MIJ821 (onfasprodil) in healthy volunteers: First-in-human, randomized, placebo-controlled study (single ascending dose and repeated intravenous dose).

This single-center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40-min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study. Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. Median age in Part 1 and Part 2 was 45.0 and 43.5 years, respectively, with the majority being Caucasian (Part 1: 84%; Part 2: 92%). 19 subjects (44.2%) in Part 1 and 8 subjects (66.7%) in Part 2 experienced at least one adverse event (AE). Following single dose in Part 1 and Part 2, the AUCinf values of MIJ821 increased in a dose-proportional manner across the dose range 0.016-0.48 mg/kg and the Cmax values in a slight overproportional manner across the dose range 0.048-0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUCinf was 708 h ng/mL and the geometric mean Cmax was 462 ng/mL. Inspection of 1-h post-dose resting electroencephalography activity across cohorts showed a relationship to administered dose, providing exploratory evidence of distal target engagement. In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative AEs were mild, transient, and dose-dependent.

A Study of Novel Exploratory Tools, Digital Technologies, and Central Nervous System Biomarkers to Characterize Unipolar Depression.

Background: Digital technologies have the potential to provide objective and precise tools to detect depression-related symptoms. Deployment of digital technologies in clinical research can enable collection of large volumes of clinically relevant data that may not be captured using conventional psychometric questionnaires and patient-reported outcomes. Rigorous methodology studies to develop novel digital endpoints in depression are warranted. Objective: We conducted an exploratory, cross-sectional study to evaluate several digital technologies in subjects with major depressive disorder (MDD) and persistent depressive disorder (PDD), and healthy controls. The study aimed at assessing utility and accuracy of the digital technologies as potential diagnostic tools for unipolar depression, as well as correlating digital biomarkers to clinically validated psychometric questionnaires in depression. Methods: A cross-sectional, non-interventional study of 20 participants with unipolar depression (MDD and PDD/dysthymia) and 20 healthy controls was conducted at the Centre for Human Drug Research (CHDR), the Netherlands. Eligible participants attended three in-clinic visits (days 1, 7, and 14), at which they underwent a series of assessments, including conventional clinical psychometric questionnaires and digital technologies. Between the visits, there was at-home collection of data through mobile applications. In all, seven digital technologies were evaluated in this study. Three technologies were administered via mobile applications: an interactive tool for the self-assessment of mood, and a cognitive test; a passive behavioral monitor to assess social interactions and global mobility; and a platform to perform voice recordings and obtain vocal biomarkers. Four technologies were evaluated in the clinic: a neuropsychological test battery; an eye motor tracking system; a standard high-density electroencephalogram (EEG)-based technology to analyze the brain network activity during cognitive testing; and a task quantifying bias in emotion perception. Results: Our data analysis was organized by technology - to better understand individual features of various technologies. In many cases, we obtained simple, parsimonious models that have reasonably high diagnostic accuracy and potential to predict standard clinical outcome in depression. Conclusion: This study generated many useful insights for future methodology studies of digital technologies and proof-of-concept clinical trials in depression and possibly other indications.

Prospective longitudinal investigation shows correlation of event-related potential to mild traumatic brain injury in adolescents.

STUDY DESIGN: Prospective longitudinal cohort study. BACKGROUND: Adolescent athletes may be more susceptible to the long-term effects of mild traumatic brain injury (mTBI). A diagnostic and prognostic neuromarker may optimize management and return-to-activity decision-making in athletes who experience mTBI. OBJECTIVE: Measure an event-related potential (ERP) component captured with electroencephalography (EEG), called processing negativity (PN), at baseline and post-injury in adolescents who suffered mTBI and determine their longitudinal response relative to healthy controls. METHODS: Thirty adolescents had EEG recorded during an auditory oddball task at a pre-mTBI baseline session and subsequent post-mTBI sessions. Longitudinal EEG data from patients and healthy controls (n= 77) were obtained from up to four sessions in total and processed using Brain Network Analysis algorithms. RESULTS: The average PN amplitude in healthy controls significantly decreased over sessions 2 and 3; however, it remained steady in the mTBI group's 2nd (post-mTBI) session and decreased only in sessions 3 and 4. Pre- to post-mTBI amplitude changes correlated with the time interval between sessions. CONCLUSION: These results demonstrate that PN amplitude changes may be associated with mTBI exposure and subsequent recovery in adolescent athletes. Further study of PN may lead to it becoming a neuromarker for mTBI prognosis and return-to-activity decision-making in adolescents.

Over-generalization in youth with anxiety disorders.

