In functional magnetic resonance imaging (fMRI) studies that apply a "subsequent memory" approach, successful encoding is indicated by increased fMRI activity during the encoding phase for hits vs. misses, in areas underlying memory encoding such as the hippocampal formation. Signal-detection theory (SDT) can be used to analyze memory-related fMRI activity as a function of the participant's memory trace strength (d(')). The goal of the present study was to use SDT to examine the relationship between fMRI activity during incidental encoding and participants' recognition performance. To implement a new approach, post-experimental group assignment into High- or Low Performers (HP or LP) was based on 29 healthy participants' recognition performance, assessed with SDT. The analyses focused on the interaction between the factors group (HP vs. LP) and recognition performance (hits vs. misses). A whole-brain analysis revealed increased activation for HP vs. LP during incidental encoding for remembered vs. forgotten items (hits > misses) in the insula/temporo-parietal junction (TPJ) and the fusiform gyrus (FFG). Parameter estimates in these regions exhibited a significant positive correlation with d('). As these brain regions are highly relevant for salience detection (insula), stimulus-driven attention (TPJ), and content-specific processing of mnemonic stimuli (FFG), we suggest that HPs' elevated memory performance was associated with enhanced attentional and content-specific sensory processing during the encoding phase. We provide first correlative evidence that encoding-related activity in content-specific sensory areas and content-independent attention and salience detection areas influences memory performance in a task with incidental encoding of facial stimuli. Based on our findings, we discuss whether the aforementioned group differences in brain activity during incidental encoding might constitute the basis of general differences in memory performance between HP and LP.

Recent evidence suggests that the experience of stress can be communicated between individuals via chemosensory cues. Little is known, however, about the impact of these cues on neurophysiological responses during a socially threatening situation. In the current investigation we implemented a widely used paradigm to study social exclusion-Cyberball-to examine whether chemosensory cues signaling anxiety modulate the neuronal effects of ostracism. In a double-blind, within-subjects design, 24 healthy, normosmic participants were presented with chemosensory cues of anxiety (or control samples) and completed the Cyberball task while in a 3T fMRI scanner. Axillary sweat collected from male students awaiting an oral examination served as the anxiety cues while the chemosensory control stimuli consisted of sweat collected from the same individuals participating in an ergometer training session. The neuroimaging data revealed that under the control chemosensory condition, exclusion from Cyberball was associated with significantly higher orbitofrontal cortex and anterior cingulate cortex activity, which is consistent with previous studies in the field. However, when participants were primed with the anxiety sweat, the activity in these regions was not observed. Further, under exposure to anxiety cues during ostracism the participants showed deactivations in brain regions involved in memory (hippocampus), social cognition (middle temporal gyrus, superior temporal gyrus) and processing of salience (inferior frontal gyrus). These results suggest that successful communication of anxiety via the chemosensory domain may moderate the experience of social exclusion. It is possible that the anxiety signals make it easier for the individuals to detach from the group, pointing to the communicative role of chemosensory anxiety cues in enhancing adjustment mechanisms in light of a distressing situation.

Despite a fundamental interest in the relationship between structure and function, the relationships between measures of white matter microstructural coherence and functional brain responses to pain are poorly understood. We investigated whether fractional anisotropy (FA) in 2 white matter regions in pathways associated with pain is related to the functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to thermal stimulation. BOLD fMRI was measured from 16 healthy male subjects during painful thermal stimulation of the right arm. Diffusion-weighted images were acquired for each subject and FA estimates were extracted from the posterior internal capsule and the cingulum (cingulate gyrus). These values were then included as covariates in the fMRI data analysis. We found BOLD response in the midcingulate cortex (MCC) to be positively related to FA in the posterior internal capsule and negatively related to FA in the cingulum. Our results suggest that the MCC's involvement in processing pain can be further delineated by considering how the magnitude of the BOLD response is related to white matter microstructural coherence and to subjective perception of pain. Considering relationships to white matter microstructural coherence in tracts involved in transmitting information to different parts of the pain network can help interpretation of MCC BOLD activation.

