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.

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.

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.

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.

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.

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.

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.

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.

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

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.

Pedophilia is linked to reduced activation in hypothalamus and lateral prefrontal cortex during visual erotic stimulation.

BACKGROUND: Although pedophilia is of high public concern, little is known about underlying neural mechanisms. Although pedophilic patients are sexually attracted to prepubescent children, they show no sexual interest toward adults. This study aimed to investigate the neural correlates of deficits of sexual and emotional arousal in pedophiles. METHODS: Thirteen pedophilic patients and 14 healthy control subjects were tested for differential neural activity during visual stimulation with emotional and erotic pictures with functional magnetic resonance imaging. RESULTS: Regions showing differential activations during the erotic condition comprised the hypothalamus, the periaqueductal gray, and dorsolateral prefrontal cortex, the latter correlating with a clinical measure. Alterations of emotional processing concerned the amygdala-hippocampus and dorsomedial prefrontal cortex. CONCLUSIONS: Hypothesized regions relevant for processing of erotic stimuli in healthy individuals showed reduced activations during visual erotic stimulation in pedophilic patients. This suggests an impaired recruitment of key structures that might contribute to an altered sexual interest of these patients toward adults.

Favorite brands as cultural objects modulate reward circuit.

On the basis of the hypothesis that brands may function as reward stimuli, we investigated brain responses to favorite brands. Participants viewed brand logos while we measured cortical activity with functional magnetic resonance imaging. Results revealed activity in the striatum for favorite brands that positively correlated with sports and luxury characteristics, but negatively with attributions to a brand of rational choice. Reduced activation of a single region in the dorsolateral prefrontal cortex was demonstrated when viewing the most beloved brand, possibly suggesting reduced strategic reasoning on the basis of affect. The results propose that brands that have been associated with appetitive stimuli owing to marketing efforts engage brain networks similar to those engaged by artificially associated reward stimuli. Moreover, social stimuli may function as secondary inducers of reward mechanisms.

Thinking on luxury or pragmatic brand products: Brain responses to different categories of culturally based brands.

Culturally based brands have a high impact on people's economic actions. Here we aimed to examine whether socioeconomic information conveyed by certain classes of brands (prestigious versus pragmatic classes) differentially evoke brain response. We presented icons of brands while recording subject's brain activity during a functional magnetic resonance imaging (fMRI) session. After the experiment, we asked subjects to assess the brands according to different characteristics. Results revealed an active network of bilateral superior frontal gyri, hippocampus and posterior cingulate related to familiar brands in general. Brands of the category sports and luxury activated regions in medial prefrontal cortex (MPFC) and precuneus. In contrast, brands rated as value products activated the left superior frontal gyrus and anterior cingulate cortex (ACC). The results suggest an active cortical network related to cognitive control for value brands and a network known to be associated with self-relevant processing for prestigious brands. We discuss the results as differential engagement of the prefrontal cortex depending on the attributed characteristic of a brand.

Verbal memory encoding in patients with left-sided hippocampal sclerosis.

Patients with medial temporal lobe epilepsy based on left hippocampal sclerosis often show severe verbal memory deficits. Recent studies suggest that memory formation in these patients may be reallocated to the right hemisphere owing to left hippocampal pathology. To test this hypothesis, we used functional magnetic resonance imaging to examine encoding-related activity of verbal items in temporal lobe epilepsy patients with left hippocampal sclerosis and patients with idiopathic epilepsy as a control group. Results demonstrated that patients with idiopathic epilepsy showed more activation in both left and right hippocampi. The temporal lobe epilepsy group showed enhanced activation in left fusiform gyrus. We discuss these results in terms of different strategy use by the groups.

Hunger and satiety in anorexia nervosa: fMRI during cognitive processing of food pictures.

