Immunological and behavioral responses to in vivo lipopolysaccharide administration in young and healthy obese and normal-weight humans

Obesity is associated with an increase prevalence of neuropsychiatric symptoms and diseases, such as depression. Based on the facts that pro-inflammatory cytokines are able to modulate behavior, and that obesity is characterized by a chronic low-grade inflammatory state, inflammation has been hypothesized to contribute to the neuropsychiatric comorbidity in obese individuals. However, a causal link between inflammation and the development of neuropsychiatric symptoms is hard to establish in humans. Here, we used an inflammatory stimulus, i.e. the intravenous injection of lipopolysaccharide (LPS), in a double-blind placebo-controlled design, to determine the vulnerability of obese individuals to inflammation-induced behavioral changes. The hypothesis was that obese individuals would show heightened behavioral response compared to normal-weight subjects for the same inflammatory stimulus, reflecting an increased sensitivity to the behavioral effects of pro-inflammatory cytokines. LPS (dose 0.8 ng/kg body weight, adjusted for estimated blood volume in obese subjects) and placebo (saline) were intravenously injected in 14 obese healthy subjects and 23 normal-weight healthy subjects in a within-subject, randomized, crossover design. LPS administration induced, in both groups, an acute increase in blood concentrations of cytokines (interleukin-6, tumor necrosis factor-α, and IL-10), as well as in body temperature, cortisol, norepinephrine, sickness symptoms, fatigue, negative mood, and state anxiety. There were little differences in the immune and behavioral responses to LPS between obese and normal-weight subjects, but the cortisol response to LPS was strongly attenuated in obese individuals. Higher percentage of body fat was related to a lower cortisol response to LPS. Taken together, the population of young and healthy obese individuals in this study did not exhibit an increased behavioral sensitivity to cytokines, but an attenuated cortisol response to the immune challenge. Future studies will need to determine whether additional physiological and psychological factors interact with the state of obesity to increase the risk for inflammation-induced neuropsychiatric symptoms.     

Men and women differ in inflammatory and neuroendocrine responses to endotoxin but not in the severity of sickness symptoms

Impaired mood and increased anxiety represent core symptoms of sickness behavior that are thought to be mediated by pro-inflammatory cytokines. Moreover, excessive inflammation seems to be implicated in the development of mood/affective disorders. Although women are known to mount stronger pro-inflammatory responses during infections and are at higher risk to develop depressive and anxiety disorders compared to men, experimental studies on sex differences in sickness symptoms are scarce. Thus, the present study aimed at comparing physiological and psychological responses to endotoxin administration between men and women. Twenty-eight healthy volunteers (14 men, 14 women) were intravenously injected with a low dose (0.4 ng/kg) of lipopolysaccharide (LPS) and plasma concentrations of cytokines and neuroendocrine factors as well as negative state emotions were measured before and until six hours after LPS administration. Women exhibited a more profound pro-inflammatory response with significantly higher increases in tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, the LPS-induced increase in anti-inflammatory IL-10 was significantly higher in men. The cytokine alterations were accompanied by changes in neuroendocrine factors known to be involved in inflammation regulation. Endotoxin injection induced a significant increase in noradrenaline, without evidence for sex differences. The LPS-induced increase in cortisol was significantly higher in woman, whereas changes in dehydroepiandrosterone were largely comparable. LPS administration also increased secretion of prolactin, but only in women. Despite these profound sex differences in inflammatory and neuroendocrine responses, men and women did not differ in endotoxin-induced alterations in mood and state anxiety or non-specific sickness symptoms. This suggests that compensatory mechanisms exist that counteract the more pronounced inflammatory response in women, preventing an exaggerated sickness response. Disturbance of these compensatory mechanisms by environmental factors such as stress may promote the development of affective disorders in women.     