The neuropathological hallmark of the autosomal dominantly inherited, neurodegenerative disorder Huntington's disease is progressive striatal loss starting several years prior to symptom manifestation. Magnetic resonance (MR) imaging has been widely used to detect altered structure in premanifest and early Huntington's disease. Given that neurodegeneration is likely preceded by substantial neuronal dysfunction, we used in vivo sodium MR imaging, which has been shown to be sensitive to cell death and viability, to investigate cellular and metabolic integrity of Huntington's disease brain tissue. We studied a total of thirteen healthy controls and thirteen Huntington's disease gene carriers (11 manifest and 2 premanifest). The manifest Huntington's disease group was subdivided into stages 1 and 2 according to their Total Functional Capacity scores. Clinical total motor and cognitive scores, as well as calibrated sodium and T1-weighted MR images were obtained with a 4 T Siemens MR scanner. Sodium images were acquired by means of a constant time imaging technique with an ultra-short "echo time". T1-weighted MR images were further analysed with voxel-based morphometry. The absolute total sodium concentration and grey matter values were measured in several Huntington's disease-specific and also non-specific areas. Statistical analysis of variance and Pearson correlation were applied. In Huntington's disease subjects, we found an increase of total sodium concentration of the entire brain compared to controls. Increased total sodium concentration values were found in structurally affected, but also in some non-affected, regions. The highest total sodium concentration values were found in the bilateral caudate, which was associated with caudate grey matter atrophy and CAG repeat length. In all Huntington's disease subjects we further found a profound increase of total sodium concentration in the putamen, pallidum, thalamus, hippocampus, insula, precuneus and occipital cortex compared to controls. No change of total sodium concentration was observed in the amygdala, pre- and postcentral gyrus, frontal and temporal cortices or in the cerebellum. This is the first in vivo sodium MR imaging study carried out on a 4 T MR scanner in Huntington's disease gene carriers demonstrating a significant enhancement in sodium concentration in the bilateral striatum, a key region in Huntington's disease, and also in other disease-related atrophic areas. Sodium MR imaging may provide a deeper insight into the pathophysiological mechanisms of tissue degeneration in Huntington's disease, presenting potential to detect changes preceding neurodegeneration.

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive administration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200 mg/kg) and 10-day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1 ± 1.1, 41.5 ± 0.5 and 85.1 ± 5.9 in untreated, HAB treated and SU+HAB treated rats, respectively). In rats, repetitive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted.

SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077.

Animal studies suggest a causal link between testosterone and aggression. However, in human research the exact role of this hormone is still unclear, having been linked to dominance and approach behavior rather than to aggression per se. In a social context, the induction of aggression might be confounded with dominance or status changes, which potentially influence the association between aggression and testosterone. The objective of the current study was to investigate the influence of testosterone on non-social aggression in a double-blind, placebo-controlled experiment including 90 healthy male participants. To this end, we developed an innovative paradigm in which participants were provoked by a malfunctioning joystick restraining them from a promised reward. As measures for aggression throughout the task the joystick amplitude was recorded and anger was assessed via emotional self-ratings. Participants reacted to the provocation with a significant shift to more negative emotions and increased implicit aggressive behavior, reflected in the force exerted to pull the joystick following provocation. Importantly, the study demonstrated first evidence for a modulating influence of testosterone on non-social aggression in males: Self-rated anger was significantly elevated in the testosterone group compared to the placebo group as a function of provocation. Testosterone administration did not significantly influence the implicit aggressive response. These findings demonstrate a potentiating effect of testosterone on provocation-related anger in a non-social context. Furthermore, the results highlight the importance of disentangling different components of aggression and characterizing different influencing factors when inferring on hormonal effects.

Schizophrenia is a severe neuropsychiatric disorder with high heritability, though its exact etiopathogenesis is yet unknown. An increasing number of studies point to the importance of white matter anomalies in the pathophysiology of schizophrenia. While several studies have identified the impact of schizophrenia susceptibility gene variants on gray matter anatomy in both schizophrenia patients and healthy risk variant carriers, studies dealing with the impact of these gene variants on white matter integrity are still scarce. We here present a study on the effects of a Dysbindin schizophrenia susceptibility gene variant on fiber tract integrity in healthy young subjects. 101 subjects genotyped for Dysbindin-gene variant rs1018381, though without personal or first degree relative history of psychiatric disorders underwent diffusion tensor imaging (DTI), 83 of them were included in the final analysis. We used Tract-Based Spatial Statistics (TBSS) analysis to delineate the major fiber tracts. Carriers of the minor allele T of the rs1018381 in the Dysbindin gene showed two clusters of reduced fractional anisotropy (FA) values in the perihippocampal region of the right temporal lobe compared to homozygote carriers of the major allele C. Clusters of increased FA values in T-allele carriers were found in the left prefrontal white matter, the right fornix, the right midbrain area, the left callosal body, the left cerebellum and in proximity of the right superior medial gyrus. Dysbindin has been implicated in neurite outgrowth and morphology. Impairments in anatomic connectivity as found associated with the minor Dysbindin allele in our study may result in increased risk for schizophrenia due to altered fiber tracts.