Neuroimaging studies of visually presented food stimuli in patients with anorexia nervosa have demonstrated decreased activations in inferior parietal and visual occipital areas, and increased frontal activations relative to healthy persons, but so far no inferences could be drawn with respect to the influence of hunger or satiety. Thirteen patients with AN and 10 healthy control subjects (aged 13-21) rated visual food and non-food stimuli for pleasantness during functional magnetic resonance imaging (fMRI) in a hungry and a satiated state. AN patients rated food as less pleasant than controls. When satiated, AN patients showed decreased activation in left inferior parietal cortex relative to controls. When hungry, AN patients displayed weaker activation of the right visual occipital cortex than healthy controls. Food stimuli during satiety compared with hunger were associated with stronger right occipital activation in patients and with stronger activation in left lateral orbitofrontal cortex, the middle portion of the right anterior cingulate, and left middle temporal gyrus in controls. The observed group differences in the fMRI activation to food pictures point to decreased food-related somatosensory processing in AN during satiety and to attentional mechanisms during hunger that might facilitate restricted eating in AN.

Human hippocampal and parahippocampal activity during visual associative recognition memory for spatial and nonspatial stimulus configurations.

Evidence from animal studies points to the importance of the parahippocampal region (PHR) [including entorhinal, perirhinal, and parahippocampal (PHC) cortices] for recognition of visual stimuli. Recent findings in animals suggest that PHR may also be involved in visual associative recognition memory for configurations of stimuli. Thus far, however, such involvement has not been demonstrated in humans. In fact, it has been argued that associative recognition in humans is critically dependent on the hippocampal formation (HF). To better understand the division of function between HF and PHR during recognition memory in humans, we measured the activity of both areas in healthy young adults during an associative recognition memory task using functional magnetic resonance imaging. To more precisely characterize the nature of the associations that might be coded by the HF and PHR during recognition, subjects were required to learn and were later tested for associations based on either the spatial arrangements of two stimuli or the identity of two stimuli (a face and a tool). An area in the PHC was found to be more active for recognized old configurations than new configurations in both the spatial and identity conditions. The HF, on the other hand, was more active for recognition of new configurations than old configurations and also more active in the spatial than the identity condition. These data highlight the involvement of PHR in the long-term coding of associative relationships between stimuli and help to clarify the nature of its functional distinction from the HF.

Viewing touch improves tactile sensory threshold.

Previous research on multisensory integration has demonstrated that viewing the stimulated body part enhances discrimination ability. Participants in this experiment watched a video showing a hand being touched by a stick and a second video showing the stick touching the space beneath the hand. Sensory thresholds of the index fingers were tested with von Frey filaments. We found significant enhancements of the sensory threshold after showing the video with the touched hand but not after showing the video with no touch of the hand. This enhancement was specific for the index finger shown in the video. The results link the visuotactile enhancement of this study to the observation of touch rather than to the simple depiction of the body part.

Seeing the hand being touched modulates the primary somatosensory cortex.

Recent behavioral studies have shown that viewing the stimulated body part can enhance tactile acuity. We examined effects of viewing the stimulated body part by using neuromagnetic source imaging. Study participants were covertly stimulated on their first digit (D1) while watching a video that showed a hand where D1 was stimulated. The video hand appeared in the region where the real hand would be expected. In addition, participants were stimulated on D1 without watching the video. The results demonstrated a shift of D1 to a more inferior position and an increase of the dipole strength of D1 during the observation of tactile stimulation. We discuss these cross-modal interactions with recent studies on visuotactile enhancement.

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.

Short-term plasticity of the primary somatosensory cortex during tool use.

Plastic changes within the primary somatosensory cortex (SI) related to tool use are reported. Subjects manipulated a small object with a pair of tongs or with their hand. Functional organization of SI during tool use was compared with that during executing the task with the fingers and during rest, respectively. Topography of SI was assessed using neuromagnetic source imaging based on tactile stimulation of the first (D1) and fifth digit (D5). We found that cortical representations of D1 and D5 are further apart during tool use than during non-tool use and rest. Our data suggest that somatosensory cortical maps are part of the neural network representing the modified schema of the hand in which the tool was incorporated.