Impact of acute inflammation on the extinction of aversive gut memories

Impaired extinction of pain-related fear memories can lead to persistent or resurging fear of pain, contributing to the development and maintenance of chronic pain conditions. The mechanisms underlying maladaptive pain-related learning and memory processes remain incompletely understood, particularly in the context of interoceptive, visceral pain. Inflammation is known to interfere with learning and memory, but its effects on the extinction of pain-related fear memories have never been tested. In a randomized, double-blind, placebo-controlled study, we assessed the impact of experimental acute inflammation on the extinction and reinstatement of conditioned visceral pain-related fear. Forty healthy male volunteers underwent differential fear conditioning with visceral pain as clinically relevant unconditioned stimulus (US). Participants then received an intravenous injection of either 0.8 ng/kg lipopolysaccharide (LPS) as inflammatory stimulus or physiological saline as placebo, and extinction training was conducted at the peak of the inflammatory response. Extinction recall and reinstatement test were performed after overnight consolidation. Results showed that visceral pain represents an effective US, eliciting pronounced conditioned pain-related fear responses. Repeated unreinforced presentation of the pain-predictive cue during extinction training resulted in full extinction of the conditioned behavioral response. However, unexpected re-exposure to the US during reinstatement test resulted in return of fear. Despite pronounced LPS-induced effects on inflammatory markers, cortisol, and negative affect, we did not find evidence that acute inflammation resulted in altered fear extinction. The findings support the notion that visceral pain-related fear learning establishes a robust aversive memory trace that remains preserved during inhibitory learning, leaving a latent vulnerability for the return of fear. Inflammation during inhibitory learning did neither weaken nor further amplify this aversive memory trace, suggesting that it is rather resistant to acute inflammation-induced effects, at least in healthy individuals with no additional vulnerability factors.     

Glutamine preserves skeletal muscle force during an inflammatory insult

The purpose of this study was to test the hypothesis that acute glutamine (GLN) supplementation can counteract skeletal muscle contractile dysfunction occurring in response to inflammation by elevating muscle heat shock protein (Hsp) expression and reducing inflammatory cytokines. Mice received 5 mg/kg lipopolysaccharide (LPS) concurrently with 1 g/kg GLN or vehicle treatments. Plantarflexor isometric force production was measured at 2 hours post‐injection. Blood and gastrocnemius muscles were collected, and serum and muscle tumor necrosis factor‐alpha (TNF‐α) and interleukin‐6 (IL‐6) and muscle Hsp70 and Hsp25 were quantified. Saline/LPS treatment was associated with a 33% reduction in maximal force and elevated serum TNF‐α and IL‐6. GLN completely prevented this force decrement with LPS. GLN was found to reduce muscle Hsp70 and IL‐6, but only in the presence of LPS. GLN supplementation provides an effective, novel, clinically applicable means of preserving muscle force during acute inflammation. These data indicate that force preservation is not dependent on reductions in serum cytokines or muscle TNF‐α, or elevated Hsp levels. Muscle Nerve, 2009     

Experimental human endotoxemia enhances brain activity during social cognition

Acute peripheral inflammation with corresponding increases in peripheral cytokines affects neuropsychological functions and induces depression-like symptoms. However, possible effects of increased immune responses on social cognition remain unknown. Therefore, this study investigated the effects of experimentally induced acute inflammation on performance and neural responses during a social cognition task assessing Theory of Mind (ToM) ability. In this double-blind randomized crossover functional magnetic resonance imaging study, 18 healthy right-handed male volunteers received an injection of bacterial lipopolysaccharide (LPS; 0.4 ng/kg) or saline, respectively. Plasma levels of pro- and anti-inflammatory cytokines as well as mood ratings were analyzed together with brain activation during a validated ToM task (i.e. Reading the Mind in the Eyes Test). LPS administration induced pronounced transient increases in pro- (IL-6, TNF-α) and anti-inflammatory (IL-10, IL-1ra) cytokines as well as decreases in mood. Social cognition performance was not affected by acute inflammation. However, altered neural activity was observed during the ToM task after LPS administration, reflected by increased responses in the fusiform gyrus, temporo-parietal junction, superior temporal gyrus and precuneus. The increased task-related neural responses in the LPS condition may reflect a compensatory strategy or a greater social cognitive processing as a function of sickness.     

Serotonin transporter genotype (5-HTTLPR): effects of neutral and undefined conditions on amygdala activation.

BACKGROUND: A polymorphism of the human serotonin transporter gene (SCL6A4) has been associated with serotonin transporter expression and with processing of aversive stimuli in the amygdala. Functional imaging studies show that during the presentation of aversive versus neutral cues, healthy carriers of the short (s) allele showed stronger amygdala activation than long (l) carriers. However, a recent report suggested that this interaction is driven by amygdala deactivation during presentation of neutral stimuli in s carriers. METHODS: Functional MRI was used to assess amygdala activation during the presentation of a fixation cross or affectively aversive or neutral visual stimuli in 29 healthy men. RESULTS: Amygdala activation was increased in s carriers during undefined states such as the presentation of a fixation cross compared with emotionally neutral conditions. CONCLUSIONS: This finding suggests that s carriers show stronger amygdala reactivity to stimuli and contexts that are relatively uncertain, which we propose are stressful.     