Considerable variability across individuals has been reported in both the behavioral and fMRI blood oxygen level-dependent (BOLD) response to nicotine. We aimed to investigate (1) whether there is a heterogeneous effect of nicotine on behavioral and BOLD responses across participants and (2) if heterogeneous BOLD responses are associated with behavioral performance measures. In this double-blind, placebo-controlled, cross-over study, 41 healthy participants (19 smokers)--drawn from a larger population-based sample--performed a visual oddball task after acute challenge with 1 mg nasal nicotine. fMRI data and reaction time were recorded during performance of the task. Across the entire group of subjects, we found increased activation in the anterior cingulate cortex, middle frontal gyrus, superior temporal gyrus, post-central gyrus, planum temporal and frontal pole in the nicotine condition compared with the placebo condition. However, follow-up analyses of this difference in activation between the placebo and nicotine conditions revealed that some participants showed an increase in activation while others showed a decrease in BOLD activation from the placebo to the nicotine condition. A reduction of BOLD activation from placebo to nicotine was associated with a decrease in reaction time and reaction time variability and vice versa, suggesting that it is the direction of BOLD response to nicotine which is related to task performance. We conclude that the BOLD response to nicotine is heterogeneous and that the direction of response to nicotine should be taken into account in future pharmaco-fMRI research on the central action of nicotine.

Emotions are often encountered in a multimodal fashion. Consequently, contextual framing by other modalities can alter the way that an emotional facial expression is perceived and lead to emotional conflict. Whole brain fMRI data was collected when 35 healthy subjects judged emotional expressions in faces while concurrently being exposed to emotional (scream, laughter) or neutral (yawning) sounds. The behavioral results showed that subjects rated fearful and neutral faces as being more fearful when accompanied by screams than compared to yawns (and laughs for fearful faces). Moreover, the imaging data revealed that incongruence of emotional valence between faces and sounds led to increased activation in the middle cingulate cortex, right superior frontal cortex, right supplementary motor area as well as the right temporoparietal junction. Against expectations no incongruence effects could be found in the amygdala. Further analyses revealed that, independent of emotional valence congruency, the left amygdala was consistently activated when the information from both modalities was emotional. If a neutral stimulus was present in one modality and emotional in the other, activation in the left amygdala was significantly attenuated. These results indicate that incongruence of emotional valence in audiovisual integration activates a cingulate-fronto-parietal network involved in conflict monitoring and resolution. Furthermore in audiovisual pairing amygdala responses seem to signal also the absence of any neutral feature rather than only the presence of an emotionally charged one.

Echo time dependence of the BOLD sensitivity is an important topic in fMRI whenever brain regions are considered where the EPI data quality suffers from susceptibility gradients. Here, an fMRI study is presented showing that a reduced echo time EPI sequence significantly enhances the statistical inference in subcortical (limbic) brain regions, with special focus on the amygdala. As a consequence, to facilitate whole-brain fMRI with optimal echo times, a sequence with slice-dependent echo time is demonstrated with a focus on structures suffering from susceptibility changes. The applicability of this method is shown in a second fMRI study aimed at both, cortical, and limbic brain regions. The results are in good agreement with theoretical descriptions of the BOLD sensitivity under the influence of susceptibility gradients.

Previous studies of somatosensory object discrimination have been focused on the primary and secondary sensorimotor cortices. However, we expected the prefrontal cortex to also become involved in sequential tactile discrimination on the basis of its role in working memory and stimulus discrimination as established in other domains. To investigate the contributions of the different cerebral structures to tactile discrimination of sequentially presented objects, we obtained event-related functional magnetic resonance images from seven healthy volunteers. Our results show that right hand object exploration involved left sensorimotor cortices, bilateral premotor, parietal and temporal cortex, putamen, thalamus, and cerebellum. Tactile exploration of parallelepipeds for subsequent object discrimination activated further areas in the dorsal and ventral portions of the premotor cortex, as well as parietal, midtemporal, and occipital areas of both cerebral hemispheres. Discriminating a parallelepiped from the preceding one involved a bilateral prefrontal-anterior cingulate-superior temporal-posterior parietal circuit. While the prefrontal cortex was active with right hemisphere dominance during discrimination, there was left hemispheric prefrontal activation during the delay period between object presentations. Delay related activity was further seen in the anterior intraparietal area and the fusiform gyrus. The results reveal a prominent role of the human prefrontal cortex for somatosensory object discrimination in correspondence with recent models on stimulus discrimination and working memory.

