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Introduction : Hemophilia comprises a group of X-linked hemorrhagic disorders that result from a deficiency of coagulation factors. The disorder affects mainly males and leads to chronic pain, joint deformity, reduced mobility, and increased mortality. Current therapies require frequent administration of replacement clotting factors, but the emergence of alloantibodies (inhibitors) diminishes their efficacy. New therapies are being developed to produce the deficient clotting factors and prevent the emergence of inhibitors. Areas covered : This article provides an update on the characteristics and disease pathophysiology of hemophilia A, as well as current treatments, with a special focus on ongoing clinical trials related to gene replacement therapies. Expert opinion : Gene replacement therapies provide safe, durable, and stable transgene expression while avoiding the challenges of clotting factor replacement therapies in patients with hemophilia. Improving the specificity of the viral construct and decreasing the therapeutic dose are critical toward minimizing cellular stress, induction of the unfolded protein response, and the resulting loss of protein production in liver cells. Next-generation gene therapies incorporating chimeric DNA sequences in the transgene can increase clotting factor synthesis and secretion, and advance the efficacy, safety, and durability of gene replacement therapy for hemophilia A as well as other blood clotting disorders.

Numerous studies have shown that neural activity in sensory cortices is remarkably variable over time and across trials even when subjects are presented with an identical repeating stimulus or task. This trial-by-trial neural variability is relatively large in the pre-stimulus period and considerably smaller (quenched) following stimulus presentation. Previous studies have suggested that the magnitude of neural variability affects behavior such that perceptual performance is better on trials and in individuals where variability quenching is larger. To what degree are neural variability magnitudes of individual subjects flexible or static? Here, we used EEG recordings from adult humans to demonstrate that neural variability magnitudes in visual cortex are remarkably consistent across different tasks and recording sessions. While magnitudes of neural variability differed dramatically across individual subjects, they were surprisingly stable across four tasks with different stimuli, temporal structures, and attentional/cognitive demands as well as across experimental sessions separated by one year. These experiments reveal that, in adults, neural variability magnitudes are mostly solidified individual characteristics that change little with task or time, and are likely to predispose individual subjects to exhibit distinct behavioral capabilities.Significance statementBrain activity varies dramatically from one moment to the next. Recent research has revealed that humans exhibit different magnitudes of trial-by-trial neural variability, which explain differences in their perceptual performance. How stable are neural variability magnitudes over time and across tasks? Here, subjects performed four different experiments in two experimental sessions separated by one year. The results revealed that neural variability magnitudes were remarkably consistent over time and across tasks, suggesting that the magnitude of neural variability is a solidified neural characteristic that may predispose individual subjects to exhibit different behavioral capabilities.

Attention Deficit Hyperactivity Disorder (ADHD) has been described as a disorder where frequent lapses of attention impair the ability of an individual to focus/attend in a sustained manner, thereby generating abnormally large intra-individual behavioral variability across trials. Indeed, increased reaction time (RT) variability is a fundamental behavioral characteristic of individuals with ADHD found across a large number of cognitive tasks. But what is the underlying neurophysiology that might generate such behavioral instability? Here, we examined trial-by-trial EEG response variability to visual and auditory stimuli while subjects' attention was diverted to an unrelated task at the fixation cross. Comparisons between adult ADHD and control participants revealed that neural response variability was significantly larger in the ADHD group as compared with the control group in both sensory modalities. Importantly, larger trial-by-trial variability in ADHD was apparent before and after stimulus presentation as well as in trials where the stimulus was omitted, suggesting that ongoing (rather than stimulus-evoked) neural activity is continuously more variable (noisier) in ADHD. While the patho-physiological mechanisms causing this increased neural variability remain unknown, they appear to act continuously rather than being tied to a specific sensory or cognitive process.

