Investigating the Primate Prefrontal Cortex Correlates of Cognitive Deficits In the Ketamine Model of Schizophrenia

The World Health Organization has classified schizophrenia as one of the five leading causes of disability worldwide. Afflicting almost 1% of the world’s population, the disease’s greatest impact stems from its reduction in patients’ cognitive faculties. In order to better study these impairments, a pharmacological model has been developed using the NMDA antagonist, ketamine. This disease model successfully recreates the cognitive dysfunction of schizophrenia, allowing researchers to search for associated electrophysiological changes. In this project I examined the behavioural and neurophysiological effects of ketamine on non-human primates performing the anti-saccade task. Success in this task requires a degree of cognitive control over behaviour and previous studies have described poor performance in both patients with schizophrenia and healthy controls administered ketamine. Our intracranial recordings are localized in the prefrontal cortex (PFC), a region associated with many of the cognitive functions impaired in schizophrenia. The first study shows that neurons in the PFC exhibit selectivity for the task rule. This rule selectivity is lost after ketamine administration due to an indiscriminate increase in the neuronal firing rate. These changes were also associated with an increased error rate and longer reaction times. The second study shows that neurons in the PFC are also sensitive to the outcome of the trial, firing more for either correct or erroneous responses. Once again, selectivity is lost following ketamine administration and the neurons show increased, nonspecific activity. Lastly, we recorded the local field potential of the PFC and found changes in the oscillatory patterns during the anti-saccade task. Prior to ketamine there was a significantly stronger beta-band activity after correct trials compared to error trials, but this selective activity was lost due to an overall decrease in the outcome selective oscillatory events. These findings show that ketamine’s effect on the PFC is one of selectivity reduction. Patients with schizophrenia have been shown to require increased PFC activity but only reach moderate performance levels in cognitive challenges. It is possible that their brains suffer the same changes highlighted in this research. Although the signals are still present in their PFC, they are being lost amongst the noise

Flow through the Emergency Department for Patients Presenting with Substance Use Disorder in Alberta, Canada

Introduction: Since 2016 the province of Alberta, Canada, has seen a significant increase in substance use disorder (SUD) presentations to the emergency department (ED) with a large surge during the COVID-19 pandemic. In this retrospective study we deconstruct the total length of stay (LOS) in the ED into stages for patients presenting with SUD and estimate the effects of covariates on the time to transition between stages. Methods: Using the Canadian Coding Standards for International Classification of Diseases, 10 th Modification, codes F10.0-F19.9 and T36.0-T50.9, we extracted data from the National Ambulatory Care Reporting System between April 1, 2019–March 31, 2020 on all ED presentations for SUD by Alberta residents. We used a multistate model to deconstruct the EDLOS into eight mutually exclusive states and determine which factors affected the time spent in each state. Results: We analyzed 66,880 presentations (37,530 patients). The mean age was 37.2 years, and 61% were male. The median total LOS in the ED was 6 hours 13 minutes. Patients presenting with methamphetamines (METH) intoxication and patients from low-income neighborhoods had significantly increased transition times between all states. Opposite this, opiate use was associated with faster transition times between almost all states. Metro EDs experienced slower transitions when attempting to discharge or admit patients when compared to urban or rural EDs. Emergency department crowding also had a dramatic effect on physician initial assessment times, while discharge and admission times in patients presenting with SUD were also significantly affected. Conclusion: Patients with SUD experience a variety of delays during their ED stay. Those with METH intoxication and those from the lowest income neighborhoods were most likely to experience slower transitions from state to state in the ED and may benefit from a focused approach to improve ED flow

Flow Through the Emergency Department for Patients Presenting with Substance Use Disorder in Alberta, Canada

Introduction: Since 2016 the province of Alberta, Canada, has seen a significant increase in substance use disorder (SUD) presentations to the emergency department (ED) with a large surge during the COVID-19 pandemic. In this retrospective study we deconstruct the total length of stay (LOS) in the ED into stages for patients presenting with SUD and estimate the effects of covariates on the time to transition between stages.Methods: Using the Canadian Coding Standards for International Classification of Diseases, 10th Modification, codes F10.0-F19.9 and T36.0-T50.9, we extracted data from the National Ambulatory Care Reporting System between April 1, 2019–March 31, 2020 on all ED presentations for SUD by Alberta residents.We used a multistate model to deconstruct theEDLOS into eight mutually exclusive states and determine which factors affected the time spent in each state.Results: We analyzed 66,880 presentations (37,530 patients). The mean age was 37.2 years, and 61% were male. The median total LOS in the ED was 6 hours 13 minutes. Patients presenting with methamphetamines (METH) intoxication and patients from low-income neighborhoods had significantly increased transition times between all states. Opposite this, opiate use was associated with faster transition times between almost all states. Metro EDs experienced slower transitions when attempting to discharge or admit patients when compared to urban or rural EDs. Emergency department crowding also had a dramatic effect on physician initial assessment times, while discharge and admission times in patients presenting with SUD were also significantly affected.Conclusion: Patients with SUD experience a variety of delays during their ED stay. Those with METH intoxication and those from the lowest income neighborhoods were most likely to experience slower transitions from state to state in the ED and may benefit from a focused approach to improve ED flow

Cloning, characterization, and functional studies of a human 40-kDa catecholamine-regulated protein: implications in central nervous system disorders

Catecholamine-regulated proteins (CRPs) have been shown to bind dopamine and other structurally related catecholamines; in particular, the 40-kDa CRP (CRP40) protein has been previously cloned and functionally characterized. To determine putative human homologs, BLAST analysis using the bovine CRP40 sequence identified a human established sequence tag (EST) with significant homology (accession #BQ224193). Using this EST, we cloned a recombinant human brain CRP40-like protein, which possessed chaperone activity. Radiolabeled dopamine binding studies with recombinant human CRP40 protein demonstrated the ability of this protein to bind dopamine with low affinity and high capacity. The full-length human CRP40 nucleotide sequence was elucidated (accession #DQ480334) with RNA ligase-mediated rapid amplification of complementary DNA ends polymerase chain reaction, while Northern blot hybridization suggested that human CRP40 is an alternative splice variant of the 70-kDa mitochondrial heat shock protein, mortalin. Human SH-SY5Y neuroblastoma cells treated with the antipsychotic drug, haloperidol, exhibited a significant increase in CRP40 messenger RNA expression compared to untreated control cells, while other dopamine agonists/antagonists also altered CRP40 expression and immunolocalization. In conclusion, these results show that we have cloned a splice variant of mortalin with a novel catecholamine binding function and that this chaperone-like protein may be neuroprotective in dopamine-related central nervous system disorders