Tourette syndrome is a neuropsychiatric disorder with the cardinal symptoms of motor and vocal tics. Often tics are accompanied by comorbidities such as obsessive-compulsive disorder, attention-deficit-hyperactivity disorder or depression. Research has mainly focused on the cortico-striato-thalamo circuit, but clinical symptoms and recent neuroimaging studies reporting altered resting network connectivity have suggested abnormalities in Tourette syndrome beyond the major motor circuits. We acquired diffusion-weighted data at 1.5T in nineteen adult patients fulfilling the DSM-IV-TR criteria for Tourette syndrome and in a healthy control group. Diffusion tensor imaging (DTI) analysis in our adult TS sample shows a decrease of FA and increase in radial diffusivity in the corticospinal tract. There are widespread changes (reduced FA and increased radial diffusivity) in the anterior and posterior limb of the internal capsule. Furthermore, it confirms prior findings of altered interhemispheric connectivity as indicated by a FA-decrease in the corpus callosum. In addition, our results indicate that TS is not restricted to motor pathways alone but affects association fibres such as the inferior fronto-occipitalis fascicle, the superior longitudinal fascicle and fascicle uncinatus as well. Tics are the hallmark of Tourette syndrome, so the involvement of the corticospinal tract fits in well with clinical symptoms. Cortical regions as well as limbic structures take part in the modulation of tics. Our findings of alterations in long association fibre tracts and the corpus callosum are a potential source for hindered interhemispheric and transhemispheric interaction. The change in radial diffusivity points toward a deficit in myelination as one pathophysiological factor in Tourette syndrome.

The tumor necrosis factor (TNF)-receptor 1-associated death domain protein (TRADD) mediates induction of apoptosis as well as activation of NF-kappaB by cellular TNF-receptor 1 (TNFR1). TRADD is also recruited by the latent membrane protein 1 (LMP1) oncoprotein of Epstein-Barr virus, but its role in LMP1 signaling has remained enigmatic. In human B lymphocytes, we have generated, to our knowledge, the first genetic knockout of TRADD to investigate TRADD's role in LMP1 signal transduction. Our data from TRADD-deficient cells demonstrate that TRADD is a critical signaling mediator of LMP1 that is required for LMP1 to recruit and activate I-kappaB kinase beta (IKKbeta). However, in contrast to TNFR1, LMP1-induced TRADD signaling does not induce apoptosis. Searching for the molecular basis for this observation, we characterized the 16 C-terminal amino acids of LMP1 as an autonomous and unique virus-derived TRADD-binding domain. Replacing the death domain of TNFR1 by LMP1's TRADD-binding domain converts TNFR1 into a nonapoptotic receptor that activates NF-kappaB through a TRAF6-dependent pathway, like LMP1 but unlike wild-type TNFR1. Thus, the unique interaction of LMP1 with TRADD encodes the transforming phenotype of viral TRADD signaling and masks TRADD's pro-apoptotic function.

Pridopidine is an oral drug in clinical development for treatment of patients with Huntington's disease. This study examined the interactions of pridopidine with in vitro cytochrome P450 activity and characterized the effects of pridopidine on CYP2D6 activity in healthy volunteers using metoprolol as a probe substrate. The effect of food on pridopidine exposure was assessed.

Precise and comprehensive mapping of somatotopic representations in the motor cortex is clinically essential to achieve maximum resection of brain tumours whilst preserving motor function, especially since the current gold standard, that is, intraoperative direct cortical stimulation (DCS), holds limitations linked to the intraoperative setting such as time constraints or anatomical restrictions. Non-invasive techniques are increasingly relevant with regard to pre-operative risk-assessment. Here, we assessed the congruency of neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) with DCS. The motor representations of the hand, the foot and the tongue regions of 36 patients with intracranial tumours were mapped pre-operatively using nTMS and fMRI and by intraoperative DCS. Euclidean distances (ED) between hotspots/centres of gravity and (relative) overlaps of the maps were compared. We found significantly smaller EDs (11.4 ± 8.3 vs. 16.8 ± 7.0 mm) and better spatial overlaps (64 ± 38% vs. 37 ± 37%) between DCS and nTMS compared with DCS and fMRI. In contrast to DCS, fMRI and nTMS mappings were feasible for all regions and patients without complications. In summary, nTMS seems to be the more promising non-invasive motor cortex mapping technique to approximate the gold standard DCS results.

Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). One study was an open-label 2-part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.5, 15, and 22.5 mg) compared with tetrabenazine 25 mg. The second study was an open-label 5-way crossover study in healthy volunteers (n = 32) to evaluate relative bioavailability of 4 dose levels of the commercial formulation of deutetrabenazine (6, 12, 18, and 24 mg) with a standard meal and 18 mg with a high-fat meal. Both studies confirmed longer half-lives for active metabolites and lower peak-to-trough fluctuations for the sum of the metabolites (total [α+β]-HTBZ) following deutetrabenazine compared with tetrabenazine (3- to 4-fold and 11-fold, respectively) in steady-state conditions. Deutetrabenazine doses estimated to provide total (α+β)-HTBZ exposure comparable to tetrabenazine 25 mg were 11.4-13.2 mg. Food had no effect on exposure to total (α+β)-HTBZ, as measured by AUC. Although the total (α+β)-HTBZ Cmax of deutetrabenazine was increased by ≈50% in the presence of food, it remained lower than that of tetrabenazine.

Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in Huntington's disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (β-HTBZ), metabolite profile, safety, and tolerability. In the two-way, cross-over study, the mean elimination half-life of deuterated total (α + β)-HTBZ was doubled compared with nondeuterated total (α + β)-HTBZ, with a twofold increase in overall mean exposure (area under the concentration-time curve from zero to infinity (AUC0-inf )) and a marginal increase in mean peak plasma concentration (Cmax ). In the mass balance and metabolite profiling study, there were no novel plasma or urinary metabolites of [14 C]-deutetrabenazine relative to [14 C]-tetrabenazine. Specific deuteration in deutetrabenazine resulted in a superior pharmacokinetic profile and an increased ratio of active-to-inactive metabolites, attributes considered to provide significant benefits to patients.

The pathogenesis of severe COVID-19 remains poorly understood. While several studies suggest that immune dysregulation plays a central role, the key mediators of this process are yet to be defined. Here, we demonstrate that plasma from a high proportion (77%) of critically ill COVID-19 patients, but not healthy controls, contains broadly auto-reactive immunoglobulin M (IgM), and only infrequently auto-reactive IgG or IgA. Importantly, these auto-IgM preferentially recognize primary human lung cells in vitro, including pulmonary endothelial and epithelial cells. By using a combination of flow cytometry, LDH-release assays, and analytical proteome microarray technology, we identified high-affinity, complement-fixing, auto-reactive IgM directed against 263 candidate auto-antigens, including numerous molecules preferentially expressed on cellular membranes in pulmonary, vascular, gastrointestinal, and renal tissues. These findings suggest that broad IgM-mediated autoimmune reactivity may be involved in the pathogenesis of severe COVID-19, thereby identifying a potential target for novel therapeutic interventions.

TV-46000 is a long-acting subcutaneous antipsychotic that uses a novel copolymer drug delivery technology in combination with a well-characterized molecule, risperidone, that is in clinical development as a treatment for schizophrenia. A population pharmacokinetic (PPK) modeling and simulation approach was implemented to identify TV-46000 doses and dosing schedules for clinical development that would provide the best balance between clinical efficacy and safety. The PPK model was created by applying pharmacokinetic data from a phase 1 study of 97 patients with a diagnosis of schizophrenia or schizoaffective disorder who received either single or repeated doses of TV-46000. The PPK model was used to characterize the complex release profile of the total active moiety (TAM; the sum of the risperidone and 9-OH risperidone concentrations) concentration following subcutaneous injections of TV-46000. The PK profile was best described by a double Weibull function of the in vivo release rate and by a 2-compartment disposition and elimination model. Simulations were performed to determine TV-46000 doses and dosing schedules that maintained a median profile of TAM concentrations similar to published TAM exposure following oral risperidone doses that have been correlated to a 40% to 80% dopamine-D2 receptor occupancy therapeutic window. The simulations showed that therapeutic dose ranges for TV-46000 are 50 to 125 mg for once-monthly and 100 to 250 mg for the once every 2 months regimens. This PPK model provided a basis for prediction of patient-specific exposure and dopamine-D2 receptor occupancy estimates to support further clinical development and dose selection for the phase 3 studies.