Anti‐inflammatory effects of ADAMTS‐4 in a mouse model of ischemic stroke

ADAMTS‐4 (a disintegrin and metalloproteinase with thrombospondin motifs type 4) is a metalloprotease capable to degrade chondroitin sulfate proteoglycans leading to cartilage destruction during arthritis or to neuroplasticity during spinal cord injury (SCI). Although ADAMTS‐4 is an inflammatory‐regulated enzyme, its role during inflammation has never been investigated. The aim of this study was to investigate the role of ADAMTS‐4 in neuroinflammation. First, we evidenced an increase of ADAMTS‐4 expression in the ischemic brain hemisphere of mouse and human patients suffering from ischemic stroke. Then, we described that ADAMTS‐4 has predominantly an anti‐inflammatory effect in the CNS. Treatment of primary microglia or astrocyte cultures with low doses of a human recombinant ADAMTS‐4 prior to LPS exposure decreased NO production and the synthesis/release of pro‐inflammatory cytokines including NOS2, CCL2, TNF‐α, IL‐1β and MMP‐9. Accordingly, when cell cultures were transfected with silencing siRNA targeting ADAMTS‐4 prior to LPS exposure, the production of NO and the synthesis/release of pro‐inflammatory cytokines were increased. Finally, the feasibility of ADAMTS‐4 to modulate neuroinflammation was investigated in vivo after permanent middle cerebral artery occlusion in mice. Although ADAMTS‐4 treatment did not influence the lesion volume, it decreased astrogliosis and macrophage infiltration, and increased the number of microglia expressing arginase‐1, a marker of alternatively activated cells with inflammation inhibiting functions. Additionally, ADAMTS‐4 increased the production of IL‐10 and IL‐6 in the peri‐ischemic area. By having anti‐inflammatory and neuroregenerative roles, ADAMTS‐4 may represent an interesting target to treat acute CNS injuries, such as ischemic stroke, SCI or traumatic brain injury. GLIA 2016;64:1492–1507     

Multi-systemic evaluation of biological and emotional responses to the Trier Social Stress Test: A meta-analysis and systematic review

Humans experience multiple biological and emotional changes under acute stress. Adopting a multi-systemic approach, we summarized 61 studies on healthy people’s endocrinological, physiological, immunological and emotional responses to the Trier Social Stress Test. We found salivary cortisol and negative mood states were the most sensitive markers to acute stress and recovery. Biomarkers such as heart rate and salivary alpha-amylase also showed sensitivity to acute stress, but the numbers of studies were small. Other endocrinological (e.g., dehydroepiandrosterone), inflammatory (C-Reactive Protein, Interleukin-6) and physiological (e.g., skin conductance level) measures received modest support as acute stress markers. Salivary cortisol showed some associations with mood measures (e.g., state anxiety) during acute stress and recovery, and heart rate showed preliminary positive relationship with calmness ratings during response to TSST, but the overall evidence was mixed. While further research is needed, these findings provide updated and comprehensive knowledge on the integrated psychobiological response profiles to TSST.     

Blockade of IL‐15 activity inhibits microglial activation through the NFκB,p38, and ERK1/2 pathways,reducing cytokine and chemokine release

Reactive glia formation is one of the hallmarks of damage to the CNS, but little information exists on the signals that direct its activation. Microglial cells are the main regulators of both innate and adaptative immune responses in the CNS. The proinflammatory cytokine IL‐15 is involved in regulating the response of T and B cells, playing a key role in regulating nervous system inflammatory events. We have used a microglial culture model of inflammation induced by LPS and IFNγ to evaluate the role of IL‐15 in the proinflammatory response. Our results indicate that IL‐15 is necessary for the reactive response, its deficiency (IL‐15‐/‐) leading to the development of a defective proinflammatory response. Blockade of IL‐15, both with blocking antibodies or with the ganglioside Neurostatin, inhibited the activation of the NFκB pathway, decreasing iNOS expression and NO production. Inhibiting IL‐15 signaling also blocked the activation of the mitogen‐activated protein kinase (MAPK) pathways ERK1/2 and p38. The major consequence of these inhibitory effects, analyzed using cytokine antibody arrays, was a severe decrease in the production of chemokines, cytokines and growth factors, like CCL17, CCL19, IL‐12, or TIMP‐1, that are essential for the development of the phenotypic changes of glial activation. In conclusion, activation of the IL‐15 system seems a necessarystep for the development of glial reactivity and the regulation of the physiology of glial cells. Modulating IL‐15 activity opens the possibility of developing new strategies to control gliotic events upon inflammatory stimulation. © 2009 Wiley‐Liss, Inc.     

