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Abstract Corticospinal motor neurons (CSMN), located in the motor cortex of the brain, are one of the key components of the motor neuron circuitry. They are in part responsible for the initiation and modulation of voluntary movement, and their degeneration is the hallmark for numerous diseases, such as amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, and primary lateral sclerosis. Cortical hyperexcitation followed by in-excitability suggests the early involvement of cortical dysfunction in ALS pathology. However, a high-spatiotemporal resolution on our understanding of their functional health and connectivity is lacking. Here, we combine optical imaging with high-density microelectrode array (HD-MEA) system enabling single cell resolution and utilize UCHL1-eGFP mice to bring cell-type specificity to our understanding of the electrophysiological features of healthy CSMN, as they mature and form network connections with other cortical neurons, in vitro. This novel approach lays the foundation for future cell-type specific analyses of CSMN that are diseased due to different underlying causes with cellular precision, and it will allow the assessment of their functional response to compound treatment, especially for drug discovery efforts in upper motor neuron diseases.

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

Abstract Historically, eloquent functions have been viewed as localized to focal areas of human cerebral cortex, while more recent studies suggest they are encoded by distributed networks. We examined the network properties of cortical sites defined by stimulation to be critical for speech and language, using electrocorticography from sixteen participants during word-reading. We discovered distinct network signatures for sites where stimulation caused speech arrest and language errors. Both demonstrated lower local and global connectivity, whereas sites causing language errors exhibited higher inter-community connectivity, identifying them as connectors between modules in the language network. We used machine learning to classify these site types with reasonably high accuracy, even across participants, suggesting that a site’s pattern of connections within the task-activated language network helps determine its importance to function. These findings help to bridge the gap in our understanding of how focal cortical stimulation interacts with complex brain networks to elicit language deficits.

Abstract Objective This study was designed to investigate if highly epileptic electroencephalogram (EEG) findings in patients with acute brain injury increase the long‐term risk of epilepsy development. Methods Adults patients, lacking epilepsy history, with electrographic seizures or lateralized periodic discharges (LPDs) (cases) were identified and matched based on age, mental status, and etiology with the ones lacking any epileptiform activity (controls) on continuous EEG (cEEG) during hospitalization. The primary outcome of clinical seizures after hospital discharge and their antiepileptic drug (AED) status was determined using a telephonic interview. Logistic regression models using generalized estimating equations to account for the matched nature of the data were performed. Results A total of 70 cases [16 (22.9%) “LPDs only,” 34 (48.6%) “electrographic seizure only,” and 20 (28.6%) “both”] and controls were enrolled. A total of 22 (31.4%) cases developed epilepsy after a mean follow‐up duration of 20.6 ± 5.0 months compared to three (4.3%) controls. After adjusting for cEEG indication and follow‐up duration, the odds of cases developing epilepsy were almost 15 times higher compared to the controls (OR = 14.8, 95% CI = 2.4–92.3, P = 0.004). This elevated risk was despite a 10 times higher likelihood of cases to be taking AEDs at the last follow‐up (OR = 10.34, 95% CI = 3.7–29, P

Background: When treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice. Objectives: The main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia. Design: The study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks. Settings: The study was set in NHS multidisciplinary teams in adult psychiatry. Participants: Eligible participants were people aged 18–65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy. Interventions: Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks. Main outcome measures: The primary outcome measure was the proportion of ‘responders’, using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale. Results: A total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between £329 and £2011; no difference in quality-adjusted life-years (QALYs)] and possibly in the longer term. Limitations: The trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants. Conclusions: The risk–benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride–clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride–clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings. Trial registration: EudraCT number 2010-018963-40 and Current Controlled Trials ISRCTN68824876. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 49. See the NIHR Journals Library website for further project information.