The evolution and comparative neurobiology of endocannabinoid signalling

CB(1)- and CB(2)-type cannabinoid receptors mediate effects of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide in mammals. In canonical endocannabinoid-mediated synaptic plasticity, 2-AG is generated postsynaptically by diacylglycerol lipase alpha and acts via presynaptic CB(1)-type cannabinoid receptors to inhibit neurotransmitter release. Electrophysiological studies on lampreys indicate that this retrograde signalling mechanism occurs throughout the vertebrates, whereas system-level studies point to conserved roles for endocannabinoid signalling in neural mechanisms of learning and control of locomotor activity and feeding. CB(1)/CB(2)-type receptors originated in a common ancestor of extant chordates, and in the sea squirt Ciona intestinalis a CB(1)/CB(2)-type receptor is targeted to axons, indicative of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling. Although CB(1)/CB(2)-type receptors are unique to chordates, enzymes involved in biosynthesis/inactivation of endocannabinoids occur throughout the animal kingdom. Accordingly, non-CB(1)/CB(2)-mediated mechanisms of endocannabinoid signalling have been postulated. For example, there is evidence that 2-AG mediates retrograde signalling at synapses in the nervous system of the leech Hirudo medicinalis by activating presynaptic transient receptor potential vanilloid-type ion channels. Thus, postsynaptic synthesis of 2-AG or anandamide may be a phylogenetically widespread phenomenon, and a variety of proteins may have evolved as presynaptic (or postsynaptic) receptors for endocannabinoids

Delay-independent asymptotic stability in monotone systems

Monotone systems comprise an important class of dynamical systems that are of interest both for their wide applicability and because of their interesting mathematical properties. It is known that under the property of quasimono-tonicity time-delayed systems become monotone, and some remarkable properties have been reported for such systems. These include, for example, the fact that for linear systems global asymptotic stability of the undelayed system implies global asymptotic stability for the delayed system under arbitrary bounded delays. Nevertheless, extensions to nonlinear systems have thus far relied on various restrictive conditions, such as homogeneity and subhomogeneity, and it has been conjectured that these can be relaxed. Our aim in this paper is to show that this is feasible for a general class of nonlinear monotone systems, by deriving asymptotic stability results in which simple properties of the undelayed system lead to delay-independent stability. In particular, one of our results is to show that if the undelayed system has a convergent trajectory that is unbounded in all components as t → -∞ then the system is globally asymptotically stable for arbitrary time-varying delays. This follows from a more general result derived in the paper where delay-independent regions of attraction are quantified from the asymptotic behavior of individual trajectories of the undelayed system. This result recovers various known delay-independent stability results, and several examples are included in the paper to illustrate the significance of the proposed stability conditions.This is the author accepted manuscript. The final version is available from IEEE via http://dx.doi.org/10.1109/ACC.2015.717206

Receiving Aphasia Intervention in a Virtual Environment: The Participants’ Perspective

Background: Digital technology is making an increasing contribution to aphasia therapy. However applications of virtual reality are rare. EVA Park is a virtual island developed with and for people with aphasia. It is a multi-user environment, which enables people with aphasia to interact with support workers, therapists and each other. The first study to use EVA Park in aphasia rehabilitation demonstrated significant gains in functional communication. This paper augments the findings of that study, by reporting results from qualitative interviews conducted with the 20 study participants. Aims: This study aimed to determine the views of participants about the intervention that they received in EVA Park, and the impacts of that intervention. Long-term retrospective views were also explored. Methods & Procedures: Participants took part in 1:1, semi-structured interviews two weeks before (Entry) and to weeks after (Exit) the intervention. Questions focussed on activities undertaken by participants, communication, changes since the stroke and uses of technology. Exit interviews additionally explored participants’ views and experiences of EVA Park and any perceived impacts of the intervention. A sub-set of 5 participants was interviewed at least one year later, to explore long term recollections of the EVA Park intervention and any perceived long term impacts. Interview data were transcribed and subject to framework analysis. Outcomes & Results: The thematic framework comprised 10 parent themes and 33 sub-themes. Following ‘affect’, the largest single theme related to EVA Park, with 636 coded references. Comments were overwhelmingly positive. EVA Park intervention was strongly associated with fun and enjoyment. Participants particularly valued their relationship with the support workers who delivered the intervention. The virtual locations and activities in EVA Park were also appreciated, together with the contact with other participants. Perceived impacts related to communication, activity, computer use and confidence. Most participants in the long term interviews described maintained impacts. Conclusions: These interview results indicate that the first intervention delivered in EVA Park was highly acceptable to participants and perceived as beneficial. They augment the findings of our experimental study and suggest that EVA Park could be a valuable addition to the resources available to practising clinician

