A longitudinal study of the impacts of a stay in a Prevention and Recovery Care service in Victoria, Australia.

BACKGROUND: Prevention and Recovery Care services are residential sub-acute services in Victoria, Australia, guided by a commitment to recovery-oriented practice. The evidence regarding the effectiveness of this service model is limited, largely relying on small, localised evaluations. This study involved a state-wide investigation into the personal recovery, perceived needs for care, well-being and quality-of-life outcomes experienced by Prevention and Recovery Care services' consumers. METHODS: A longitudinal cohort design examined the trajectory of self-reported personal recovery and other outcomes for consumers in 19 Victorian Prevention and Recovery Care services over 4 time points (T1 - 1 week after admission; T2 - within 1 week of discharge; T3 - 6 months after discharge; T4 - 12 months after discharge). T2-T4 time frames were extended by approximately 3 weeks due to recruitment challenges. The Questionnaire about the Process of Recovery was the primary outcome measure. RESULTS: At T1, 298 consumers were recruited. By T4, 114 remained in the study. Participants scored higher on the Questionnaire about the Process of Recovery at all three time points after T1. There were also sustained improvements on all secondary outcome measures. Improvements were then sustained at each subsequent post-intervention time point. Community inclusion and having needs for care met also improved. CONCLUSION: The findings provide a consistent picture of benefits for consumers using Prevention and Recovery Care services, with significant improvement in personal recovery, quality of life, mental health and well-being following an admission to a Prevention and Recovery Care service. Further attention needs to be given to how to sustain the gains made through a Prevention and Recovery Care service admission in the long term.

Classification of antiseizure drugs in cultured neuronal networks using multielectrode arrays and unsupervised learning.

OBJECTIVE: Antiseizure drugs (ASDs) modulate synaptic and ion channel function to prevent abnormal hypersynchronous or excitatory activity arising in neuronal networks, but the relationship between ASDs with respect to their impact on network activity is poorly defined. In this study, we first investigated whether different ASD classes exert differential impact upon network activity, and we then sought to classify ASDs according to their impact on network activity. METHODS: We used multielectrode arrays (MEAs) to record the network activity of cultured cortical neurons after applying ASDs from two classes: sodium channel blockers (SCBs) and γ-aminobutyric acid type A receptor-positive allosteric modulators (GABA PAMs). A two-dimensional representation of changes in network features was then derived, and the ability of this low-dimensional representation to classify ASDs with different molecular targets was assessed. RESULTS: A two-dimensional representation of network features revealed a separation between the SCB and GABA PAM drug classes, and could classify several test compounds known to act through these molecular targets. Interestingly, several ASDs with novel targets, such as cannabidiol and retigabine, had closer similarity to the SCB class with respect to their impact upon network activity. SIGNIFICANCE: These results demonstrate that the molecular target of two common classes of ASDs is reflected through characteristic changes in network activity of cultured neurons. Furthermore, a low-dimensional representation of network features can be used to infer an ASDs molecular target. This approach may allow for drug screening to be performed based on features extracted from MEA recordings.

Outcomes of Victorian Prevention and Recovery Care Services: A matched pairs comparison.

OBJECTIVE: In Victoria, Prevention and Recovery Care Services have been established to provide a partial alternative to inpatient admissions through short-term residential mental health care in the community. This study set out to determine whether Prevention and Recovery Care Services are achieving their objectives in relation to reducing service use and costs, fostering least restrictive care and leading to positive clinical outcomes. METHODS: We matched 621 consumers whose index admission in 2014 was to a Prevention and Recovery Care ('PARCS consumers') with 621 similar consumers whose index admission in the same year was to an acute inpatient unit and who had no Prevention and Recovery Care stays for the study period ('inpatient-only consumers'). We used routinely collected data to compare them on a range of outcomes. RESULTS: Prevention and Recovery Care Services consumers made less subsequent use of acute inpatient services and, on balance, incurred costs that were similar to or lower than inpatient-only consumers. They were also less likely to spend time on an involuntary treatment order following their index admission. Prevention and Recovery Care Services consumers also experienced positive clinical outcomes over the course of their index admission, but the magnitude of this improvement was not as great as for inpatient-only consumers. This type of clinical improvement is important for Prevention and Recovery Care Services, but they may place greater emphasis on personal recovery as an outcome. CONCLUSION: Prevention and Recovery Care Services can provide an alternative, less restrictive care option for eligible consumers who might otherwise be admitted to an acute inpatient unit and do so at no greater cost.

