Treatment with psychostimulants and atomoxetine in people with psychotic disorders: reassessing the risk of clinical deterioration in a real-world setting.

BACKGROUND: Although attention-deficit hyperactivity disorder (ADHD) is often comorbid with schizophrenia spectrum and other psychotic disorders (SZSPD), concerns about an increased risk of psychotic events have limited its treatment with either psychostimulants or atomoxetine. AIMS: To examine whether the risk of hospital admission for psychosis in people with SZSPD was increased during the year following the introduction of such medications compared with the year before. METHOD: This was a retrospective cohort study using Quebec (Canada) administrative health registries, including all Quebec residents with a public prescription drug insurance plan and a diagnosis of psychotic disorder, defined by relevant ICD-9 or ICD-10 codes, who initiated either methylphenidate, amphetamines or atomoxetine, between January 2010 and December 2016, in combination with antipsychotic medication. The primary outcome was time to hospital admission for psychosis within 1 year of initiation. State sequence analysis was also used to visualise admission trajectories for psychosis in the year following initiation of these medications, compared with the previous year. RESULTS: Out of 2219 individuals, 1589 (71.6%) initiated methylphenidate, 339 (15.3%) amphetamines and 291 (13.1%) atomoxetine during the study period. After adjustment, the risk of hospital admission for psychosis was decreased during the 12 months following the introduction of these medications when used in combination with antipsychotics (adjusted HR = 0.36, 95% CI 0.24-0.54; P < 0.0001). CONCLUSIONS: These findings suggest that, in a real-world setting, when used concurrently with antipsychotic medication, methylphenidate, amphetamines and atomoxetine may be safer than generally believed in individuals with psychotic disorders.

Problem gambling in psychotic disorders: A systematic review and meta-analysis of prevalence.

INTRODUCTION: Problem gambling (PBG) is more common in people with mental health disorders, including substance use, bipolar, and personality disorders, than in the general population. Although individuals with psychotic disorders might be expected to be more vulnerable to PBG, fewer studies have focused on this comorbidity. The aim of this review was to estimate the prevalence of PBG in people with psychotic disorders. METHODS: Medline (Ovid), EMBASE, PsycINFO (Ovid), CINAHL, CENTRAL, Web of science, and ProQuest were searched on November 1, 2023, without language restrictions. Observational and experimental studies including individuals with psychotic disorders and reporting the prevalence of PBG were included. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal for systematic reviews of prevalence data. The pooled prevalence of PBG was calculated using a fixed effects generalized linear mixed model and presented through forest plots. RESULTS: Of 1271 records screened, 12 studies (n = 3443) were included. The overall prevalence of PBG was 8.7% (95% CI = 7.8%-9.7%, I2 = 69%). A lower prevalence was found in studies with a low risk of bias (5.6%; 95% CI = 4.4%-7.0%) compared with studies with a moderate risk of bias (10.4%; 95% CI = 9.2%-11.7%). Different methods used to assess PBG also contributed to the heterogeneity found. CONCLUSION: This meta-analysis found substantial heterogeneity, partly due to the risk of bias of the included studies and a lack of uniformity in PBG assessment. Although more research is needed to identify those at increased risk for PBG, its relatively high prevalence warrants routine screening for gambling in clinical practice.

Problem gambling among people with first-episode psychosis: protocol for a prospective multicenter cohort study.

