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Dopamine-releasing neurons of the substantia nigra pars compacta produce an extraordinarily dense and expansive plexus of innervation in the striatum converging with glutamatergic corticostriatal and thalamostriatal axon terminals at dendritic spines of medium spiny neurons. Here, we investigated whether glutamatergic signaling promotes arborization and growth of dopaminergic axons. In postnatal ventral midbrain cultures, dopaminergic axons rapidly responded to glutamate stimulation with accelerated growth and growth cone splitting when NMDA and AMPA/kainate receptors were activated. In contrast, when AMPA/kainate receptors were selectively activated, axon growth rate was decreased. To address whether this switch in axonal growth response was mediated by distinct calcium signals, we used calcium imaging. Combined NMDA and AMPA/kainate receptor activation elicited calcium signals in axonal growth cones that were mediated by calcium influx through L-type voltage-gated calcium channels and ryanodine receptor-induced calcium release from intracellular stores. AMPA/kainate receptor activation alone elicited calcium signals that were solely attributable to calcium influx through L-type calcium channels. We found that inhibitors of calcium/calmodulin-dependent protein kinases prevented the NMDA receptor-dependent axonal growth acceleration, whereas AMPA/kainate-induced axonal growth decrease was blocked by inhibitors of calcineurin and by increased cAMP levels. Our data suggest that the balance between NMDA and AMPA/kainate receptor activation regulates the axonal arborization pattern of dopamine axons through the activation of competing calcium-dependent signaling pathways. Understanding the mechanisms of dopaminergic axonal arborization is essential to the development of treatments that aim to restore dopaminergic innervation in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Catatonia is a highly morbid psychomotor and affective disorder, which can affect autistic individuals with and without intellectual disability. Catatonic symptoms are treatable with pharmacotherapy and electroconvulsive therapy, but the longitudinal effectiveness of these treatments in autistic individuals has not been described. We conducted a prospective observational cohort study of patients with autism and co-morbid catatonia who received outpatient care in a specialized outpatient clinic from July 1, 2021 to May 31, 2024. Data investigating pharmacologic interventions, and clinical measures including the Bush Francis Catatonia Rating Scale (BFCRS), Kanner Catatonia Severity Scale (KCS), Kanner Catatonia Examination (KCE), and Clinical Global Impression-Improvement (CGI-I) were collected. Forty-five autistic patients with co-morbid catatonia were treated during the study period. The mean age was 15.6 (SD = 7.9) years [Mdn = 16.0, range 6.0-31.0]. Forty-one patients (91.1%) met criteria for autism with co-occurring intellectual disability. All patients received pharmacotherapy. Forty-four (97.8%) were treated with benzodiazepines with a mean maximal daily dose of 17.4 mg (SD = 15.8) lorazepam equivalents. Thirty-five patients (77.8%) required more than one medication class for treatment. Sixteen (35.6%) patients received electroconvulsive therapy. Fourteen patients (31.1%) attempted to taper off benzodiazepines after achieving clinical improvement during the study period; of these, 5 patients (11.1%) were successfully tapered off, and the remaining 9 (17.8%) discontinued the taper due to a return of catatonic symptoms. Statistically significant improvement was observed across all clinical domains except the KCS. However, the majority remained at least partially symptomatic over the study period. Three patients (6.7%) died over the study period. Despite clinical improvements while receiving the gold standard for psychopharmacologic management of catatonia, chronic symptoms remained for the majority of catatonia patients over the study period, and few were able to taper and discontinue benzodiazepine treatment. Notably, the open label design of this study is a limiting factor when interpreting the results., (© 2025 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Prader-Willi syndrome (PWS) is a genetic disorder associated with baseline respiratory impairment caused by multiple contributing etiologies. While this may be expected to increase the risk of severe COVID-19 infections in PWS patients, survey studies have suggested paradoxically low disease severity. To better characterize the course of COVID-19 infection in patients with PWS, this study analyses the outcomes of hospitalizations for COVID-19 among patients with and without PWS. The National Inpatient Sample, an all-payors administrative claims database of hospitalizations in the United States, was queried for patients with a coded diagnosis COVID-19 in 2020 and 2021. Hospitalizations for patients with PWS compared to those for patients without PWS using Augmented Inverse Propensity Weighting (AIPW). There were 295 (95% CI: 228-362) COVID-19 hospitalizations for individuals with PWS and 4,112,400 (95% CI: 4,051,497-4,173,303) for individuals without PWS. PWS patients had a median age of 33 years compared to 63 for those without PWS. Individuals with PWS had higher baseline rates of obesity (47.5% vs. 28.4%). AIPW models show that PWS diagnosis is associated with increased hospital length of stay by 7.43 days, hospital charges by $80,126, and the odds of mechanical ventilation and in-hospital death (odds ratios of 1.79 and 1.67, respectively). PWS patients hospitalized with COVID-19 experienced longer hospital stays, higher charges, and increased risk of mechanical ventilation and death. These results suggest that PWS should be considered a risk factor for severe COVID-19, warranting continued protective measures and vaccination efforts. Further research is needed to validate coding for PWS and assess the impact of evolving COVID-19 variants and population immunity on this vulnerable population., (© 2025 Wiley Periodicals LLC.)