The hyperpolarization-activated cyclic nucleotide-gated 4 channel as a potential anti-seizure drug target.

BACKGROUND AND PURPOSE: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4) with distinct biophysical properties and functions within the brain. HCN4 channels activate slowly at robust hyperpolarizing potentials, making them more likely to be engaged during hyperexcitable neuronal network activity seen during seizures. HCN4 channels are also highly expressed in thalamic nuclei, a brain region implicated in seizure generalization. Here, we assessed the utility of targeting the HCN4 channel as an anti-seizure strategy using pharmacological and genetic approaches. EXPERIMENTAL APPROACH: The impact of reducing HCN4 channel function on seizure susceptibility and neuronal network excitability was studied using an HCN4 channel preferring blocker (EC18) and a conditional brain specific HCN4 knockout mouse model. KEY RESULTS: EC18 (10 mg·kg-1 ) and brain-specific HCN4 channel knockout reduced seizure susceptibility and proconvulsant-mediated cortical spiking recorded using electrocorticography, with minimal effects on other mouse behaviours. EC18 (10 µM) decreased neuronal network bursting in mouse cortical cultures. Importantly, EC18 was not protective against proconvulsant-mediated seizures in the conditional HCN4 channel knockout mouse and did not reduce bursting behaviour in AAV-HCN4 shRNA infected mouse cortical cultures. CONCLUSIONS AND IMPLICATIONS: These data suggest the HCN4 channel as a potential pharmacologically relevant target for anti-seizure drugs that is likely to have a low side-effect liability in the CNS.

Method of derivation and differentiation of mouse embryonic stem cells generating synchronous neuronal networks.

BACKGROUND: Stem cells-derived neuronal cultures hold great promise for in vitro disease modelling and drug screening. However, currently stem cells-derived neuronal cultures do not recapitulate the functional properties of primary neurons, such as network properties. Cultured primary murine neurons develop networks which are synchronised over large fractions of the culture, whereas neurons derived from mouse embryonic stem cells (ESCs) display only partly synchronised network activity and human pluripotent stem cells-derived neurons have mostly asynchronous network properties. Therefore, strategies to improve correspondence of derived neuronal cultures with primary neurons need to be developed to validate the use of stem cell-derived neuronal cultures as in vitro models. NEW METHOD: By combining serum-free derivation of ESCs from mouse blastocysts with neuronal differentiation of ESCs in morphogen-free adherent culture we generated neuronal networks with properties recapitulating those of mature primary cortical cultures. RESULTS: After 35days of differentiation ESC-derived neurons developed network activity very similar to that of mature primary cortical neurons. Importantly, ESC plating density was critical for network development. COMPARISON WITH EXISTING METHOD(S): Compared to the previously published methods this protocol generated more synchronous neuronal networks, with high similarity to the networks formed in mature primary cortical culture. CONCLUSION: We have demonstrated that ESC-derived neuronal networks recapitulating key properties of mature primary cortical networks can be generated by optimising both stem cell derivation and differentiation. This validates the approach of using ESC-derived neuronal cultures for disease modelling and in vitro drug screening.

Non-Neurotoxic Nanodiamond Probes for Intraneuronal Temperature Mapping.

Optical biomarkers have been used extensively for intracellular imaging with high spatial and temporal resolution. Extending the modality of these probes is a key driver in cell biology. In recent years, the nitrogen-vacancy (NV) center in nanodiamond has emerged as a promising candidate for bioimaging and biosensing with low cytotoxicity and stable photoluminescence. Here we study the electrophysiological effects of this quantum probe in primary cortical neurons. Multielectrode array recordings across five replicate studies showed no statistically significant difference in 25 network parameters when nanodiamonds are added at varying concentrations over various time periods, 12-36 h. The physiological validation motivates the second part of the study, which demonstrates how the quantum properties of these biomarkers can be used to report intracellular information beyond their location and movement. Using the optically detected magnetic resonance from the nitrogen-vacancy defects within the nanodiamonds we demonstrate enhanced signal-to-noise imaging and temperature mapping from thousands of nanodiamond probes simultaneously. This work establishes nanodiamonds as viable multifunctional intraneuronal sensors with nanoscale resolution, which may ultimately be used to detect magnetic and electrical activity at the membrane level in excitable cellular systems.