BACKGROUND: The limited available data suggest that the prevalence of problem gambling is increased among young adults with first-episode psychosis, possibly due in part to several risk factors for problem gambling that are common in this population. Aripiprazole, a widely used antipsychotic drug, has also been linked to cases of problem gambling, but causality remains uncertain. Although the consequences of problem gambling further hinder the recovery of people with first-episode psychosis, there is a paucity of research about this comorbidity and its risk factors. Additionally, to our knowledge, no screening instrument for problem gambling tailored to these individuals exists, contributing to its under-recognition. Further, treatment approaches for problem gambling adapted to this population are at an embryonic stage, while existing treatments effectiveness remains to be documented. Using an innovative screening and assessment procedure for problem gambling, this study aims to identify risk factors for problem gambling among people with first-episode psychosis and to document the effectiveness of standard treatment approaches. METHODS: This is a multicenter prospective cohort study conducted in two first-episode psychosis clinics, including all patients admitted between November 1st, 2019, and November 1st, 2023, followed for up to 3 years until May 1st, 2024. These 2 clinics admit approximately 200 patients annually, for an expected sample size of 800 individuals. The primary outcome is the occurrence of a DSM-5 diagnosis of gambling disorder. All patients are screened and evaluated for problem gambling using a systematic procedure at admission, and every 6 months thereafter. Socio-demographic and clinical variables are prospectively extracted from the patients' medical records. The nature and effectiveness of treatments for problem gambling offered to affected individuals are also documented from medical records. Survival analyses with Cox regression models will be used to identify potential risk factors for problem gambling. Descriptive statistics will document the effectiveness of treatments for problem gambling in this population. DISCUSSION: A better understanding of potential risk factors for problem gambling among people with first-episode psychosis will allow for better prevention and detection of this neglected comorbidity. Results of this study will also hopefully raise clinicians' and researchers' awareness and serve as the basis to adapted treatments that will better support recovery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05686772. Retrospectively registered, 9 January 2023.

Gaming Disorder and Psychotic Disorders: A Scoping Review.

BACKGROUND: There is a growing interest in understanding the impact of video games in the clinical field, given that their excessive use could be associated with health issues. Particularly, gaming disorder (GD) is considered as an addictive behavioral disorder. Clinicians widely recognize the comorbidity of gaming and psychotic disorders (PDs). Furthermore, association between addictive (i.e., substance use disorders) and PDs are well recognized by clinicians. It seems of high interest to explore GD among people with PDs. To this day, little is known about the consequences of GD in vulnerable populations. OBJECTIVES: The aim of this scoping review was to summarize the available research on the comorbidity between GD and PD and to identify the knowledge gaps in this field. METHODS: We used Levac's six-stage methodology for scoping review. Two-hundred and forty-two articles from seven databases were identified. Eight articles respected our inclusion and exclusion criteria. RESULTS: No available study has assessed the prevalence or incidence of GD among patients with PDs. The cases reported highlight the possibility that excessive video gameplay or abrupt gaming disruption could trigger psychosis in some patients. CONCLUSION: The results highlight a significant lack of knowledge concerning PDs associated with GD as only a few reported cases and one empirical study exposed the potential association between those conditions.

Clozapine Rechallenge or Continuation Despite Neutropenia, an Extended Follow-up of a Consecutive Quebec Case Series.

BACKGROUND: Clozapine is the most efficacious antipsychotic for treatment-resistant schizophrenia. However, clozapine-induced neutropenia may warrant treatment discontinuation, hindering recovery. Several case reports describe clozapine rechallenge or continuation despite neutropenia, although many are subject to selective reporting, with incomplete information and short follow-up periods. Thus, consecutive case series, devoid of such bias, with long-term comprehensive follow-up are needed to better assess this practice. This study aimed to describe consecutively the evolution of every patient in the Québec City catchment area for whom clozapine was either reintroduced after neutropenia during a previous clozapine trial or was maintained despite a first neutropenia. METHODS: Patients were identified through clozapine's national hematological monitoring database and their medical records between January 1, 2000, and October 22, 2017. RESULTS: Twenty-three patients were identified, 8 continued clozapine despite neutropenia, while 15 discontinued clozapine and attempted rechallenge; among the latter, 4 patients were successfully rechallenged after agranulocytosis without the use of granulocyte colony-stimulating factors, which is the largest published consecutively. A total of 6 patients experienced further neutropenia episodes. Every patient who had a neutropenia recurrence also had a possible explanation for neutropenia other than exposure to clozapine. After a median follow-up of 4.8 years, 16 patients were still on clozapine and 3 cases discontinued because of a hematological event. CONCLUSIONS: This study adds further data on the subject of clozapine rechallenge or continuation despite neutropenia. Clozapine rechallenge after agranulocytosis may be less perilous than first thought, but a systematic review on this specific subject is needed.