Objective: Catatonia is a neuropsychiatric disorder that is associated with a range of medical and psychiatric illnesses. Although many single-center studies have been conducted, uncertainty over the population-based incidence and prevalence of the disorder remains. This study reports on the incidence and prevalence rates of catatonia extrapolated from two large epidemiologic studies in the United Kingdom and United States., Methods: Incidence rates (defined as the number of catatonic episodes per 100,000 person-years) and prevalence rates (defined as the proportion of individuals with catatonia in a given year) were calculated from the two studies., Results: U.K. data showed an incidence of 4.34 (95% CI=3.98-4.72) catatonic episodes per 100,000 person-years with an average 1-year prevalence of 4.39 (95% CI=4.03-4.77) catatonic episodes per 100,000 persons. U.S. data revealed a 1-year prevalence of 5.15 (95% CI=5.08-5.23) catatonia-related hospitalizations per 100,000 persons., Conclusions: Catatonia is a rare disorder, qualifying as an orphan disease under both European Medicines Agency and U.S. Food and Drug Administration criteria. Further research is needed to rigorously define the epidemiology of catatonia in other populations., Competing Interests: Dr. Luccarelli reports receiving funding from Harvard Medical School, the Rappaport Foundation, and the Foundation for Prader-Willi Research and receiving equity in Revival Therapeutics, Inc. Dr. Smith reports receiving funding from the National Institute of Child and Human Development and support from Axial and Roche. Dr. Kalinich reports receiving compensation from Watershed Informatics and equity from Watershed Informatics and Revival Therapeutics, Inc. Dr. Rogers reports receiving research funding from the Wellcome Trust and NIHR; royalties from Taylor & Francis; payment for reviewing from Johns Hopkins University Press; and speaker fees from the Alberta Psychiatric Association, Infomed Research and Training Ltd., North East London NHS Foundation Trust, and Vanderbilt Medical Center. Dr. Amad reports no financial relationships with commercial interests.

Introduction: Catatonia is a neuropsychiatric disorder marked by significant disturbances in motor, cognitive, and affective functioning and that is frequently under-diagnosed. To enhance clinical detection of catatonia, this study aimed to develop a rapid, sensitive Catatonia Quick Screen (CQS) using a reduced set of catatonic signs to facilitate screening in adult and pediatric patients., Methods: Data were derived from two retrospective cohorts totaling 446 patients (254 adults, 192 children) who screened positive for catatonia using the Bush Francis Catatonia Screening Instrument (BFCSI). Sensitivity analyses were performed for all combinations of BFCSI signs, with sensitivity defined as the proportion of patients identified by each subset relative to the full BFCSI. The CQS was developed by selecting signs from the BFCSI based on sensitivity, ease of assessment, and relevance to diverse catatonia presentations., Results: Screening for the presence of any one of four signs-excitement, mutism, staring, or posturing-using the CQS yielded a theoretical sensitivity of 97% (95% CI: 95 to 98%) relative to the full BFCSI (which requires two signs out of 14). The CQS demonstrated 97% sensitivity across both pediatric and adult subsets., Conclusion: The Catatonia Quick Screen provides a rapid screening alternative to the BFCSI with high sensitivity, potentially improving early detection of catatonia in clinical settings. Future prospective studies are necessary to validate the CQS's sensitivity and to determine its specificity in clinical populations., Competing Interests: Declaration of Interest: JL receives funding from Harvard Medical School Dupont Warren Fellowship and Livingston Awards, the Rappaport Foundation, the American Academy of Child and Adolescent Psychiatry, and the Foundation for Prader-Willi Research. He has received equity and consulting fees from Revival Therapeutics, Inc. MK has received compensation from Watershed Informatics and equity from Watershed Informatics and Revival Therapeutics, Inc. JW receives support from the Department of Veterans Affairs, Geriatric, Research, Education and Clinical Center (GRECC) at the Tennessee Valley Healthcare System in Nashville, TN. GF has received equity from Revival Therapeutics, IP royalties from Adya Health and is on the scientific advisory board of Being Health. SH has received funding from NIH. JRS receives funding from the National Institute of Child and Human Development, Axial, and Roche. All other authors declare no conflicts of interest.

