the BOLD signal as well as functional connectivity in brain regions and networks implicated in emotion processing and regulation. These results are of translational importance to encourage further research on the role of inflammatory pathways in the pathophysiology of neuropsychiatric conditions including anxiety disorders

Neural indicators of fatigue in chronic diseases : A systematic review of MRI studies

The authors would like to thank the Sir Jules Thorn Charitable Trust for their financial support.Peer reviewedPublisher PD

Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age

Background Maternal inflammation during pregnancy increases the risk for offspring psychiatric disorders and other adverse long-term health outcomes. The influence of inflammation on the developing fetal brain is hypothesized as one potential mechanism but has not been examined in humans. Methods Participants were adult women (N = 86) who were recruited during early pregnancy and whose offspring were born after 34 weeks’ gestation. A biological indicator of maternal inflammation (interleukin-6) that has been shown to influence fetal brain development in animal models was quantified serially in early, mid-, and late pregnancy. Structural and functional brain magnetic resonance imaging scans were acquired in neonates shortly after birth. Infants’ amygdalae were individually segmented for measures of volume and as seeds for resting state functional connectivity. At 24 months of age, children completed a snack delay task to assess impulse control. Results Higher average maternal interleukin-6 concentration during pregnancy was prospectively associated with larger right amygdala volume and stronger bilateral amygdala connectivity to brain regions involved in sensory processing and integration (fusiform, somatosensory cortex, and thalamus), salience detection (anterior insula), and learning and memory (caudate and parahippocampal gyrus). Larger newborn right amygdala volume and stronger left amygdala connectivity were in turn associated with lower impulse control at 24 months of age, and mediated the association between higher maternal interleukin-6 concentrations and lower impulse control. Conclusions These findings provide new evidence in humans linking maternal inflammation during pregnancy with newborn brain and emerging behavioral phenotypes relevant for psychiatric disorders. A better understanding of intrauterine conditions that influence offspring disease susceptibility is warranted to inform targeted early intervention and prevention efforts

Neural origins of human sickness in interoceptive responses to inflammation

BACKGROUND: Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning. RESULTS: Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions. CONCLUSIONS: These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states. PMID:19409533[PubMed - indexed for MEDLINE] PMCID: PMC2885492Free PMC Articl

A deep phenotyping approach to understand major depressive disorder and responses to antidepressant pharmacotherapy

Major depressive disorder (MDD) is a debilitating psychiatric disorder characterised by a complex underlying biology and poor response to pharmacological antidepressant strategies. Given the heterogeneity of MDD and the diverse range of available treatment options, there is an increasing desire to develop and implement precision medicine approaches to tailor existing treatment strategies to the biological system of the individual. In this thesis, high-resolution omics data (connectomics [fMRI], metabolomics [1H NMR] and immunomics [inflammatory cytokines]) collected from the Canadian Biomarker Integration Network in Depression (CAN-BIND) study has been integrated to facilitate the deep phenotyping of MDD. In addition, this approach has been used to predict the treatment response to two common antidepressant drugs, monotherapy with the selective serotonin reuptake inhibitor (SSRI) escitalopram (10-20 mg) or combination therapy with escitalopram and the dopaminergic antipsychotic aripiprazole (2-10 mg). This approach identified a multi-modal panel of sex-specific biomarkers of MDD and treatment response, highlighting a strong immunometabolic component in depressed males, but not females. Unsupervised clustering methods indicated the superiority of biological (neuroimaging) over symptom-based (clinical questionnaires) data for the stratification of patients into MDD subtypes with differential response to treatment. More importantly, a set of multi-modal, sex-specific biomarkers were identified that predicted treatment response with escitalopram monotherapy (84.7% accuracy) or aripiprazole augmentation (88.5% accuracy). In addition to highlighting potential new aspects of the biology of MDD (e.g. relevance of lipoprotein size and density for their relation to depression), this work is one of the first attempts to apply systems biology approaches to high-resolution biological data from a large clinical trial to predict later treatment outcome. With the validation of the findings presented in this thesis in independent cohorts, and with further development of omics technologies, leading to cheaper and high-throughput screening of the patient population, pre-dose biomarkers have the potential to achieve personalised treatment. Each year, escitalopram and aripiprazole are prescribed to an estimated 26 million and 7 million individuals respectively, and over one third of them do not respond. Thus, being able to predict response to antidepressant medication from baseline biomarkers has enormous clinical and socioeconomic benefits.Open Acces

ASSOCIATIONS BETWEEN RETROSPECTIVE REPORTS OF ADVERSE CHILDHOOD EXPERIENCES, SYSTEMIC INFLAMMATION, AND RESTING BRAIN CONNECTIVITY IN MIDLIFE ADULTS

Adverse childhood experiences (ACEs) confer risk for negative mental and physical health outcomes across the life course. ACEs may confer this risk by affecting the functional connectivity of corticolimbic brain circuits implicated in threat processing, emotion regulation, contextual memory, and peripheral physiological regulation. Critically, the biological pathways that link ACEs to the brain are not well understood. The present study addresses this knowledge gap by considering mediators of systemic inflammation, in particular the proinflammatory cytokine interleukin(IL)-6, which may be increased following ACEs and may also influence corticolimbic brain circuits. In accordance with prior theoretical accounts, it was hypothesized that circulating IL-6 would statistically link retrospective reports of ACEs to corticolimbic connectivity in adulthood. Participants were 303 healthy midlife adults who retrospectively reported ACEs, underwent a blood draw to assess circulating IL-6, and underwent resting-state fMRI. Hierarchical linear regression analyses controlling for age, sex, race, BMI, and participant motion tested whether retrospectively reported ACEs predicts circulating IL-6 and resting corticolimbic connectivity, as well as whether circulating IL-6 predicts resting corticolimbic connectivity. Ancillary analyses tested whether corticolimbic connectivity associated with subclinical depressive symptoms, as well as whether ACEs moderated any brain-inflammation associations. Retrospective reports of physical abuse associated with IL-6 (β(SE) = 0.14(0.05), p = 0.009), but not with corticolimbic connectivity (p = 0.165). IL-6 associated negatively with connectivity in a corticolimbic circuit comprising the amygdala, hippocampus, ventromedial prefrontal cortex, and subgenual anterior cingulate cortex (β(SE) = -0.17(0.06) p = 0.006). Subclinical depressive symptoms were unrelated to corticolimbic connectivity (p > 0.75) and ACEs did not moderate any brain-inflammation associations (p > 0.29). These findings agree with studies linking ACEs to systemic inflammation and systemic inflammation to adult functional connectivity, yet they diverge from those linking ACEs and adult functional connectivity. Collectively, these results do not fully support theoretical accounts linking ACEs to adult corticolimbic connectivity via systemic inflammation