Modulation of cellular redox homeostasis by the endocannabinoid system

The endocannabinoid system (ECS) and reactive oxygen species (ROS) constitute two key cellular signalling systems that participate in the modulation of diverse cellular functions. Importantly, growing evidence suggests that cross-talk between these two prominent signalling systems acts to modulate functionality of the ECS as well as redox homeostasis in different cell types. Herein, we review and discuss evidence pertaining to ECS-induced regulation of ROS generating and scavenging mechanisms, as well as highlighting emerging work that supports redox modulation of ECS function. Functionally, the studies outlined reveal that interactions between the ECS and ROS signalling systems can be both stimulatory and inhibitory in nature, depending on cell stimulus, the source of ROS species and cell context. Importantly, such cross-talk may act to maintain cell function, whereas abnormalities in either system may propagate and undermine the stability of both systems, thereby contributing to various pathologies associated with their dysregulation

Release of anandamide from blood cells

Background: Endogenous ligands of cannabinoid receptors ( endocannabinoids), in particular anandamide ( arachidonylethanolamide), have been recognized as being of crucial importance in a variety of physiological functions. Plasma concentrations of anandamide have been measured in a number of investigations; however, discrepant data on "normal'' anandamide plasma concentrations were reported. Since this might be caused by pre-analytical variables, we investigated the impact of different sample handling conditions on measured plasma anandamide concentrations. Methods: Blood samples were taken from healthy volunteers in EDTA- or heparin-containing tubes; whole blood samples were kept at +4 degrees C, room temperature, or 37 degrees C, respectively, for up to 120 min before obtaining plasma by centrifugation. Plasma anandamide concentrations were measured by an isotope-dilution liquid chromatography tandem mass spectrometry ( LC-MS/MS) method. Results: A marked time- and temperature-dependent increase in plasma anandamide concentrations ex vivo was observed in both EDTA- and heparin-containing tubes. Mean anandamide concentrations approximately doubled when EDTA samples were kept at 4 degrees C for 60 min before centrifugation {[}immediately centrifuged, 1.3 mg/L ( SD 0.3 mg/L); 2.8 mg/L ( SD 0.5 mg/L) after storage for 60 min; n=12). After storage of heparinized whole-blood samples for 120 min at 37 degrees C, a mean plasma anandamide concentration of 11.9 mg/L ( SD 1.8 mg/L) was found. In cell-free plasma, no increase in anandamide concentrations was found. Conclusion: Anandamide is released from blood cells ex vivo at a very high rate; therefore, strictly standardized pre-analytical protocols have to be applied for plasma anandamide determination

Codesign for People with Aphasia Through Tangible Design Languages

Codesign techniques encourage designers and end-users to work together in the creation of design solutions, but often make assumptions about the ways in which participants will be able to communicate. This can lead to the unwitting exclusion of people with communication impairments from the design of technologies that have the potential to transform their lives. This paper reports our research into codesign techniques for people whose communication skills are impaired. A variety of techniques were explored on two projects; some were adaptations of existing codesign techniques, others were created specially. In both cases, the emphasis was on creating tangible design languages. The results illustrate how people with communication impairments can be given a voice in design and demonstrate the benefits of doing so

Delivering word retrieval therapies for people with aphasia in a virtual communication environment

Background: Delivering therapy remotely, via digital technology, can enhance provision for people with aphasia. EVA Park is a multi-user virtual island that can be used for such delivery. The first EVA Park study showed that daily language stimulation delivered via the platform improved functional communication and was positively received by users (Marshall et al, 2016; Amaya et al, 2018). This paper reports two single case studies, evaluating its capacity to deliver targeted language interventions. The first employed therapy for noun retrieval, using cued picture naming and modified Sematic Feature Analysis. The second employed modified Verb Network Strengthening Treatment (VNeST). Aims: This study aimed to determine if treatment delivery was feasible in EVA Park, as assessed by participant compliance, treatment fidelity and participants’ views. It explored the impact of the therapies on treated and untreated word production, connected speech and functional communication. Methods & Procedures: Two participants with aphasia each received 20 sessions of individual therapy in EVA Park, delivered over 5 weeks. Feasibility was assessed by measuring compliance with the therapy regime, recording and checking the fidelity of 20% of treatment sessions, and using post therapy interviews to explore participant views. Treatment outcomes were evaluated via repeated measures single case designs, in which assessments were administered twice before therapy, immediately post therapy and five weeks later. Outcome measures included Object Picture Naming (study 1), Sentence Elicitation Pictures (study 2), Naming 84 items from the Object and Action Naming Battery (study 2), Narrative Production (Study 2), the Northwestern Assessment of Verb and Sentences: Argument Structure Production Test (Study 2) and Communication Activities of Daily Living – 2 (Study 1 & 2). Outcomes & Results: Feasibility results were excellent. Both participants were fully compliant with the therapy regime. There was at least 90% fidelity with the treatment protocols and participant views were positive. Outcomes varied across the studies. The noun therapy significantly improved the naming of treated words, with good maintenance. Lexical gains were less evident on the Sentence Elicitation Pictures used in the VNeST study. Neither study demonstrated generalisation to untreated words, connected speech or functional communication. Conclusions: Two treatment approaches, designed for face to face delivery, could be delivered remotely in EVA Park. Outcomes for the noun treatment were comparable to previous evaluations. Comparisons with previous research were more challenging for VNeST, owing to differences in methodology. Further evaluations of other treatment approaches are warranted