Introduction: Catatonia is a highly morbid psychomotor and affective disorder which can affect autistic individuals with and without profound impairment. Catatonic symptoms are treatable with pharmacotherapy and electroconvulsive therapy, but the longitudinal effectiveness of these treatments has not been described., Methods: We conducted a prospective observational cohort study of patients with autism and co-morbid catatonia who received outpatient care in a specialized outpatient clinic from July 1 st , 2021 to May 31 st , 2024. Data investigating pharmacologic interventions, and clinical measures including the Bush Francis Catatonia Rating Scale (BFCRS), Kanner Catatonia Severity Scale (KCS), Kanner Catatonia Examination (KCE), and Clinical Global Impression - Improvement (CGI-I) were collected., Results: Forty-five patients were identified with 39 (86.7%) meeting criteria for profound autism. All patients received pharmacotherapy. 44 (97.8%) were treated with benzodiazepines with a mean maximal daily dose of 17.4 mg (SD=15.8) lorazepam equivalents. Thirty-five patients (77.8%) required more than one medication class for treatment. Fourteen patients (31.1%) attempted to taper off benzodiazepines during the study period; of these, 5 patients (11.1%) were successfully tapered off, and the remaining 9 (17.8%) discontinued the taper due to a return of catatonic symptoms. Statistically significant improvement was observed across all clinical domains except the KCS. However, the majority remained symptomatic over the study period., Conclusions: Despite clinical improvements while receiving the gold standard for psychopharmacologic management of catatonia, chronic symptoms remained for the majority of catatonia patients over the study period, and few were able to taper and discontinue benzodiazepine treatment., Competing Interests: JRS receives funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Axial Therapeutics, and Roche. ZJW has received consulting fees from Roche and Autism Speaks. He also serves as the Vice-chair of Autistic and Neurodivergent Scholars Working for Equity in Research (ANSWER), a division of the Autism Intervention Research Network on Physical Health (AIR-P). JW receives support from the Department of Veterans Affairs, Geriatric, Research, Education and Clinical Center (GRECC) at the Tennessee Valley Healthcare System in Nashville, TN. JL receives funding from Harvard Medical School, the Rappaport Foundation, and the Foundation for Prader-Willi Research. He holds equity and has received consulting income from Revival Therapeutics, Inc.

Background: Prader-Willi syndrome (PWS) is a genetic disorder associated with baseline respiratory impairment caused by multiple contributing etiologies. While this may be expected to increase the risk of severe COVID-19 infections in PWS patients, survey studies have suggested paradoxically low disease severity. To better characterize the course of COVID-19 infection in patients with PWS, this study analyzes the outcomes of hospitalizations for COVID-19 among patients with and without PWS., Methods: The National Inpatient Sample, an all-payors administrative claims database of hospitalizations in the United States, was queried for patients with a coded diagnosis COVID-19 in 2020 and 2021. Hospitalizations for patients with PWS compared to those for patients without PWS using Augmented Inverse Propensity Weighting (AIPW)., Results: There were 295 (95% CI: 228 to 362) COVID-19 hospitalizations for individuals with PWS and 4,112,400 (95% CI: 4,051,497 to 4,173,303) for individuals without PWS. PWS patients had a median age of 33 years compared to 63 for those without PWS. Individuals with PWS had higher baseline rates of obesity (47.5% vs. 28.4%). AIPW models show that PWS diagnosis is associated with increased hospital length of stay by 7.43 days, hospital charges by $80,126, and the odds of mechanical ventilation and in-hospital death (odds ratios of 1.79 and 1.67, respectively)., Conclusions: PWS patients hospitalized with COVID-19 experienced longer hospital stays, higher charges, and increased risk of mechanical ventilation and death. PWS should be considered a risk factor for severe COVID-19, warranting continued protective measures and vaccination efforts. Further research is needed to validate coding for PWS and assess the impact of evolving COVID-19 variants and population immunity on this vulnerable population., Competing Interests: JL receives funding from Harvard Medical School Dupont Warren Fellowship and Livingston Awards, the Rappaport Foundation, and the Foundation for Prader-Willi Research. He has received equity and consulting fees from Revival Therapeutics, Inc. TVS is an employee of the Foundation for Prader-Willi Research. BBR has no disclosures to report. THM receives funding, through his institution, from National Institute of Health, Telefonica Alfa, InterSystems, Philips Research North America, and honoraria from Springer Nature publishing.