The effects of antipsychotic discontinuation or maintenance on the process of recovery in remitted first-episode psychosis patients - A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The optimal duration of antipsychotic treatment following remission of first-episode psychosis (FEP) is uncertain, considering potential adverse effects and individual variability in relapse rates. This study aimed to investigate the effect of antipsychotic discontinuation compared to continuation on recovery in remitted FEP patients. METHODS: CENTRAL, MEDLINE (Ovid), Embase, and PsycINFO databases were searched on November 2, 2023, with no language restrictions. RCTs evaluating antipsychotic discontinuation in remitted FEP patients were selected. The primary outcome was personal recovery, and secondary outcomes included functional recovery, global functioning, hospital admission, symptom severity, quality of life, side effects, and employment. Risk of bias was assessed using the Cochrane risk-of-bias tool 2, and the certainty of evidence was evaluated with GRADE. Meta-analysis used a random-effect model with an inverse-variance approach. RESULTS: Among 2185 screened studies, 8 RCTs (560 participants) were included. No RCTs reported personal recovery as an outcome. Two studies measured functional recovery, and discontinuation group patients were more likely to achieve functional recovery (RR 2.19; 95% CIs: 1.13, 4.22; I2 = 0%; n = 128), although evidence certainty was very low. No significant differences were found in hospital admission, symptom severity, quality of life, global functioning, or employment between the discontinuation and continuation groups. CONCLUSIONS: Personal recovery was not reported in any antipsychotic discontinuation trial in remitted FEP. The observed positive effect of discontinuation on functional recovery came from an early terminated trial and an RCT followed by an uncontrolled period. These findings should be interpreted cautiously due to very low certainty of evidence.

Sex-specific immune mechanisms in PTSD symptomatology and risk: A translational overview and perspectives.

Altered immune function in patients with posttraumatic stress disorder (PTSD) may play a role in the disorder pathophysiology and onset. Women are more likely to develop PTSD, suggesting potential sex-specific inflammatory mechanisms underlying the dichotomous prevalence and risk of PTSD in men and women. In this review we examine the available literature to better assess the state of knowledge in the field. In humans, increased systemic inflammation is found in both men and women with PTSD, but seems to be at a greater extend in women. Despite the existence of few clinical studies taking account of sex as a factor in the observed immune changes in PTSD, challenges in the study of sex-specific immune function in humans include: controlling for confounding variates such as the type of trauma and the ethnicity; and limited methodologies available to study central nervous system (CNS)-relevant changes. Thus, preclinical studies are a valuable tool to provide us with key insights on sex-specific peripheral and CNS immune mechanisms underlying PTSD. Available preclinical studies reported increased systemic and CNS inflammation, as well as elevated trafficking of monocytes from the periphery to the brain in both male and female rodents. To date, psychological trauma-induced inflammation is more robust in female vs male rodents. Limitations of preclinical studies include animal models hardly applicable to female rodents, and hormonal changes across estrus phases that may affect immune function. The present review: (1) highlights the key findings from both human and animal studies, (2) provides guidance to address limitations; and (3) discusses the gap of knowledge on the complex intertwined interaction between the brain, neurovascular, and systemic units.

Psychophysiological models of hypovigilance detection: A scoping review.

