A proteogenomic view of Parkinson's disease causality and heterogeneity.

The pathogenesis and clinical heterogeneity of Parkinson's disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into "endotypes". The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody.

Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases.

Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study.

BACKGROUND: Primary Sjögren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjögren's syndrome have shown efficacy. CD40-CD154-mediated T cell-B cell interactions in primary Sjögren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury. Therefore, we investigated the safety and preliminary efficacy of iscalimab (CFZ533), a novel anti-CD40 monoclonal antibody, in patients with primary Sjögren's syndrome. METHODS: This multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study took place at ten investigational sites across Europe (UK, n=4; Germany, Switzerland, and Hungary, n=1 each) and the USA (n=3). Eligible patients were aged 18-75 years and fulfilled the 2002 American European consensus group diagnostic classification criteria for primary Sjögren's syndrome. In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomisation numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 2). Randomisation was stratified according to baseline intake of oral corticosteroids. At week 12, patients in both cohorts received open-label iscalimab (same dose and route) for 12 weeks. The primary objectives of the study were to assess the safety, tolerability, and efficacy of multiple doses of iscalimab in the two sequential dose cohorts. Safety and tolerability were assessed by adverse events and efficacy of iscalimab versus placebo was assessed by clinical disease activity, as measured by the change in European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI) score after 12 weeks of treatment. Analyses were done on a per-protocol basis. The trial was registered with ClinicalTrials.gov, NCT02291029. FINDINGS: Between Oct 22, 2014, and June 28, 2016, we assessed 82 patients for eligibility (25 for cohort 1 and 57 for cohort 2). 38 patients were excluded because of ineligibility. In cohort 1, 12 patients were randomly assigned to receive either 3 mg/kg doses of iscalimab (n=8) or placebo (n=4), and in cohort 2, 32 patients were randomly assigned to receive either intravenous 10 mg/kg doses of iscalimab (n=21) or placebo (n=11). Adverse events were similar between iscalimab treatment groups and placebo groups, with adverse events occurring in all patients in cohort 1, and in 52% and 64% of the iscalimab and placebo groups, respectively, in cohort 2. Two serious adverse events were reported (one case of bacterial conjunctivitis in cohort 1 and one case of atrial fibrillation in cohort 2), which were unrelated to treatment with iscalimab. Intravenous treatment with iscalimab resulted in a mean reduction of 5·21 points (95% CI 0·96-9·46; one-sided p=0·0090) in ESSDAI score compared with placebo. There was no signficiant difference in ESSDAI score between subcutaneous iscalimab and placebo. INTERPRETATION: To our knowledge, this is the first randomised, placebo-controlled proof-of-concept study of a new investigational drug for primary Sjögren's syndrome that indicates preliminary efficacy. Our data suggest a role of CD40-CD154 interactions in primary Sjögren's syndrome pathology and the therapeutic potential for CD40 blockade in this disease should be investigated further. FUNDING: Novartis Pharma.

Lying and the Subsequent Desire for Toothpaste: Activity in the Somatosensory Cortex Predicts Embodiment of the Moral-Purity Metaphor.

It is well known from literature and religious ceremonies that there is a link between physical cleansing and moral transgressions. Only recently, psychological experiments explored this association and demonstrated that a threat to moral purity increases the demand of physical cleansing. Moreover, it has been shown that physical cleansing is actually efficacious to cope with threatened morality. This so-called Macbeth effect has been explained by an embodiment of the moral-purity metaphor. We tested this hypothesis by means of an functional magnetic resonsce imaging (fMRI) experiment. Participants were instructed to enact scenarios including either an immoral act (lying) or a moral deed (telling the truth). Subsequently, the participants were asked to rate the desirableness of various products. Results revealed that participants rated cleansing products (but not other goods) more desirable after performing an immoral than after a moral act. This Macbeth effect was accompanied by an active cortical network including sensorimotor brain areas during rating of cleansing products (but not while evaluating noncleansing goods). The results demonstrate neurobiological evidence for an embodiment of the moral-purity metaphor. Thus, abstract thoughts about morality can be grounded in sensory experiences.

Dirty deeds and dirty bodies: Embodiment of the Macbeth effect is mapped topographically onto the somatosensory cortex.

