On the functional anatomy of the urge-for-action

Several common neuropsychiatric disorders (e.g., obsessive-compulsive disorder, Tourette syndrome (TS), autistic spectrum disorder) are associated with unpleasant bodily sensations that are perceived as an urge for action. Similarly, many of our everyday behaviors are also characterized by bodily sensations that we experience as urges for action. Where do these urges originate? In this paper, we consider the nature and the functional anatomy of “urges-for-action,” both in the context of everyday behaviors such as yawning, swallowing, and micturition, and in relation to clinical disorders in which the urge-for-action is considered pathological and substantially interferes with activities of daily living (e.g., TS). We review previous frameworks for thinking about behavioral urges and demonstrate that there is considerable overlap between the functional anatomy of urges associated with everyday behaviors such as swallowing, yawning, and micturition, and those urges associated with the generation of tics in TS. Specifically, we show that the limbic sensory and motor regions—insula and mid-cingulate cortex—are common to all of these behaviors, and we argue that this “motivation-for-action” network should be considered distinct from an “intentional action” network, associated with regions of premotor and parietal cortex, which may be responsible for the perception of “willed intention” during the execution of goal-directed actions

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

Disgust Sensitivity and the Neurophysiology of Left- Right Political Orientations

Disgust has been described as the most primitive and central of emotions. Thus, it is not surprising that it shapes behaviors in a variety of organisms and in a variety of contexts—including homo sapien politics. People who believe they would be bothered by a range of hypothetical disgusting situations display an increased likelihood of displaying right-of-center rather than left-of-center political orientations. Given its primal nature and essential value in avoiding pathogens disgust likely has an effect even without registering in conscious beliefs. In this article, we demonstrate that individuals with marked involuntary physiological responses to disgusting images, such as of a man eating a large mouthful of writhing worms, are more likely to self-identify as conservative and, especially, to oppose gay marriage than are individuals with more muted physiological responses to the same images. This relationship holds even when controlling for the degree to which respondents believe themselves to be disgust sensitive and suggests that people’s physiological predispositions help to shape their political orientations

European integration assessed in the light of the 'rules vs. standards debate'

The interplay of various legal systems in the European Union (EU) has long triggered a debate on the tension between uniformity and diversity of Member States' (MS) laws. This debate takes place among European legal scholars and is also paralleled by economic scholars, e.g. in the ambit of the 'theory of federalism'. This paper takes an innovative perspective on the discrepancy between 'centralized' and 'decentralized' law-making in the EU by assessing it with the help of the rules versus standards debate. When should the EU legislator grant the national legislator leeway in the formulation of new laws and when should all be fixed ex ante at European level? The literature on the 'optimal shape of legal norms' shall be revisited in the light of law-making in the EU, centrally dealing with the question how much discretion shall be given to the national legislator; and under which circumstances. This paper enhances the established decisive factors for the choice of a rule or a standard in a national setting (complexity, volatility, judges' specialization and frequency of application) by two new crucial factors (switching costs and the benefit of uniformity in terms of information costs) in order to assess law-making policies at EU level

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44⁺ Natural Killer Cells in Ulcerative Colitis

Background &amp; Aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC.</p

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44⁺ Natural Killer Cells in Ulcerative Colitis

Background &amp; Aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC.</p

Chondroitin sulfates and their binding molecules in the central nervous system

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in the central nervous system (CNS) matrix. Its sulfation and epimerization patterns give rise to different forms of CS, which enables it to interact specifically and with a significant affinity with various signalling molecules in the matrix including growth factors, receptors and guidance molecules. These interactions control numerous biological and pathological processes, during development and in adulthood. In this review, we describe the specific interactions of different families of proteins involved in various physiological and cognitive mechanisms with CSs in CNS matrix. A better understanding of these interactions could promote a development of inhibitors to treat neurodegenerative diseases

Oral Abstracts 7: RA ClinicalO37. Long-Term Outcomes of Early RA Patients Initiated with Adalimumab Plus Methotrexate Compared with Methotrexate Alone Following a Targeted Treatment Approach

Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naïve early (<1 year) RA patients. Therapy was adjusted at week 26: ADA + MTX-responders (R) who achieved DAS28 (CRP) <3.2 at weeks 22 and 26 (Period 1, P1) were re-randomized to withdraw or continue ADA and PBO + MTX-R continued randomized therapy for 52 weeks (P2); IR-patients received open-label (OL) ADA + MTX during P2. This post hoc analysis evaluated the proportion of patients at week 78 with DAS28 (CRP) <3.2, HAQ-DI <0.5, and/or ΔmTSS ≤0.5 by initial treatment. To account for patients who withdrew ADA during P2, an equivalent proportion of R was imputed from ADA + MTX-R patients. Results: At week 26, significantly more patients had low disease activity, normal function, and/or no radiographic progression with ADA + MTX vs PBO + MTX (Table 1). Differences in clinical and functional outcomes disappeared following additional treatment, when PBO + MTX-IR (n = 348/460) switched to OL ADA + MTX. Addition of OL ADA slowed radiographic progression, but more patients who received ADA + MTX from baseline had no radiographic progression at week 78 than patients who received initial PBO + MTX. Conclusions: Early RA patients treated with PBO + MTX achieved comparable long-term clinical and functional outcomes on a group level as those who began ADA + MTX, but only when therapy was optimized by the addition of ADA in PBO + MTX-IR. Still, ADA + MTX therapy conferred a radiographic benefit although the difference did not appear to translate to an additional functional benefit. Disclosures: P.E., AbbVie, Merck, Pfizer, UCB, Roche, BMS—Provided Expert Advice, Undertaken Trials, AbbVie—AbbVie sponsored the study, contributed to its design, and participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. R.F., AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, AstraZeneca, BMS, Janssen, Lilly, Novartis—Research Grants, Consultation Fees. S.F., AbbVie—Employee, Stocks. A.K., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB—Research Grants, Consultation Fees. H.K., AbbVie—Employee, Stocks. S.R., AbbVie—Employee, Stocks. J.S., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, GlaxoSmithKline, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB—Research Grants, Consultation Fees. R.V., AbbVie, BMS, GlaxoSmithKline, Human Genome Sciences, Merck, Pfizer, Roche, UCB Pharma—Consultation Fees, Research Support. Table 1.Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response ADA + MTX, n/N (%)a PBO + MTX, n/N (%)b Outcome Week 26 Week 52 Week 78 Week 26 Week 52 Week 78 DAS28 (CRP) <3.2 246/466 (53) 304/465 (65) 303/465 (65) 139/460 (30)*** 284/460 (62) 300/460 (65) HAQ-DI <0.5 211/466 (45) 220/466 (47) 224/466 (48) 150/460 (33)*** 203/460 (44) 208/460 (45) ΔmTSS ≤0.5 402/462 (87) 379/445 (86) 382/443 (86) 330/459 (72)*** 318/440 (72)*** 318/440 (72)*** DAS28 (CRP) <3.2 + ΔmTSS ≤0.5 216/462 (47) 260/443 (59) 266/443 (60) 112/459 (24)*** 196/440 (45) 211/440 (48)*** DAS28 (CRP) <3.2 + HAQ-DI <0.5 + ΔmTSS ≤0.5 146/462 (32) 168/443 (38) 174/443 (39) 82/459 (18)*** 120/440 (27)*** 135/440 (31)** aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: ΔmTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-squar

Sense of agency in the human brain

In adult life, people normally know what they are doing. This experience of controlling one's own actions and, through them, the course of events in the outside world is called 'sense of agency'. It forms a central feature of human experience; however, the brain mechanisms that produce the sense of agency have only recently begun to be investigated systematically. This recent progress has been driven by the development of better measures of the experience of agency, improved design of cognitive and behavioural experiments, and a growing understanding of the brain circuits that generate this distinctive but elusive experience. The sense of agency is a mental and neural state of cardinal importance in human civilization, because it is frequently altered in psychopathology and because it underpins the concept of responsibility in human societies