E. Cooper

Quantitative magnetization transfer imaging as a biomarker for effects of systemic inflammation on the brain

Background Systemic inflammation impairs brain function and is increasingly implicated in the etiology of common mental illnesses, particularly depression and Alzheimer’s disease. Immunotherapies selectively targeting proinflammatory cytokines demonstrate efficacy in a subset of patients with depression. However, efforts to identify patients most vulnerable to the central effects of inflammation are hindered by insensitivity of conventional structural magnetic resonance imaging. Methods We used quantitative magnetization transfer (qMT) imaging, a magnetic resonance imaging technique that enables quantification of changes in brain macromolecular density, together with experimentally induced inflammation to investigate effects of systemic inflammatory challenge on human brain microstructure. Imaging with qMT was performed in 20 healthy participants after typhoid vaccination and saline control injection. An additional 20 participants underwent fluorodeoxyglucose positron emission tomography following the same inflammatory challenge. Results The qMT data demonstrated that inflammation induced a rapid change in brain microstructure, reflected in increased magnetization exchange from free (water) to macromolecular-bound protons, within a discrete region of insular cortex implicated in representing internal physiologic states including inflammation. The functional significance of this change in insular microstructure was demonstrated by correlation with inflammation-induced fatigue and fluorodeoxyglucose positron emission tomography imaging, which revealed increased resting glucose metabolism within this region following the same inflammatory challenge. Conclusions Together these observations highlight a novel structural biomarker of the central physiologic and behavioral effects of mild systemic inflammation. The widespread clinical availability of magnetic resonance imaging supports the viability of qMT imaging as a clinical biomarker in trials of immunotherapeutics, both to identify patients vulnerable to the effects of systemic inflammation and to monitor neurobiological responses.

Central autonomic network mediates cardiovascular responses to acute inflammation: Relevance to increased cardiovascular risk in depression?

Highlight ► Acute inflammation modulates two cardiovascular risk factors: blood pressure and heart rate variability by effects on brain homeostatic control and integration centres.

A neurocomputational account of how inflammation enhances sensitivity to punishments versus rewards

Background Inflammation rapidly impairs mood and cognition and, when severe, can appear indistinguishable from major depression. These sickness responses are characterized by an acute reorientation of motivational state; pleasurable activities are avoided, and sensitivity to negative stimuli is enhanced. However, it remains unclear how these rapid shifts in behavior are mediated within the brain. Methods Here, we combined computational modeling of choice behavior, experimentally induced inflammation, and functional brain imaging (functional magnetic resonance imaging) to describe these mechanisms. Using a double-blind, randomized crossover study design, 24 healthy volunteers completed a probabilistic instrumental learning task on two separate occasions, one 3 hours after typhoid vaccination and one 3 hours after saline (placebo) injection. Participants learned to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli. An action-value learning algorithm was fit to the observed behavior, then used within functional magnetic resonance imaging analyses to identify neural coding of prediction error signals driving motivational learning. Results Inflammation acutely biased behavior, enhancing punishment compared with reward sensitivity, through distinct actions on neural representations of reward and punishment prediction errors within the ventral striatum and anterior insula. Consequently, choice options leading to potential rewards were less behaviorally attractive, and those leading to punishments were more aversive. Conclusions Our findings demonstrate the neural mediation of a rapid, state-dependent reorientation of reward versus punishment sensitivity during inflammation. This mechanism may aid the adaptive reallocation of metabolic resources during acute sickness but might also account for maladaptive, motivational changes that underpin the association between chronic inflammation and depression.

Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue

Background Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used clinically for hepatitis C treatment. Though effective, IFN-α induces marked behavioral changes that, when severe, can appear indistinguishable from major depression. Curiously, fatigue and motivational impairment evolve rapidly, suggesting acute engagement of immune-brain communicatory pathways, yet mood impairments typically emerge later, after weeks of treatment. Whether this reflects prolonged modulation of motivational processes underpinning fatigue or separate neurobiological mechanisms is currently unclear. Methods Here, we used quantitative magnetization transfer (qMT) imaging, an advanced microstructural neuroimaging technique sensitive to effects of inflammation, in a prospective study design to measure acute brain changes to IFN-α and relate these to later development of discrete behavioral changes. Twenty-three patients initiating IFN-α treatment for hepatitis C underwent qMT imaging and blood sampling at baseline and 4 hours after their first IFN-α injection. Comprehensive behavioral and psychological assessments were completed at both scanning sessions and at treatment weeks 4, 8, 12, and 24. Results IFN-α injection stimulated an acute inflammatory cytokine response and evoked fatigue that peaked between 4 and 12 weeks, preceding mood change by 4 weeks. In the brain, IFN-α induced an acute change in striatal microstructure that additionally predicted development of fatigue but not mood symptoms. Conclusions Our findings highlight qMT as an in vivo biomarker of central effects of peripheral inflammation. We demonstrate exquisite sensitivity of the striatum to IFN-α, implicate striatal perturbation in IFN-α-induced fatigue, and dissociate this from mechanisms underlying IFN-α-induced mood symptoms, providing empirical support for distinct neural substrates mediating actions on motivation and mood.