The theory of embodied cognition claims that knowledge is represented in modal systems derived from perception. Recent behavioral studies found evidence for this hypothesis, for example, by linking moral purity with physical cleansing (the Macbeth effect). Neurophysiological approaches provided further support by showing an involvement of sensorimotor cortices for embodied metaphors. However, the exact role of this brain region for embodied cognitions remains to be cleared. Here we demonstrate that the involvement of the sensorimotor cortex for the embodied metaphor of moral-purity is somatotopically organized. Participants enacted in scenarios where they had to perform immoral or moral acts either with their mouths or their hands. Results showed that mouthwash products were particularly desirable after lying in a voice mail and hand wash products were particularly desirable after writing a lie, thus demonstrating that the moral-purity metaphor is specific to the sensorimotor modality involved in earlier immoral behavior. FMRI results of this interaction showed activation in sensorimotor cortices during the evaluation phase that was somatotopically organized with respect to preceding lying in a voice mail (mouth-area) or in a written note (hand-area). Thus, the results provide evidence for a central role of the sensorimotor cortices for embodied metaphors.

Belief in a just world is associated with activity in insula and somatosensory cortices as a response to the perception of norm violations.

Previous studies identified a network of brain regions involved in the perception of norm violations, including insula, anterior cingulate cortex (ACC), and right temporoparietal junction area (RTPJ). Activations in these regions are suggested to reflect the perception of norm violations and unfairness. The current study aimed to test this hypothesis by exploring whether a personal disposition to perceive the world as being just is related to neural responses to moral evaluations. The just-world-hypothesis describes a cognitive bias to believe in a just world in which everyone gets what he or she deserves and deserves what he or she gets. Since it has been demonstrated that ACC, RTPJ, and insula are involved in the perception of unfairness, we hypothesized that individual differences in the belief in a just world are reflected by different activations of these brain areas. Participants were confronted with scenarios describing norm-violating or -confirming behavior. FMRI results revealed an activation of dorsal ACC, RTPJ, and insula when perceiving norm violations, but only activity in insula/somatosensory cortex correlated with the belief in a just world. Thus, our results suggest a role for insula/somatosensory cortex for the belief in a just world.

Rough primes and rough conversations: evidence for a modality-specific basis to mental metaphors.

How does our brain organize knowledge? Traditional theories assume that our knowledge is represented abstractly in an amodal conceptual network of formal logic symbols. The theory of embodied cognition challenges this view and argues that conceptual representations that constitute our knowledge are grounded in sensory and motor experiences. We tested this hypothesis by examining how the concept of social coordination is grounded metaphorically in the tactile sensation of roughness. Participants experienced rough or smooth touch before being asked to judge an ambiguous social interaction. Results revealed that rough touch made social interactions appear more difficult and adversarial, consistent with the rough metaphor. This impact of tactile cues on social impressions was accompanied by a network including primary and secondary somatosensory cortices, amygdala, hippocampus and inferior prefrontal cortex. Thus, the roughness of tactile stimulation affected metaphor-relevant (but not metaphor-irrelevant) behavioral and neural responses. Receiving touch from a rough object seems to trigger the application of associated ontological concepts (or scaffolds) even for unrelated people and situations (but not to unrelated or more general feelings). Since this priming was based on somatosensory brain areas, our results provide support for the theory that sensorimotor grounding is intrinsic to cognitive processes.

Communicative versus strategic rationality: Habermas theory of communicative action and the social brain.

In the philosophical theory of communicative action, rationality refers to interpersonal communication rather than to a knowing subject. Thus, a social view of rationality is suggested. The theory differentiates between two kinds of rationality, the emancipative communicative and the strategic or instrumental reasoning. Using experimental designs in an fMRI setting, recent studies explored similar questions of reasoning in the social world and linked them with a neural network including prefrontal and parietal brain regions. Here, we employed an fMRI approach to highlight brain areas associated with strategic and communicative reasoning according to the theory of communicative action. Participants were asked to assess different social scenarios with respect to communicative or strategic rationality. We found a network of brain areas including temporal pole, precuneus, and STS more activated when participants performed communicative reasoning compared with strategic thinking and a control condition. These brain regions have been previously linked to moral sensitivity. In contrast, strategic rationality compared with communicative reasoning and control was associated with less activation in areas known to be related to moral sensitivity, emotional processing, and language control. The results suggest that strategic reasoning is associated with reduced social and emotional cognitions and may use different language related networks. Thus, the results demonstrate experimental support for the assumptions of the theory of communicative action.

Mirror-like brain responses to observed touch and personality dimensions.