Hypovigilance represents a major contributor to accidents. In operational contexts, the burden of monitoring/managing vigilance often rests on operators. Recent advances in sensing technologies allow for the development of psychophysiology-based (hypo)vigilance prediction models. Still, these models remain scarcely applied to operational situations and need better understanding. The current scoping review provides a state of knowledge regarding psychophysiological models of hypovigilance detection. Records evaluating vigilance measuring tools with gold standard comparisons and hypovigilance prediction performances were extracted from MEDLINE, PsychInfo, and Inspec. Exclusion criteria comprised aspects related to language, non-empirical papers, and sleep studies. The Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS) and the Prediction model Risk Of Bias ASsessment Tool (PROBAST) were used for bias evaluation. Twenty-one records were reviewed. They were mainly characterized by participant selection and analysis biases. Papers predominantly focused on driving and employed several common psychophysiological techniques. Yet, prediction methods and gold standards varied widely. Overall, we outline the main strategies used to assess hypovigilance, their principal limitations, and we discuss applications of these models.

Impact of gaming disorder on first episode psychosis patients' evolution: Protocol for a multicentered prospective study.

AIMS: The objective of this study is to underline the impact of Gaming Disorder on the clinical evolution of patients with First Episode Psychosis. The specific aims of the study are to determine the prevalence of gaming disorder among those patients and assess the consequences of gaming on their clinical trajectory. METHODS: This is a prospective multicenter cohort study that will enrol 800 patients diagnosed with a first episode psychosis, with a follow-up period of up to 3 years. Using a systematic screening procedure for gaming disorder, the clinical staff will assess patients gaming habits at admission and every 6 months thereafter. Information from patients' medical records will also be extracted using the same timeframe. RESULTS: The patients' characteristics at admission and during follow-up will be presented in the form of descriptive statistics and compared between different subgroups of patients using uni- and multivariate logistic regression models. Repeated measures ANCOVA will also be performed to analyse the impact of gaming disorders on patients' clinical path as assessed by the Positive and Negative Syndrome Scale and the Clinical Global Impression scale, considering covariates such as psychiatric diagnosis, pharmacological treatment, age, sex/gender, and duration of untreated psychosis. CONCLUSION: These findings will guide the development of prevention, detection, and treatment strategies for the comorbidity between gaming disorder and first episode psychosis, ultimately improving the patients' recovery.

Clozapine rechallenge or continuation despite neutropenia or agranulocytosis using colony-stimulating factor: A systematic review.

OBJECTIVES: Rechallenge/continuation of clozapine in association with colony-stimulating factors (CSFs) following neutropenia/agranulocytosis has been reported, but many questions remain unanswered about efficacy and safety. This systematic review aims to assess the efficacy and safety of rechallenging/continuing clozapine in patients following neutropenia/agranulocytosis using CSFs. METHODS: MEDLINE, Embase, PsycInfo, and Web of Science databases were searched from inception date to July 31, 2022. Articles screening and data extraction were realized independently by two reviewers, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 systematic review guidance. Included articles had to report on at least one case where clozapine was rechallenged/continued using CSFs despite previous neutropenia/agranulocytosis. RESULTS: Eight hundred forty articles were retrieved; 34 articles met the inclusion criteria, totaling 59 individual cases. Clozapine was successfully rechallenged/continued in 76% of patients for an average follow-up period of 1.9 years. There was a trend toward better efficacy reported in case reports/series, compared with consecutive case series (overall success rates of 84% and 60%, respectively, p-value = 0.065). Two administration strategies were identified, "as-needed" and prophylactic, both yielding similar success rates (81% and 80%, respectively). Only mild and transient adverse events were documented. CONCLUSIONS: Although limited by the relatively small number of published cases, factors such as time of onset to first neutropenia and severity of the episode did not seem to impact the outcome of a subsequent clozapine rechallenge using CSFs. While the efficacy of this strategy remains to be further adequately evaluated in more rigorous study designs, its long-term innocuity warrants considering its use more proactively in the management of clozapine hematological adverse events as to maintain this treatment for as many individuals as possible.