Interferon-α acutely impairs whole-brain functional connectivity network architecture - A preliminary study

Highlights • IFN-α induced deep topological changes in whole-brain functional network connectivity.• Global reduction in nodal connectivity and network efficiency observed within 4 h.• Local changes observed in a sub-network connecting striatum to cortex.• Global changes in network efficiency correlated tightly with associated mood change.

Waiting Impulsivity: The Influence of Acute Methylphenidate and Feedback.

Background: The ability to wait and to weigh evidence is critical to behavioral regulation. These behaviors are known as waiting and reflection impulsivity. In Study 1, we examined the effects of methylphenidate, a dopamine and norepinephrine reuptake inhibitor, on waiting and reflection impulsivity in healthy young individuals. In study 2, we assessed the role of learning from feedback in disorders of addiction. Methods: We used the recently developed 4-Choice Serial Reaction Time task and the Beads task. Twenty-eight healthy volunteers were tested twice in a randomized, double-blind, placebo-controlled cross-over trial with 20mg methylphenidate. In the second study, we analyzed premature responses as a function of prior feedback in disorders of addiction. Results: Study 1: Methylphenidate was associated with greater waiting impulsivity to a cue predicting reward along with faster responding to target onset without a generalized effect on reaction time or attention. Methylphenidate influenced reflection impulsivity based on baseline impulsivity. Study 2: More premature responses occurred after premature responses in stimulant-dependent subjects. Conclusions: We show that methylphenidate has dissociable effects on waiting and reflection impulsivity. Chronic stimulant exposure impairs learning from prior premature responses, suggesting a failure to learn that premature responding is suboptimal. These findings provide a greater mechanistic understanding of waiting impulsivity.

91. Acute inflammation modulates substantia nigra responses to stimulus novelty and may underpin effects on exploratory behaviour

Introduction: Humans are naturally inquisitive. This tendency is adaptive, serving to reduce uncertainty associated with novel stimuli. Dopaminergic substantia nigra (SN) has been shown to mediate effects of novelty and motivation to explore novel and potentially valuable outcomes. Interestingly, inflammation impairs rodent exploration, limiting exposure to uncertain outcomes during times of limited metabolic resource. Though changes in SN activity are observed during inflammation-induced psychomotor slowing whether they also mediate effects on novelty and exploratory behaviour remains unknown. Methods: We scanned 17 healthy human participants twice, 3 h after experimental inflammation (Typhoid vaccination) and placebo (saline injection). Familiarised and novel face and place stimuli were presented during fMRI and magnetisation transfer images acquired to aid visualisation of SN. Results: Typhoid vaccination was associated with an increase in IL-6 and IL-1ra group x time interaction F (1,16) = 6.91, p < 0.02, F (1,16) = 11.77, p < 0.003 demonstrating induction of mild systemic inflammation. Face and place stimuli were associated with anticipated main effects in fusiform face and parahippocampal place area respectively. Neither region showed an interaction with stimulus novelty (p < 0.001). Right SN [10,−17,−16] demonstrated anticipated sensitivity to novelty for places following placebo. However, this was lost following inflammation: group x novelty interaction (p < 0.001). Conclusion: We have previously described SN sensitivity to mild inflammation, these data suggest this may impair processing of stimulus novelty and underpin inflammatory effects on exploratory behaviour.

120. Does disease avoidance form a functional basis for stigmatisation towards the elderly

Background: Elderly individuals frequently experience segregation and greater social exclusion. Infected/diseased individuals experience similar isolation-disease avoidance though this typically resolves on recovery. Oaten has proposed that activation of a disease-avoidance system, responding to visible signs denoting disease (irrespective of their accuracy) may underpin stigma. Diseased/sick individuals are perceived as more disgusting suggesting that disgust may mediate this link. To address this we investigated implicit disgust/fear responses to old/young faces using a lexical decision making task. Methods: Thirty healthy participants (20 male, range 19–51 years) performed a speeded word non-word judgement on 240 disgust, fear and neutral words presented after 3-s presentation of a young/old/fearful/disgusted face (240 images taken from validated face databases). Words were subsequently rated for disgust and fear to obtain 120 participant-specific words rated for either disgust or fear for use in subsequent analyses. Results: Congruent disgust words/faces were associated with significant RT slowing. 2 (disgust-neutral/young face) × 2 (disgust neutral word) rmANOVA interaction F(1, 29) = 6.30, p < 0.02. A weak trend to speeded RT responses was observed to congruent fear words/faces F(1, 29) = 1.98, p = 0.17. Critically, old faces preceding disgust (but not fear) words were also associated with significant RT slowing, interaction F(1, 29) = 5.24, p < 0.03. Conclusions: Pictures of elderly faces are associated with implicit disgust responses supporting the proposition that disease avoidance mechanism may underpin stigma toward the elderly.