The last years have shown a growing interest in research on the neural mechanisms for perceiving and understanding social interactions. Only very recently, a role for somatosensation in social perception has been suggested. Numerous studies reported vicarious responses in the primary somatosensory cortex (SI) and other areas merely when seeing others being touched. Moreover, it has been demonstrated that these vicarious somatosensory responses can be linked with inter-individual differences in empathy. However, beyond empathy other personality traits have been shown to interact with social perception and behavior. Here we tested if personality traits according to the Five-Factor-Model interact with vicarious activation in somatosensory brain regions. We conducted a functional magnetic resonance imaging (fMRI) study in which subjects viewed video clips showing simple non-painful touch to a hand and a control condition including the same visual and motion parts. Results revealed vicarious somatosensory activation when viewing the touched hand, as expected. Vicarious activation in SI showed a trend for a positive correlation with the personality trait openness to experience. Moreover, mirror-like responses in the insula were strongly correlated with the personality trait conscientiousness, suggesting links to processes of self-control. We conclude that vicarious brain responses to seen touch seem to interact with personality traits.

Referral of touch and ownership between the hands and the role of the somatosensory cortices.

Recent studies have shown that the feeling of body ownership can be fooled by simple visuo-tactile manipulations. Perceptual illusions have been reported in which participants sense phantom touch seen on a rubber hand (rubber hand illusion). While previous studies used homologous limbs for those experiments, we here examined an illusion where people feel phantom touch on a left rubber hand when they see it brushed simultaneously with brushes applied to their right hand. Thus, we investigated a referral of touch from the right to the left hand (across the body midline). Since it is known from animal studies that tactile illusions may alter early sensory processing, we expected a modulation of the primary somatosensory cortex (SI) corresponding to this illusion. Neuromagnetic source imaging of the functional topographic organization in SI showed a shift in left SI, associated with the strength of the referral of touch. Hence, we argue that SI seems to be closely associated with this perceptual illusion. The results suggest that the transfer of tactile information across the body midline could be mediated by neurons with bilateral tactile receptive fields (most likely BA2).

Close to you: embodied simulation for peripersonal space in primary somatosensory cortex.

BACKGROUND: An increasing body of evidence has demonstrated that in contrast to the classic understanding the primary somatosensory cortex (SI) reflects merely seen touch (in the absence of any real touch on the own body). Based on these results it has been discussed that SI may play a role in understanding touch seen on other bodies. In order to further examine this understanding of observed touch, the current study aimed to test if mirror-like responses in SI are affected by the perspective of the seen touch. Thus, we presented touch on a hand and close to the hand either in first-person-perspective or in third-person-perspective. PRINCIPAL FINDINGS: Results of functional magnetic resonance imaging (fMRI) revealed stronger vicarious brain responses in SI/BA2 for touch seen in first-person-perspective. Surprisingly, the third-person viewpoint revealed activation in SI both when subjects viewed a hand being stimulated as well as when the space close to the hand was being touched. CONCLUSIONS/SIGNIFICANCE: Based on these results we conclude that vicarious somatosensory responses in SI/BA2 are affected by the viewpoint of the seen hand. Furthermore, we argue that mirror-like responses in SI do not only reflect seen touch, but also the peripersonal space surrounding this body (in third-person-perspective). We discuss these findings with recent studies on mirror responses for action observation in peripersonal space.

Touch and personality: extraversion predicts somatosensory brain response.

The Five-Factor-Model describes human personality in five core dimensions (extraversion, neuroticism, agreeableness, conscientiousness, and openness). These factors are supposed to have different neural substrates. For example, it has been suggested that behavioral differences between introverts and extraverts can be explained by the fact that introverts exhibit an inherent drive to compensate for overactive cortical activity in reticulo-thalamo-cortical pathways. The current study examined if responses in somatosensory cortices due to tactile stimulation are affected by personality traits. Based on previous studies and theoretical models we hypothesized a relationship of extraversion with somatosensory responses in primary somatosensory cortex (SI). In order to test this hypothesis we applied nonpainful tactile stimulation on the fingers of both hands of 23 healthy young participants (mean 25 years, standard deviation ± 2.8 years). Personality traits were assessed according to the Five-Factor-Model (NEO-FFI). Neuromagnetic source imaging revealed that the cortical activity (dipole strengths) for sources in SI were closely associated with the personality trait extraversion. Thus, the less extraverted the participants were, the higher was the cortical activity in SI. This relationship was in particular valid for the right hemisphere. We conclude that personality seems to depend on primary cortex activity. Furthermore, our results provide further evidence for an inter-hemispheric asymmetry of the social brain.