Objective: Generalized periodic discharges are a repeated and generalized electroencephalography (EEG) pattern that can be seen in the context of altered mental status. This article describes a series of five individuals with generalized periodic discharges who demonstrated signs and symptoms of catatonia, a treatable neuropsychiatric condition., Methods: Inpatients with a clinical diagnosis of catatonia, determined with the Bush-Francis Catatonia Rating Scale (BFCRS), and EEG recordings with generalized periodic discharges were analyzed in a retrospective case series., Results: Five patients with catatonia and generalized periodic discharges on EEG were evaluated from among 106 patients with catatonia and contemporaneous EEG measurements. Four of these patients showed an improvement in catatonia severity when treated with benzodiazepines, with an average reduction of 6.75 points on the BFCRS., Conclusions: Among patients with generalized periodic discharges, catatonia should be considered, in the appropriate clinical context. Patients with generalized periodic discharges and catatonia may benefit from treatment with empiric trials of benzodiazepines., Competing Interests: Dr. Luccarelli has received funding from Harvard Medical School Dupont Warren Fellowship and Livingston Awards, and he holds equity in Revival Therapeutics. Dr. Smith has received support from Axial and Roche for clinical trial work. Dr. Fricchione has served as a consultant for Revival Therapeutics; he has received royalties from Adya Health; and he has received honoraria or royalties from American Psychiatric Association Publishing, Belvoir Press, Johns Hopkins University Press, and the University of Chicago Press. Dr. Westover is a cofounder of Beacon Biosignals.

Objectives: Electroconvulsive therapy (ECT) is an effective treatment for a range of psychiatric disorders. Although much research has examined what patients receive ECT, there is less research describing those physicians who provide ECT services. This study examines the ECT workforce in the United States by analyzing publicly available Medicare billing records., Methods: Data regarding the providers performing ECT were accessed from the Medicare Physician and Other Supplier Data for the years 2013 through 2021 based on those physicians who billed the ECT procedural code 90870., Results: During the study period, 1402 physicians performed ECT in at least 1 calendar year on a minimum of 11 Medicare beneficiaries, representing 3.9% of the 36,116 psychiatrists who billed Medicare during this period. Female physicians made up 39% of psychiatrists overall who bill Medicare, but 23% of psychiatrists billing for ECT. Fifty percent of billed ECT treatments were performed by 12% of ECT doctors; among these high-volume ECT providers, 16% were female., Conclusions: Only a small subset of psychiatrists who bill Medicare provide ECT services, and female physicians are under-represented in the ECT workforce and among high-volume ECT providers. Improving workforce equity and with it access to ECT requires further study of psychiatric training and practice environment that may impose barriers on female participation as ECT providers., Competing Interests: Conflicts of Interest: Dr Luccarelli receives funding from the National Institute of Mental Health, Harvard Medical School, the Rappaport Foundation, and the Foundation for Prader-Willi Research. He has received equity and consulting fees from Revival Therapeutics, Inc. Dr McCoy receives funding, through his institution, from the National Institutes of Health, Telefonica Alfa, InterSystems, and honoraria from Springer Nature publishing. Ms Hart has no disclosures to report., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Catatonia is a neuropsychiatric disorder that occurs in pediatric patients with a range of associated medical, psychiatric, and neurodevelopmental disorders (NDDs). This study describes hospital care of pediatric catatonia patients and compares treatments for neurotypical patients and those with NDDs., Methods: Retrospective cohort study from 1/1/2018 to 6/1/2023 of two academic medical centers of patients aged 18 and younger with catatonia. Patients were retrospectively assessed using the clinical global impressions-improvement (CGI-I) by two independent reviewers., Results: One hundred sixty-five patients were hospitalized for catatonia, of whom 50.3% had an NDD. Median age was 15. One hundred sixty-four patients were treated with a benzodiazepine, with a median maximum 24-hour dose of 6 mg lorazepam-equivalents, which did not differ for patients with and without NDDs. Electroconvulsive therapy (ECT) was utilized in 14.5% of patients. Median length of medical hospitalization was 5 days and hospitalizations were longer in neurotypical patients than in patients with NDDs. In an ordinal regression model, the probability