Real-life effectiveness of transitioning from paliperidone palmitate 1-monthly to paliperidone palmitate 3-monthly long-acting injectable formulation.

Background: Non-adherence to antipsychotics in schizophrenia is associated with an increased risk of psychotic relapse and hospitalization, a risk that is reduced with the use of long-acting injectable (LAI) antipsychotics. Randomized clinical trials (RCTs) have demonstrated the efficacy of paliperidone palmitate 3-monthly (PP3M) for psychotic relapse prevention in schizophrenia, but it remains poorly documented among individuals treated in real-life settings who can benefit the most out of LAIs. Objectives: The objective of this study was to evaluate the effectiveness of PP3M in relapse prevention among patients with schizophrenia. Methods: This is a multicentre retrospective study conducted in four outpatients' clinics across Canada. All consecutive patients with a main diagnosis of schizophrenia who initiated PP3M between June 2016 and March 2020 were included. The primary outcome was psychotic relapse, defined using broad and clinically relevant criteria. Results: Among 178 consecutive patients who were switched to PP3M, the 12-month relapse rate was 18.5% and the relapse-free survival probability was 0.788 (95% confidence interval [CI] = 0.725-0.856). Comorbid diagnoses of personality disorders and substance use disorders were associated with hazard rates (HRs) of 3.6 (95% CI = 1.8-7.3, p < 0.001) and 3.1 (95% CI = 1.6-6.2), respectively. Increased psychopathology severity was associated with an increased likelihood of relapse, while having a job or being in school was protective. Conclusion: These findings reinforce the necessity of conducting research in patients with comorbid psychiatric disorders who are typically underrepresented in RCTs, yet overrepresented in real-life settings, in order to better inform and guide clinical practice.

Assessment of Corticospinal Excitability in Awake Rodents Using EMG-Controlled Intracortical Stimulation.

Assessment of corticospinal excitability (CSE) is an essential component of experiments designed to induce or study neuronal plasticity in the motor system. Common examples are paired associative stimulation (PAS), theta-burst stimulation (TBS), intensive motor training, or any methods aimed at potentiating the corticomotor system in the hope of promoting better recovery after neurological insult. To date, rodent models of CSE assessment have mostly been completed under anaesthesia, which greatly affects the level of CSE, as well as the mechanisms of plasticity. Experiments in awake animals are difficult because the ongoing state of behavior affects the excitability of the motor system and complicates the assessment of CSE. To address this issue, we have designed a novel approach for CSE assessment in awake behaving rodents, enabling a reliable measure of evoked motor responses obtained from cortical microstimulation in repeatable conditions of ongoing motor activity. The system relies on chronically implanted intracortical and intramuscular electrodes and a custom-made software control system, enabling the user to require that precise parameters of EMG activity be met before cortical stimulation probes are delivered. This approach could be used for further studies of PAS, TBS or other interventions requiring the assessment of CSE under repeatable conditions. We provide fabrication schematics and a list of materials for the implant, as well as instructions for running a custom-made MATLAB codebase, customizing the PAS protocol, and performing the complete analysis of experimental data. We hope these tools can further facilitate animal research in the field of neuroplasticity and neurorehabilitation.

Evidence Supporting the Management of Medical Conditions During Long-Duration Spaceflight: Protocol for a Scoping Review.