Embodied empathy for tactile events: Interindividual differences and vicarious somatosensory responses during touch observation.

A growing body of evidence suggests an involvement of the somatosensory cortices for social perception. For example, it has been shown that observing touch on other bodies (in the absence of any real touch on the own body) affects somatosensory brain areas. Thus, understanding others' sensory experiences seems to rely on vicarious activation of somatosensory cortices. Recent studies also demonstrated that observation of painful and nonpainful touch engages the observer's somatosensory cortex differentially. The somatosensory activation during observation of painful stimulation has been related to trait differences in empathy, thereby drawing the attention to inter-individual differences in vicarious somatosensory activation. The current study aims to test the hypothesis if vicarious somatosensory activation during observation of nonpainful touch is also linked to inter-individual differences in empathy. We employed a functional magnetic resonance imaging (fMRI) paradigm to present video clips showing simple non-painful touch with a paintbrush to a hand relative to a control condition including the same visual and motion parts. Results revealed vicarious somatosensory activation when seeing the hand being touched. This activation was associated with trait differences in interpersonal reactivity. Thus, we found that the somatosensory response in primary somatosensory cortex (SI) was associated with the empathy subscale perspective taking. This link demonstrates that vicarious somatosensory responses for simple touch are influenced by the observer's personality traits, therefore suggesting a role for personality traits in a putative mirror neuron system.

Sibutramine promotes amygdala activity under fasting conditions in obese women.

RATIONALE: Sibutramine, a centrally-acting selective monoamine reuptake inhibitor, has been used as an appetite suppressant drug in obesity. OBJECTIVES: To gain insight into the central nervous actions of sibutramine, brain responses to pictures of food items after sibutramine vs placebo application were assessed by functional magnetic resonance imaging (fMRI) in obese women. METHODS: In a randomized double-blind crossover design, 10 healthy obese women (BMI 31.8-39.9 kg/m(2)) received 15 mg/d of sibutramine vs placebo for 14 d. Obese participants, and a group of 10 age-matched normal weight controls, viewed pictures of food items and control objects in hungry and satiated states while lying in the MR scanner. The paradigm followed a block design. In obese participants, fMRI measurements were conducted prior and after two weeks of daily sibutramine or placebo administration, whereas control participants were scanned only at one point in time. RESULTS: Upon food item presentation, obese participants showed increased brain activity in areas related to emotional and reward processing, perceptual processing, and cognitive control as compared to normal weight controls. Sibutramine exerted a divergent satiety-dependent effect on amygdala activity in obese participants, increasing activity in the hungry state while decreasing it under conditions of satiation. CONCLUSIONS: Our results demonstrate a modulatory influence of sibutramine on amygdala activity in obese women which may underlie the appetite suppressant effects of the drug.

Combining a semantic differential with fMRI to investigate brands as cultural symbols.

Traditionally, complex cultural symbols like brands are investigated with psychological approaches. Often this is done by using semantic differentials, in which participants are asked to rate a brand regarding different pairs of adjectives. Only recently, functional magnetic resonance imaging (fMRI) has been used to examine brands. In the current work we used fMRI in combination with a semantic differential to cross-validate both methods and to improve the characterization of the basic factors constituting the semantic space. To this end we presented pictures of brands while recording subject's brain activity during an fMRI experiment. Results of the semantic differential arranged the brands in a semantic space illustrating their relationships to other cultural symbols. FMRI results revealed activation of the medial prefrontal cortex for brands that loaded high on the factor 'social competence', suggesting an involvement of a cortical network associated with social cognitions. In contrast, brands closely related to the factor 'potency' showed decreased activity in the superior frontal gyri, possibly related to working memory during task performance. We discuss the results as a different engagement of the prefrontal cortex when perceiving brands as cultural symbols.

Differential parametric modulation of self-relatedness and emotions in different brain regions.

Our sense of self is strongly colored by emotions although at the same time we are well able to distinguish affect and self. Using functional magnetic resonance imaging, we here tested for the differential effects of self-relatedness and emotion dimensions (valence, intensity) on parametric modulation of neural activity during perception of emotional stimuli. We observed opposite parametric modulation of self-relatedness and emotion dimensions in the dorsomedial prefrontal cortex and the ventral striatum/nucleus accumbens, whereas neural activity in subcortical regions (tectum, right amygdala, hypothalamus) was modulated by self-relatedness and emotion dimensions in the same direction. In sum, our results demonstrate that self-relatedness is closely linked to emotion dimensions of valence and intensity in many lower subcortical brain regions involved in basic emotional systems and, at the same time, distinct from them in higher cortical regions that mediate cognitive processes necessary for becoming aware of one's self, for example self-consciousness. Hum

Preceding attention and the dorsomedial prefrontal cortex: process specificity versus domain dependence.