Pubertal-related changes in hypothalamic-pituitary-adrenal axis reactivity and cytokine secretion in response to an immunological stressor

Pubertal development is marked by profound changes in stress reactivity. For example, following a brief stressor, such as foot shock, ether inhalation or restraint, prepubertal rats display a prolonged adrenocorticotrophic hormone (ACTH) and corticosterone response that takes twice as long to return to baseline compared to adults. Pubertal‐related differences in the recovery of the hormonal stress response following a more protracted systemic stressor, such as an immunological challenge, have not yet been investigated. Moreover, it is unclear whether an immunological stressor leads to a differential cytokine response in animals before and after pubertal maturation. To examine these issues, we used a single injection of lipopolysaccharide (LPS; 0.1 mg/kg) to induce a hormonal stress and innate immune response and measured plasma ACTH, corticosterone, and the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐6 in prepubertal and adult male rats 0, 2, 4, 6, 8, or 24 h after LPS exposure. In a follow‐up experiment, we assessed neural activation, as indexed by FOS immunohistochemistry, in the paraventricular nucleus of the hypothalamus (PVN) in prepubertal and adult males 0, 4, 8, or 24 h after a 0.1 mg/kg injection of LPS. By contrast to the prolonged response observed in prepubertal animals following a variety of acute stressors, we found that corticosterone and IL‐6 responses induced by LPS recover toward baseline faster in prepubertal compared to adult rats. Along with these different peripheral responses, we also found that LPS‐induced neural activation in the PVN of prepubertal animals showed a faster return to baseline compared to adults. Together, these data indicate that prepubertal and adult animals react in distinct ways, both peripherally and centrally, to an immunological stressor.     

Emotional memory: separating content and context

It is now well established that emotion enhances episodic memory. However, it remains unclear whether the same neural processes underlie enhancement of memory for both emotional stimuli and neutral stimuli encoded in an emotive context. We designed an experiment that specifically attempted to separate these effects and that was validated on 30 participants. We then used functional magnetic resonance imaging (fMRI) to examine the neural correlates of encoding and retrieval of the two classes of stimuli in 12 healthy male volunteers. We predicted that aversive emotional context would enhance memory regardless of content and that activation of anterior cingulate would be inversely related to retrieval of aversive items. Both predictions were supported. Furthermore we demonstrated apparent asymmetrical lateralisation of activation in the hippocampal/parahippocampal complex during recognition of words from aversive sentences: more left-sided activation for neutral words from aversive contexts, and more right-sided activation for aversive content words. These findings, if applicable to the wider population, may have application in a range of psychiatric disorders where interactions between emotion and cognition are relevant.     

Inflammasome signaling at the heart of central nervous system pathology

Neuroinflammation is a complex innate response of neural tissue against harmful effects of diverse stimuli viz., pathogens, damaged cells and irritants within the Central Nervous System (CNS). Studies show that multiple inflammatory mediators including cytokines, chemokines and prostaglandins are elevated in the Cerebrospinal Fluid (CSF) and in post‐mortem brain tissues of patients with history of neuroinflammatory conditions as well as neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. The innate immunity mediators in the brain, namely microglia and astrocytes, express certain Pattern Recognition Receptors (PRRs), which are always on ‘high‐alert’ for pathogens or other inflammatory triggers and participate in the assembly and activation of the inflammasome. The inflammasome orchestrates the activation of the precursors of proinflammatory caspases, which in turn, cleave the precursor forms of interleukin‐1β, IL‐18 and IL‐33 into their active forms; the secretion of which leads to a potent inflammatory response, and/or influences the release of toxins from glial and endothelial cells. Altered expression of inflammasome mediators can either promote or inhibit neurodegenerative processes. Therefore, modulating the inflammasome machinery seems a better combat strategy than summarily suppressing all inflammation in most neuroinflammatory conditions. In the current review we have surveyed the identified triggers and pathways of inflammasome activation and the following events which ultimately accomplish the innate inflammatory response in the CNS, with a goal to provide an analytical insight into disease pathogenesis that might provide cues for devising novel therapeutic strategies. © 2010 Wiley‐Liss, Inc.     