BACKGROUND: Future long-duration space exploration missions, such as traveling to Mars, will create an increase in communication time delays and disruptions and remove the viability of emergency returns to Earth for timely medical treatment. Thus, higher levels of medical autonomy are necessary. Crew selection is proposed as the first line of defense to minimize medical risk for future missions; however, the second proposed line of defense is medical preparedness and crew member autonomy. In an effort to develop a decision support system, the Canadian Space Agency mandated a team of scientists from Thales Research and Technology Canada (Québec, QC) and Université Laval (Québec, QC) to create an evidence-based medical condition database linking mission-critical human conditions with key causal factors, diagnostic and treatment information, and probable outcomes. OBJECTIVE: To complement this database, we are currently conducting a scoping review to better understand the depth and breadth of evidence about managing medical conditions in space. METHODS: This scoping review will adhere to quality standards for scoping reviews, employing Levac, Colquhoun, and O'Brien's 6-stage methodology; the reported results will follow the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) extension for scoping reviews. In stage 1, we identified the research question in collaboration with the Canadian Space Agency (CSA), the main knowledge user. We prioritized 10 medical conditions: (1) acute coronary syndrome, (2) atrial fibrillation, (3) eye penetration, (4) herniated disk, (5) nephrolithiasis, (6) pulmonary embolism, (7) retinal detachment, (8) sepsis, (9) stroke, and (10) spaceflight associated neuro-ocular syndrome. In stage 2, with the help of an information specialist from Cochrane Canada Francophone, papers were identified through searches of the following databases: ARC, Embase, IeeeXplore, Medline Ovid, PsychINFO, and Web of Science. In stage 3, studies will be selected and assessed using a 3-step process and emerging, refined exclusion criteria. In stage 4, the data will be charted in a table based on parameters required by the CSA and developed using Google spreadsheets for shared access. In stage 5, evidence-based descriptive summaries will be produced for each condition, as well as descriptive analyses of collected data. Finally, in stage 6, the findings will be shared with the CSA to guide the completion of this project. RESULTS: This study was planned in December 2018. Stage 1 has been completed. The initial database search strategy with all target conditions combined identified a total of 10,403 citations to review through title and abstract screening and after duplicate removal. We plan to complete stages 2-6 by the beginning of 2021. CONCLUSIONS: This scoping review will map the literature on the management of 10 priority medical conditions in space. It will also enable us to identify knowledge gaps that must be addressed in future research, ensuring successful and medically safe future missions as humankind embarks upon new frontiers of space exploration. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24323.

Paired Associative Stimulation Fails to Induce Plasticity in Freely Behaving Intact Rats.

Paired associative stimulation (PAS) has been explored in humans as a noninvasive tool to drive plasticity and promote recovery after neurologic insult. A more thorough understanding of PAS-induced plasticity is needed to fully harness it as a clinical tool. Here, we tested the efficacy of PAS with multiple interstimulus intervals in an awake rat model to study the principles of associative plasticity. Using chronically implanted electrodes in motor cortex and forelimb, we explored PAS parameters to effectively drive plasticity. We assessed changes in corticomotor excitability using a closed-loop, EMG-controlled cortical stimulation paradigm. We tested 11 PAS intervals, chosen to force the coincidence of neuronal activity in the motor cortex and spinal cord of rats with timings relevant to the principles of Hebbian spike timing-dependent plasticity. However, despite a relatively large number of stimulus pairings (300), none of the tested intervals reliably changed corticospinal excitability relative to control conditions. Our results question PAS effectiveness under these conditions.

Learning Integrated Health System to Mobilize Context-Adapted Knowledge With a Wiki Platform to Improve the Transitions of Frail Seniors From Hospitals and Emergency Departments to the Community (LEARNING WISDOM): Protocol for a Mixed-Methods Implementation Study.