Prospective memory is the ability to remember to execute future intentions and thoughts. It is probably the newest established field of memory research. We provide a selective review of work conducted in the last two decades with respect to the following issues: (1) the different types and characteristics of prospective tasks, (2) the theoretical models of the cognitive processes supporting prospective memory, (3) prospective memory performance in younger and older adults and (4) the findings from neuropsychological and neuroimaging studies. The findings indicate an extraordinarily fast progress in our understanding of the behaviour and the brain regions that are involved in this important ability, and suggest at least two possible emerging areas of enquiry for future research: a link with the closely related field of prospection (i.e., thinking about the future), and “expectation prospective memory” (triggering of behaviour in the absence of awareness depending on contingencies learnt from the environment).

Highlights ► Prospective memory (PM) is a key cognitive component required in multitasking. ► This lesion study examines the critical regions for event- and time-based PM ► We show that the right rostral prefrontal cortex is necessary for time-based PM. ► Distinct prefrontal regions are associated with deficits in event- and time-based PM. ► The PM deficit of rostral patients might explain their deficit in multitasking situations., Patients with lesions in rostral prefrontal cortex (PFC) often experience problems in everyday-life situations requiring multitasking. A key cognitive component that is critical in multitasking situations is prospective memory, defined as the ability to carry out an intended action after a delay period filled with unrelated activity. The few functional imaging studies investigating prospective memory have shown consistent activation in both medial and lateral rostral PFC but also in more posterior prefrontal regions and non-frontal regions. The aim of this study was to determine regions that are necessary for prospective memory performance, using the human lesion approach. We designed an experimental paradigm allowing us to assess time-based (remembering to do something at a particular time) and event-based (remembering to do something in a particular situation) prospective memory, using two types of material, words and pictures. Time estimation tasks and tasks controlling for basic attention, inhibition and multiple instructions processing were also administered. We examined brain-behaviour relationships with a voxelwise lesion method in 45 patients with focal brain lesions and 107 control subjects using this paradigm. The results showed that lesions in the right polar prefrontal region (in Brodmann area 10) were specifically associated with a deficit in time-based prospective memory tasks for both words and pictures. This deficit could not be explained by impairments in basic attention, detection, inhibition or multiple instruction processing, and there was also no deficit in event-based prospective memory conditions. In addition to their prospective memory difficulties, these polar prefrontal patients were significantly impaired in time estimation ability compared to other patients. The same region was found to be involved using both words and pictures, suggesting that right rostral PFC plays a material nonspecific role in prospective memory. This is the first lesion study showing that rostral PFC is crucial for time-based prospective memory. The findings suggest that time-based and event-based prospective memory might be supported at least in part by distinct brain regions. Two particularly plausible explanations for the deficit rest upon a possible role for polar prefrontal structures in supporting in time estimation, and/or in retrieving an intention to act. More broadly, the results are consistent with the view that the deficit of rostral patients in multitasking situations might at least in part be explained by a deficit in prospective memory.

Recent studies have shown that functional connectivity in the human brain may be detected by analyzing the likelihood with which different brain regions are simultaneously activated, or "co-activated", across multiple neuroimaging experiments. We applied this technique to investigate whether distinct subregions within rostral prefrontal cortex (RoPFC) tend to co-activate with distinct sets of brain regions outside RoPFC, in a meta-analysis of 200 activation peaks within RoPFC (approximating Brodmann Area 10) and 1712 co-activations outside this region, drawn from 162 studies. There was little evidence for distinct connectivity between hemispheres or along rostral/caudal or superior/inferior axes. However, there was a clear difference between lateral and medial RoPFC: activation in lateral RoPFC was particularly associated with co-activation in dorsal anterior cingulate, dorsolateral PFC, anterior insula and lateral parietal cortex; medial RoPFC activation was particularly associated with co-activation in posterior cingulate, posterior superior temporal sulcus and temporal pole. These findings are consistent with anatomical studies of connectivity in non-human primates, despite strong cross-species differences in RoPFC. Furthermore, associations between brain regions inside and outside RoPFC were in some cases strongly influenced by the type of task being performed. For example, dorsolateral PFC, anterior cingulate and lateral parietal cortex tended to co-activate with lateral RoPFC in most tasks but with medial RoPFC in tasks involving mentalizing. These results suggest the importance of changes in effective connectivity in the performance of cognitive tasks.