Faculty Bibliography

Prediction of future events is essential for guiding effective actions in dynamic environments. Studies on the neural mechanisms for time-forward predictions have typically used stimuli with relatively simple statistical regularities. Here, we investigated time-forward predictions using stimuli containing statistical regularities similar to those found in natural auditory stimuli. Using intracranial EEG recordings in neurosurgical patients, we found that prediction signals were primarily carried by low-frequency activity across widespread cortical regions, including sensory, parietal, and frontal areas. Prediction-error (PE) signals were found in both low- and high-frequency activity, with high-frequency components localized mainly to sensory areas. Contrary to previous hypotheses, prediction and PE signals did not show a clear spatial or spectral segregation. Directed connectivity between brain regions decreased over the course of the stimulus sequence as predictability increased, except for pathways originating from the parietal cortex. These results reveal integrative and distributed predictive processing and highlight the dorsal auditory pathway in time-forward prediction.

Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.

OBJECTIVE:To evaluate cannabidiol (CBD) in pediatric patients with autism spectrum disorder (ASD), fluent verbal language and an estimated full-scale IQ of 80 or above. BACKGROUND:Preliminary evidence suggests CBD may ameliorate challenges associated with ASD. Whether CBD benefits pediatric ASD without accompanying intellectual or language impairment remains unknown. METHODS:, 100 mg/mL) at 3, 6, or 9 mg/kg/day using a Bayesian optimal interval dosing design. The primary endpoint was the CBD dose associated with the highest response rate (i.e., Clinical Global Impression Scale-Improvement [CGI-I] score = 1 or 2) on a target symptom domain designated individually based on informant report, standardized scales, and clinical observation. Secondary endpoints were effect sizes of changes from baseline in measures assessing ASD core and associated symptoms, and global functioning. Adverse events (AEs) were assessed weekly. Plasma CBD levels and clinical labs were obtained at the final visit. RESULTS:= 1.36, 95% CI [0.78-1.93]).Of 222 reported AEs, 27 unique AEs were considered treatment-related. Most AEs (93%) were mild and expected (82%); none was severe. The most frequent related AEs were increased salivation (30%), increased sleep duration (39%), sleepiness/sedation (26%), increased dream activity (35%), and polyuria (22%). Vital signs, physical exams, weight, liver function tests, and complete blood counts were unaffected. CBD plasma levels did not correlate with response. CONCLUSIONS:In this preliminary study, CBD was well tolerated; AEs were mild-moderate. Mean SRS2-T and subscores decreased significantly with large effect sizes, shifting from the severe to the moderate range. CLINICAL TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier NCT03900923.

Urolithiasis is increasingly common, with rising rates driven by obesity, diabetes and metabolic syndrome. Patients with cancer have additional, unique risks of stone formation owing to effects on fluid and electrolyte balance, systemic cancer therapies, tumour lysis syndrome and anatomical alterations after urinary diversion or nephrectomy. Moreover, urolithiasis itself has been linked to increased rates of renal cell carcinoma, urothelial carcinoma and bladder cancer, potentially mediated by chronic inflammation, recurrent infections and shared metabolic or environmental factors. Management in this setting is complex and must be individualized. Percutaneous nephrolithotomy achieves the highest stone-free rates in patients with altered urinary tract anatomy, whereas retrograde intrarenal surgery and shock wave lithotripsy have more selective roles. Preventive strategies focus on thorough metabolic evaluation, hydration optimization and addressing cancer-specific risk factors such as hypercalcaemia, acidosis and chronic urinary stasis. Despite these insights, data on the epidemiology, mechanistic underpinnings and optimal management of urolithiasis in patients with cancer remain limited. Prospective studies are needed to clarify causal relationships, refine preventive strategies and develop evidence-based treatment algorithms for this growing and complex population.

The role of genetic testing for kidney stone formers remains incompletely resolved. The purpose of this paper is to review the role of genetics in kidney stone disease and provide guidance on the utility of genetic testing to overall reduce the burden of the disease for our patients. Genetic testing is a send-out laboratory test for most medical centers in the United States. However, access to such testing has been easier with options for genetic kit delivery to health care offices and even conveniently to patients' homes. The rise of genetic testing in medicine has advanced the field of nephrology in general and kidney stones specifically. It is our aim to provide basic knowledge on the approach to kidney stone disease to physicians, especially nephrologists and nephrology fellows, while also considering the appropriateness of genetic testing.