BACKGROUND: Elderly patients discharged from hospital experience fragmented care, repeated and lengthy emergency department (ED) visits, relapse into their earlier condition, and rapid cognitive and functional decline. The Acute Care for Elders (ACE) program at Mount Sinai Hospital in Toronto, Canada uses innovative strategies, such as transition coaches, to improve the care transition experiences of frail elderly patients. The ACE program reduced the lengths of hospital stay and readmission for elderly patients, increased patient satisfaction, and saved the health care system over Can $4.2 million (US $2.6 million) in 2014. In 2016, a context-adapted ACE program was implemented at one hospital in the Centre intégré de santé et de services sociaux de Chaudière-Appalaches (CISSS-CA) with a focus on improving transitions between hospitals and the community. The quality improvement project used an intervention strategy based on iterative user-centered design prototyping and a "Wiki-suite" (free web-based database containing evidence-based knowledge tools) to engage multiple stakeholders. OBJECTIVE: The objectives of this study are to (1) implement a context-adapted CISSS-CA ACE program in four hospitals in the CISSS-CA and measure its impact on patient-, caregiver-, clinical-, and hospital-level outcomes; (2) identify underlying mechanisms by which our context-adapted CISSS-CA ACE program improves care transitions for the elderly; and (3) identify underlying mechanisms by which the Wiki-suite contributes to context-adaptation and local uptake of knowledge tools. METHODS: Objective 1 will involve staggered implementation of the context-adapted CISSS-CA ACE program across the four CISSS-CA sites and interrupted time series to measure the impact on hospital-, patient-, and caregiver-level outcomes. Objectives 2 and 3 will involve a parallel mixed-methods process evaluation study to understand the mechanisms by which our context-adapted CISSS-CA ACE program improves care transitions for the elderly and by which our Wiki-suite contributes to adaptation, implementation, and scaling up of geriatric knowledge tools. RESULTS: Data collection started in January 2019. As of January 2020, we enrolled 1635 patients and 529 caregivers from the four participating hospitals. Data collection is projected to be completed in January 2022. Data analysis has not yet begun. Results are expected to be published in 2022. Expected results will be presented to different key internal stakeholders to better support the effort and resources deployed in the transition of seniors. Through key interventions focused on seniors, we are expecting to increase patient satisfaction and quality of care and reduce readmission and ED revisit. CONCLUSIONS: This study will provide evidence on effective knowledge translation strategies to adapt best practices to the local context in the transition of care for elderly people. The knowledge generated through this project will support future scale-up of the ACE program and our wiki methodology in other settings in Canada. TRIAL REGISTRATION: ClinicalTrials.gov NCT04093245; https://clinicaltrials.gov/ct2/show/NCT04093245. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17363.

Impaired Motor Learning Following a Pain Episode in Intact Rats.

Motor learning and pain are important factors influencing rehabilitation. Despite being mostly studied independently from each other, important interactions exist between them in the context of spinal cord injury, whether to the spinal cord or the body. Ongoing or recent past episodes of nociceptive activity can prevent motor learning in spinalized rats. In intact animals, it has been proposed that supraspinal activity could counter the repressive effect of nociception on motor system plasticity, but this has not yet been verified in behavioral conditions. The aim of this study was to test whether a recent episode of nociception affects subsequent motor learning in intact animals. We trained rodents to walk on a custom-made horizontal ladder. After initial training, the rats underwent a week-long rest, during which they were randomly assigned to a control group, or one out of two pain conditions. Nociceptive stimuli of different durations were induced through capsaicin or Complete Freund's Adjuvant injections and timed so that the mechanical hypersensitivity had entirely subsided by the end of the resting period. Training then resumed on a modified version of the horizontal ladder. We evaluated the animals' ability to adapt to the modified task by measuring their transit time and paw misplacements over 4 days. Our results show that prior pain episodes do affect motor learning in neurologically intact rats. Motor learning deficits also seem to be influenced by the duration of the pain episode. Rats receiving a subcutaneous injection of capsaicin displayed immediate signs of mechanical hypersensitivity, which subsided rapidly. Nonetheless, they still showed learning deficits 24 h after injection. Rats who received a Complete Freund's Adjuvant injection displayed mechanical hypersensitivity for up to 7 days during the resting period. When trained on the modified ladder task upon returning to normal sensitivity levels, these rats exhibited more prolonged motor learning deficits, extending over 3 days. Our results suggest that prior pain episodes can negatively influence motor learning, and that the duration of the impairment relates to the duration of the pain episode. Our results highlight the importance of addressing pain together with motor training after injury.