Trait and state corticostriatal dysfunction in bipolar disorder during emotional face processing

Liu J, Blond BN, van Dyck LI, Spencer L, Wang F, Blumberg HP. Trait and state corticostriatal dysfunction in bipolar disorder during emotional face processing.
Bipolar Disord 2012: 14: 432–441. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Convergent evidence supports limbic, anterior paralimbic, and prefrontal cortex (PFC) abnormalities in emotional processing in bipolar disorder (BD) and suggests that some abnormalities are mood‐state dependent and others persist into euthymia. However, few studies have assessed elevated, depressed, and euthymic mood states while individuals processed emotional stimuli of varying valence to investigate trait‐ and state‐related neural system responses. Here, regional brain responses to positive, negative, and neutral emotional stimuli were assessed in individuals with BD during elevated, depressed, and euthymic mood states. Methods: One hundred and thirty‐four subjects participated in functional magnetic resonance imaging scanning while processing faces depicting happy, fearful, and neutral expressions: 76 with BD (18 in elevated mood states, 19 depressed, 39 euthymic) and 58 healthy comparison (HC) individuals. Analyses were performed for BD trait‐ and mood state‐related features. Results: Ventral anterior cingulate cortex (VACC), orbitofrontal cortex (OFC), and ventral striatum responses to happy and neutral faces were decreased in the BD group, compared to the HC group, and were not influenced by mood state. Elevated mood states were associated with decreased right rostral PFC activation to fearful and neutral faces, and depression was associated with increased left OFC activation to fearful faces. Conclusions: The findings suggest that abnormal VACC, OFC, and ventral striatum responses to happy and neutral stimuli are trait features of BD. Acute mood states may be associated with additional lateralized abnormalities of diminished right rostral PFC responses to fearful and neutral stimuli in elevated states and increased left OFC responses to fearful stimuli in depressed states.     

Effects of emotional arousal in the cerebral hemispheres: a study of oscillatory brain activity and event-related potentials.

OBJECTIVE: The present study aimed at examining the time course and topography of oscillatory brain activity and event-related potentials (ERPs) in response to laterally presented affective pictures. METHODS: Electroencephalography was recorded from 129 electrodes in 10 healthy university students during presentation of pictures from the international affective picture system. Frequency measures and ERPs were obtained for pleasant, neutral, and unpleasant pictures. RESULTS: In accordance with previous reports, a modulation of the late positive ERP wave at parietal recording sites was found as a function of emotional arousal. Early mid gamma band activity (GBA; 30-45 Hz) at 80 ms post-stimulus was enhanced in response to aversive stimuli only, whereas the higher GBA (46-65 Hz) at 500 ms showed an enhancement of arousing, compared to neutral pictures. ERP and late gamma effects showed a pronounced right-hemisphere preponderance, but differed in terms of topographical distribution. CONCLUSIONS: Late gamma activity may represent a correlate of widespread cortical networks processing different aspects of emotionally arousing visual objects. In contrast, differences between affective categories in early gamma activity might reflect fast detection of aversive stimulus features.     

Insula–amygdala functional connectivity is correlated with habituation to repeated negative images

Behavioral habituation during repeated exposure to aversive stimuli is an adaptive process. However, the way in which changes in self-reported emotional experience are related to the neural mechanisms supporting habituation remains unclear. We probed these mechanisms by repeatedly presenting negative images to healthy adult participants and recording behavioral and neural responses using functional magnetic resonance imaging. We were particularly interested in investigating patterns of activity in insula, given its significant role in affective integration, and in amygdala, given its association with appraisal of aversive stimuli and its frequent coactivation with insula. We found significant habituation behaviorally along with decreases in amygdala, occipital cortex and ventral prefrontal cortex (PFC) activity with repeated presentation, whereas bilateral posterior insula, dorsolateral PFC and precuneus showed increased activation. Posterior insula activation during image presentation was correlated with greater negative affect ratings for novel presentations of negative images. Further, repeated negative image presentation was associated with increased functional connectivity between left posterior insula and amygdala, and increasing insula–amygdala functional connectivity was correlated with increasing behavioral habituation. These results suggest that habituation is subserved in part by insula–amygdala connectivity and involves a change in the activity of bottom-up affective networks.     

