Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline

Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood-brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.65

Haemodynamic effects of the nitroxyl donor cimlanod (BMS-986231) in chronic heart failure: a randomized trial

Aims Nitroxyl provokes vasodilatation and inotropic and lusitropic effects in animals via post-translational modification of thiols. We aimed to compare effects of the nitroxyl donor cimlanod (BMS-986231) with those of nitroglycerin (NTG) or placebo on cardiac function in patients with chronic heart failure with reduced ejection fraction (HFrEF). Methods and results In a randomized, multicentre, double-blind, crossover trial, 45 patients with stable HFrEF were given a 5 h intravenous infusion of cimlanod, NTG, or placebo on separate days. Echocardiograms were done at the start and end of each infusion period and read in a core laboratory. The primary endpoint was stroke volume index derived from the left ventricular outflow tract at the end of each infusion period. Stroke volume index with placebo was 30 ± 7 mL/m2 and was lower with cimlanod (29 ± 9 mL/m2; P = 0.03) and NTG (28 ± 8 mL/m2; P = 0.02). Transmitral E-wave Doppler velocity on cimlanod or NTG was lower than on placebo and, consequently, E/e′ (P = 0.006) and E/A ratio (P = 0.003) were also lower. NTG had similar effects to cimlanod on these measurements. Blood pressure reduction was similar with cimlanod and NTG and greater than with placebo. Conclusion In patients with chronic HFrEF, the haemodynamic effects of cimlanod and NTG are similar. The effects of cimlanod may be explained by venodilatation and preload reduction without additional inotropic or lusitropic effects. Ongoing trials of cimlanod will further define its potential role in the treatment of heart failure

An optimal multiprocessor real-time scheduling algorithm

An optimal scheduling algorithm is described that feasibly schedules a set ofmperiodic tasks onnprocessors before their respective deadlines, if the task set satisfies certain conditions. The complexity of this scheduling algorithm in terms of the number of scheduled tasks and the number of processors and upper bounds on the number of preemptions in a given time interval and for any single task is also derived. The optimal algorithm is shown to be particularly useful when schedules are built from the integral flow values obtained from the corresponding maximum flow network

Dissecting the function of hippocampal oscillations in a human anxiety model

Neural oscillations in hippocampus and medial prefrontal cortex (mPFC) are a hallmark of rodent anxiety models that build on conflict between approach and avoidance. Yet, the function of these oscillations, and their expression in humans, remain elusive. Here, we used magnetoencephalography (MEG) to investigate neural oscillations in a task that simulated approach-avoidance conflict, wherein 23 male and female human participants collected monetary tokens under a threat of virtual predation. Probability of threat was learned beforehand by direct experience. Magnitude of threat corresponded to a possible monetary loss, which was on each trial signalled as a quantity. We focused our analyses on an a priori defined region-of-interest, bilateral hippocampus. Oscillatory power under conflict was linearly predicted by threat probability in a location consistent with right mid-hippocampus. This pattern was specific to hippocampus, most pronounced in gamma band, and not explained by spatial movement or anxiety-like behaviour. Gamma power was modulated by slower theta rhythms, and this theta modulation increased with threat probability. Furthermore, theta oscillations in the same location showed greater synchrony with medial prefrontal cortex theta with increased threat probability. Strikingly, these findings were not seen in relation to an increase in threat magnitude, which was explicitly signalled as a quantity and induced similar behavioural responses as learned threat probability. Thus, our findings suggest that the expression of hippocampal and mPFC oscillatory activity in the context of anxiety is specifically linked to threat memory. These findings resonate with neurocomputational accounts of the role played by hippocampal oscillations in memory.SIGNIFICANCE STATEMENTWe employ a biologically relevant approach-avoidance conflict test in humans whilst recording neural oscillations with magnetoencephalography, in order to investigate the expression and function of hippocampal oscillations in human anxiety. Extending non-human studies, we can assign a possible function to hippocampal oscillations in this task, namely threat memory communication. This blends into recent attempts to elucidate the role of brain synchronisation in defensive responses to threat