Over-generalization of dangerous stimuli is a possible etiological account of anxiety. Recently, we demonstrated it could result from alterations in early perceptual mechanisms, i.e., a fundamental change in the way the stimulus is perceived. Yet it is still unclear if these mechanisms already exist in youth, or develop only later. The purpose of this study was therefore to explore the mechanism of generalization in youth suffering from anxiety disorders. Children and adolescents with anxiety disorders and age-matched control participants underwent a conditioning task where a loss or gain outcome was associated with two well-separated tones. A generalization probe then followed in which different surrounding tones were presented and classified. Generalization curves and changes in discrimination abilities were compared between groups and according to the background variables. We found that patients had lower perceptual discrimination thresholds after conditioning, and tended to have wider generalization curve. Relative enhanced generalization was observed in adolescents with anxiety, in males, and as the level of anxiety rose. Our results suggest that over-generalization in anxiety can start already during adolescence, and may suggest that an early perceptual source can give rise to later more cognitive over-generalization during adult anxiety.

Behavioral and Neural Mechanisms of Overgeneralization in Anxiety.

Overgeneralization of dangerous stimuli is a possible etiological account for anxiety disorders, yet the underlying behavioral and neural origins remain vague. Specifically, it is unclear whether this is a choice behavior in an unsafe environment ("better safe than sorry") or also a fundamental change in how the stimulus is perceived. We show that anxiety patients have wider generalization for loss-conditioned tone when compared to controls and do so even in a safe context that requires a different behavioral policy. Moreover, patients overgeneralized for gain-conditioned tone as well. Imaging (fMRI) revealed that in anxiety only, activations during conditioning in the dACC and the putamen were correlated with later overgeneralization of loss and gain, respectively, whereas valence distinction in the amygdala and hippocampus during conditioning mediated the difference between loss and gain generalization. During generalization itself, neural discrimination based on multivoxel patterns in auditory cortex and amygdala revealed specific stimulus-related plasticity. Our results suggest that overgeneralization in anxiety has perceptual origins and involves affective modulation of stimulus representations in primary cortices and amygdala.

Monetary loss alters perceptual thresholds and compromises future decisions via amygdala and prefrontal networks.

The influence of monetary loss on decision making and choice behavior is extensively studied. However, the effect of loss on sensory perception is less explored. Here, we use conditioning in human subjects to explore how monetary loss associated with a pure tone can affect changes in perceptual thresholds for the previously neutral stimulus. We found that loss conditioning, when compared with neutral exposure, decreases sensitivity and increases perceptual thresholds (i.e., a relative increase in the just-noticeable-difference). This was so even when compared with gain conditioning of comparable intensity, suggesting that the finding is related to valence. We further show that these perceptual changes are related to future decisions about stimuli that are farther away from the conditioned one (wider generalization), resulting in overall increased and irrational monetary loss for the subjects. We use functional imaging to identify the neural network whose activity correlates with the deterioration in sensitivity on an individual basis. In addition, we show that activity in the amygdala was tightly correlated with the wider behavioral generalization, namely, when wrong decisions were made. We suggest that, in principle, less discrimination can be beneficial in loss scenarios, because it assures an accurate and fast response to stimuli that resemble the original stimulus and hence have a high likelihood of entailing the same outcome. But whereas this can be useful for primary reinforcers that can impact survival, it can also underlie wrong and costly behaviors in scenarios of contemporary life that involve secondary reinforcers.

Negative valence widens generalization of learning.

Learning includes the ability to generalize to new situations and respond to similar, yet not identical stimuli. We use stimulus generalization in humans to show that tones that were negatively reinforced induce wider generalization curves than tones that were positively reinforced, and these in turn induce wider curves than neutral memory. Importantly, these wider generalization curves persist even if outcomes for all tones are made identical, indicating that the learning induced a perceptual change, and not merely a decision bias. Moreover, it persists after taking into account loss-aversion, suggesting it is a result of valence per se, and not intensity that reflects overweighting of the aversive stimuli. This effect of emotional valence on learning suggests different locations of plasticity and network mechanisms in the brain. Particularly, it suggests that brain areas that mediate reinforcement and emotions are involved during the learning process to induce a neural representation that can support this broader behavioral generalization. In addition, these findings highlight a model for anxiety and trauma disorders in which aversive experiences affect more than they should, sometimes even in seemingly irrational situations.

BAG-1M is up-regulated in hippocampus of Alzheimer's disease patients and associates with tau and APP proteins.

The accumulation of tau and amyloid beta proteins is the major molecular pathology of Alzheimer's disease (AD). The mechanisms leading to the accumulation of these proteins are not completely clear. Hsc-70/Hsp-70, a chaperone protein, has been shown to bind both these proteins and regulate their degradation. We have previously shown that the co-chaperone protein BAG-1 can inhibit the degradation of tau by forming a complex with Hsc-70 and tau. In this current work, we show that there is an increase in the BAG-1M isoform in the hippocampus of AD patients. In addition, BAG-1 binds to both tau and amyloid precursor protein physically, and is found highly expressed in the same neurons that contain intracellular tau or amyloid in hippocampal sections from AD patients. Over-expression of BAG-1M in cell culture also induced an increase in both tau and amyloid precursor protein levels. In conclusion, we report a specific increase of BAG-1M in human AD patients, which is both physically and functionally associated to the two major molecular markers of AD.