The dorsomedial prefrontal cortex (DMPFC) has been shown to be involved in attending different states, all including a strong emotional component. It remains unclear, though, whether neural activity in the DMPFC is predominantly determined by either a particular domain, as emotional stimuli, or by a specific process, as attention. Here, we used functional magnetic resonance imaging to test the alternative hypotheses of domain- versus process-specificity in DMPFC. Subjects had to perceive pictures from three different domains, sexual, emotional, and neutral stimuli, in both a nonattended, i.e., unexpected, and attended, i.e., expected mode. Our results show DMPFC activation during attended, i.e., expected stimulus perception when compared with nonattended, i.e., unexpected stimuli perception. DMPFC activation and corresponding behavioral changes (reaction time, subjective ratings) were observed in all three domains, sexual, emotional, and neutral stimuli. As opposed to those process-specific effects that were found predominantly in posterior DMPFC, a process by domain interaction was found to be characteristic for more anterior parts of the DMPFC. Taken together, our findings favour the hypothesis that neural activity in the posterior DMPFC is determined by a specific process, i.e., attending stimuli, and thus characterized by process-specificity rather than by a particular domain, i.e., sexual, emotional, or neutral stimuli, reflecting domain-specificity. This suggests that the anterior and posterior DMPFC is involved in the process of attending mental states while remaining more (posterior DMPFC) or less (anterior DMPFC) independent of the type or domain of the respective stimulus.

My third arm: shifts in topography of the somatosensory homunculus predict feeling of an artificial supernumerary arm.

The classic understanding of the role of the primary somatosensory cortex (SI) is to be a first major unimodal area processing somatosensory input and reflecting the physical location of peripheral stimulation in the form of the famous homunculus. Whereas in the past this functional topography was believed to be fixed, recent studies challenge this view. For example, in upper extremity amputees the cortical representation of the mouth was found to invade the region that formerly represented the amputated limb. Moreover, several studies demonstrated dynamic modulations of the body map in SI by tactile illusions. The present study aims to further explore the role of SI by creating an illusion of feeling a supernumerary artificial limb. Using an artificial hand and arm that were connected to their body, subjects were given the visual impression that they had a supernumerary third arm. The topography in SI was examined with neuromagnetic source localization. Results revealed that the participants not only viewed the artificial arm but felt to have three arms. Thus, a simple visuo-tactile illusion evoked feelings of ownership of a supernumerary body part. Furthermore, during the illusion the cortical representation of the thumb shifted to a more medial and superior position. Because this modulation in SI could predict the strength of the feeling that the third arm was belonging to the own body, the results suggest that the somatosensory homunculus is reflecting the perceived shape of the body rather than physical aspects of peripheral stimulation even when feeling an artificial third arm.

Observing the touched body magnified alters somatosensory homunculus.

This study aimed to investigate effects of observing the own body being touched on the functional topography of the somatosensory homunculus. We used neuromagnetic source imaging to map the topography in primary somatosensory cortex (SI) while manipulating the visibility of a touched hand. Participants were either able to observe the stimulation in real size or strongly magnified. Results demonstrated a significant shift in SI when participants viewed their stimulated body compared with a rest state or with viewing a neutral object. The magnification of the seen stimulated hand similarly resulted in a shift of the cortical representation zone in SI. We discuss the results as dynamic interactions between vision and touch in SI via back projections from multimodal cortical areas.

Functional neuroanatomy of meaning acquisition from context.

An important issue in language learning is how new words are integrated in the brain representations that sustain language processing. To identify the brain regions involved in meaning acquisition and word learning, we conducted a functional magnetic resonance imaging study. Young participants were required to deduce the meaning of a novel word presented within increasingly constrained sentence contexts that were read silently during the scanning session. Inconsistent contexts were also presented in which no meaning could be assigned to the novel word. Participants showed meaning acquisition in the consistent but not in the inconsistent condition. A distributed brain network was identified comprising the left anterior inferior frontal gyrus (BA 45), the middle temporal gyrus (BA 21), the parahippocampal gyrus, and several subcortical structures (the thalamus and the striatum). Drawing on previous neuroimaging evidence, we tentatively identify the roles of these brain areas in the retrieval, selection, and encoding of the meaning.