OBJECTIVES/UNASSIGNED:Although cardiac function is truly vital, and can be adversely affected by many diseases, conventional quantitative global function analysis from images is largely limited to assessing the cardiac volumes at end-diastole and end-systole, and the associated ejection fraction, due to the time-consuming associated image segmentation. Advances in AI-assisted cardiac image segmentation can potentially enable more detailed analysis of the dynamic changes in cardiac volumes over the cardiac cycle, in clinically practical times, but there are now no standardized ways to analyze such data. In this work, we propose a systematic approach to the analysis of dynamic global cardiac function from imaging data. DESIGN/UNASSIGNED:We use some cardiac magnetic resonance imaging (CMR) data here to illustrate this approach, but the methods are not limited to MRI. The focus here is on the technical approach, rather than on potential clinical applications. Representative short-axis cine CMRs from 19 normal subjects and 22 patients with clinical diagnosis of "heart failure with preserved ejection fraction" were analyzed for ventricular volumes over the cardiac cycle. The resulting data were used to calculate a set of dynamic global function variables. RESULTS/UNASSIGNED:A set of representative measures of the timing and rates of ventricular emptying and filling is promising as compact means to characterize dynamic global function. CONCLUSIONS/UNASSIGNED:More efficient cardiac segmentation offers the potential to characterize dynamic global cardiac function, through a set of representative measures of the timing and rates of ventricular emptying and filling.

Larry Young had a huge impact on the study of neuropeptides and social behavior. Here I give an autobiographical perspective on how Larry and his work influenced the field and my own career.

Oral cancer is one of the most painful malignancies, with pain driven primarily by algogenic mediators in the tumor microenvironment, including nerve growth factor (NGF). Although NGF monoclonal antibodies alleviate cancer pain in patients, clinical development was halted because of adverse effects, highlighting the need for safer alternatives. Neuropilin-1 (NRP1), a nonenzymatic NGF coreceptor, mediates NGF and tropomyosin receptor kinase A (TrkA) signaling, yet its role in cancer pain is unknown. We found that NRP1 is robustly coexpressed with TrkA in peptidergic nociceptors of mouse trigeminal ganglia. NRP1 antagonists inhibited NGF-induced sensitization of transient receptor potential vanilloid 1 in isolated trigeminal nociceptors and reduced NGF-induced periorbital mechanical allodynia in mice. Conditioned medium from human tongue squamous carcinoma HSC-3 cells contained NGF and sensitized transient receptor potential vanilloid 1 in trigeminal nociceptors and induced periorbital mechanical allodynia. Immunoneutralization of NGF and NRP1 blockade inhibited these effects. Our results show that NRP1 is a necessary coreceptor for the pronociceptive effects of NGF/TrkA signaling in the trigeminal system and implicate NGF and NRP1 in oral cancer pain. Current oral cancer pain management strategies, including opioids, are inadequate and are burdened by unacceptable side effects. By abrogating the actions of growth factors, including NGF, NRP1-targeted therapies represent an alternative approach to mitigate cancer pain and possibly slow tumor growth.

RATIONALE/BACKGROUND:Aggression is an innate social behavior prevalent across animal species. However, in modern human society, inter-personal aggression is considered disruptive and detrimental to both families and communities. Clinically, antipsychotics, which primarily target dopamine (DA) receptors, have been widely used to suppress hyper-aggression. However, the mechanisms underlying the effect of the antipsychotics remain incompletely understood. OBJECTIVES/OBJECTIVE:We reviewed key steps in brain DA synthesis and summarized genetic and pharmacological evidence supporting the role of the mesolimbic DA system in aggression. Next, we discussed recent circuit studies that elucidate the DA action in modulating aggression-related brain regions. These lines of evidence collectively suggest that DA acts on different brain regions to facilitate aggression and self-learning, and signals the valence of the fighting experience.