Challenging the challenge: A randomized controlled trial evaluating the inflammatory response and pain perception of healthy volunteers after single-dose LPS administration,as a potential model for inflammatory pain in early-phase drug development

Background and aimsFollowing an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the acute inflammatory response induced by a human endotoxemia model, and its effect on pain perception using evoked pain tests in two different dose levels. We also attempted to determine whether combining a human endotoxemia challenge with measurement of pain thresholds in healthy subjects could serve as a model to study drug effects on inflammatory pain.Methods and resultsThis was a placebo-controlled, randomized, cross-over study in 24 healthy males. Twelve subjects were administered a bolus of 1 ng/kg LPS intravenously, and twelve 2 ng/kg LPS. Before days of placebo/LPS administration, subjects completed a full study day without study drug administration, but with identical pain threshold testing. Blood sampling and evoked pain tests (electrical burst and -stair, heat, pressure, and cold pressor test) were performed pre-dose and at frequent intervals up to 10hr post-dose. Data were analysed with a repeated-measures ANCOVA. For both dose levels, LPS induced an evident acute inflammatory response, but did not significantly affect any of the pain modalities. In a post-hoc analysis, lowering of pain thresholds was observed in the first 3 h after dosing, corresponding with the peak of the acute inflammatory response around 1–3 h post-dose.ConclusionMild acute systemic inflammation, as induced by 1 ng/kg and 2 ng/kg LPS intravenous administration, did not significantly change pain thresholds in this study. The endotoxemia model in combination with evoked pain tests is not suitable to study acute inflammatory hyperalgesia in healthy males.     

The effect of graded aversive stimuli on limbic and visual activation

Activation studies have shown that in response to evocative visual stimuli, brain activity increases in the visual cortex and limbic areas. However, non-affective characteristics of these images, such as color composition and visual complexity, confound the interpretation of these results. To address this issue, we had subjects rate over 100 images on aversive intensity (facial mutilation, dead bodies) and semantic complexity (number of objects subjects could name). From these images, we assembled digitized image sets of non-aversive, mild and strong intensity, balanced on semantic complexity and content (human faces and figures), and adjusted for color composition. A fourth condition consisted of a fixation cross on a blank screen. Thirteen subjects underwent eight positron emission tomography scans using the [(15)O] water methodology. Measurement of skin conductance was recorded simultaneously. All picture conditions, relative to the blank screen, activated the amygdalae and bilateral orbitofrontal cortex, while we found activation trends associated with increasing aversive content in the sub-lenticular region. Skin conductance increased during all picture conditions. Relative to the non-aversive pictures, aversive image content caused modulation of occipital and occipital-temporal cortex. These results demonstrated activation of the amygdala to salient, arousing stimuli, and not just aversive stimuli. In addition, they suggest that pictorial complexity, as indexed by our semantic measure, does not account for the modulation of visual cortex by aversive, emotional stimuli.     

Subthalamic nucleus stimulation affects incentive salience attribution in Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can induce nonmotor side effects such as behavioral and mood disturbances or body weight gain in Parkinson's disease (PD) patients. We hypothesized that some of these problems could be related to an altered attribution of incentive salience (ie, emotional relevance) to rewarding and aversive stimuli. Twenty PD patients (all men; mean age ± SD, 58.3 ± 6 years) in bilateral STN DBS switched ON and OFF conditions and 18 matched controls rated pictures selected from the International Affective Picture System according to emotional valence (unpleasantness/pleasantness) and arousal on 2 independent visual scales ranging from 1 to 9. Eighty‐four pictures depicting primary rewarding (erotica and food) and aversive fearful (victims and threat) and neutral stimuli were selected for this study. In the STN DBS ON condition, the PD patients attributed lower valence scores to the aversive pictures compared with the OFF condition (P < .01) and compared with controls (P < .01). The difference between the OFF condition and controls was less pronounced (P < .05). Furthermore, postoperative weight gain correlated with arousal ratings from the food pictures in the STN DBS ON condition (P < .05 compensated for OFF condition). Our results suggest that STN DBS increases activation of the aversive motivational system so that more relevance is attributed to aversive fearful stimuli. In addition, STN DBS–related sensitivity to food reward stimuli cues might drive DBS‐treated patients to higher food intake and subsequent weight gain. © 2011 Movement Disorder Society