of observing at least "much improvement" (CGI < 3) was 88.3% (95% CI: 82.4% to 92.3%), with NDD diagnosis associated with a lower odds of clinical response., Conclusions: The probability of patients achieving a CGI-I score indicating at least "much improvement" was 88.3%. Administered benzodiazepine dose and ECT treatment were similar for all patients, but neurotypical patients had longer hospitalizations than those with NDDs and had a higher odds of a more favorable clinical response. Research under controlled conditions is needed to optimize and endure equitable catatonia treatment in youth., Competing Interests: JL receives funding from Harvard Medical School Dupont Warren Fellowship and Livingston Awards, the Rappaport Foundation, and the Foundation for Prader-Willi Research. He has received equity and consulting fees from Revival Therapeutics, Inc. JAC receives funding from the Harvard Medical School Dupont-Warren Fellowship, the Chen Institute Mass General Neuroscience Transformative Scholar Award, and the Louis V. Gerstner Award. GF has received equity from Revival Therapeutics, IP royalties from Adya Health and is on the scientific advisory board of Being Health. JRS receives funding from Roche, Axial Therapeutics, and the National Institute of Child and Human Development.All other authors report no disclosures.

Introduction: Electroconvulsive therapy (ECT) and ketamine are two effective treatments for depression with similar efficacy; however, individual patient outcomes may be improved by models that predict optimal treatment assignment. Here, we adapt the Personalized Advantage Index (PAI) algorithm using machine learning to predict optimal treatment assignment between ECT and ketamine using medical record data from a large, naturalistic patient cohort. We hypothesized that patients who received a treatment predicted to be optimal would have significantly better outcomes following treatment compared to those who received a non-optimal treatment., Methods: Data on 2526 ECT and 235 mixed IV ketamine and esketamine patients from McLean Hospital was aggregated. Depressive symptoms were measured using the Quick Inventory of Depressive Symptomatology (QIDS) before and during acute treatment. Patients were matched between treatments on pretreatment QIDS, age, inpatient status, and psychotic symptoms using a 1:1 ratio yielding a sample of 470 patients (n=235 per treatment). Random forest models were trained and predicted differential patientwise minimum QIDS scores achieved during acute treatment (min-QIDS) scores for ECT and ketamine using pretreatment patient measures. Analysis of Shapley Additive exPlanations (SHAP) values identified predictors of differential outcomes between treatments., Results: Twenty-seven percent of patients with the largest PAI scores who received a treatment predicted optimal had significantly lower min-QIDS scores compared to those who received a non-optimal treatment (mean difference=1.6, t=2.38, q<0.05, Cohen's D=0.36). Analysis of SHAP values identified prescriptive pretreatment measures., Conclusions: Patients assigned to a treatment predicted to be optimal had significantly better treatment outcomes. Our model identified pretreatment patient factors captured in medical records that can provide interpretable and actionable guidelines treatment selection., Competing Interests: Conflict of Interest JL has received funding from Harvard Medical School and the National Institute of Mental Health. He has received equity from Revival Therapeutics. The remaining authors report no conflict of interest.

Hydrogen bonding plays an essential part in dictating the properties of natural and synthetic materials. Secondary amides are well suited to cross-strand interactions through the display of both hydrogen bond donors and acceptors and are prevalent in polymers such as proteins, nylon, and Kevlar™. In attempting to measure hydrogen bond strength and to delineate the stereoelectronic components of the interaction, context frequently becomes vitally important. This makes molecular balances - systems in which direct comparison of two groups is possible - an appealing bottom up approach that allows the complexity of larger systems to be stripped away. We have previously reported a family of single molecule conformational switches that are responsive to diverse stimuli including Brønsted and Lewis acids, anions, and redox gradients. In this work we assess the ability of the scaffold, based on a 2,6-disubstituted diphenylacetylene, to measure accurately the difference in hydrogen bond strength between variously functionalised amides. In all of the examples investigated hydrogen bond strength closely correlate to measures of Brønstead acidity suggesting that the scaffold is well-suited as a platform for the accurate determination of bond strength in variously substituted systems.