Impact of Acute Visual Experience on Development of LGN Receptive Fields in the Ferret.

Selectivity for direction of motion is a key feature of primary visual cortical neurons. Visual experience is required for direction selectivity in carnivore and primate visual cortex, but the circuit mechanisms of its formation remain incompletely understood. Here, we examined how developing lateral geniculate nucleus (LGN) neurons may contribute to cortical direction selectivity. Using in vivo electrophysiology techniques, we examined LGN receptive field properties of visually naive female ferrets before and after exposure to 6 h of motion stimuli to assess the effect of acute visual experience on LGN cell development. We found that acute experience with motion stimuli did not significantly affect the weak orientation or direction selectivity of LGN neurons. In addition, we found that neither latency nor sustainedness or transience of LGN neurons significantly changed with acute experience. These results suggest that the direction selectivity that emerges in cortex after acute experience is computed in cortex and cannot be explained by changes in LGN cells.SIGNIFICANCE STATEMENT The development of typical neural circuitry requires experience-independent and experience-dependent factors. In the visual cortex of carnivores and primates, selectivity for motion arises as a result of experience, but we do not understand whether the major brain area that sits between the retina and the visual cortex-the lateral geniculate nucleus of the thalamus-also participates. Here, we found that lateral geniculate neurons do not exhibit changes as a result of several hours of visual experience with moving stimuli at a time when visual cortical neurons undergo a rapid change. We conclude that lateral geniculate neurons do not participate in this plasticity and that changes in cortex are likely responsible for the development of direction selectivity in carnivores and primates.

A Case Series of Clinical Limitations to the Clinical Course of Neurogenic Fever.

Nurses play a vital role in the care of neurocritical patients. Fever is a common and dangerous occurrence, and there is a substantial lack of consistency in how to maintain normothermia in these patients. We present five cases in which patients were confirmed to have neurogenic fever (NF) and the documented interventions. In all five cases, temperature and interventions were not documented consistently, making it difficult to assess how nurses acted to avoid hyperthermia in these patients. Additional research is needed to determine interventions, processes, procedures, and documentation of NF in neurocritical patients.

Quantitative pupillometry and radiographic markers of intracranial midline shift: A pilot study.

Background: Asymmetric pupil reactivity or size can be early clinical indicators of midbrain compression due to supratentorial ischemic stroke or primary intraparenchymal hemorrhage (IPH). Radiographic midline shift is associated with worse functional outcomes and life-saving interventions. Better understanding of quantitative pupil characteristics would be a non-invasive, safe, and cost-effective way to improve identification of life-threatening mass effect and resource utilization of emergent radiographic imaging. We aimed to better characterize the association between midline shift at various anatomic levels and quantitative pupil characteristics. Methods: We conducted a multicenter retrospective study of brain CT images within 75 min of a quantitative pupil observation from patients admitted to Neuro-ICUs between 2016 and 2020 with large (>1/3 of the middle cerebral artery territory) acute supratentorial ischemic stroke or primary IPH > 30 mm3. For each image, we measured midline shift at the septum pellucidum (MLS-SP), pineal gland shift (PGS), the ratio of the ipsilateral to contralateral midbrain width (IMW/CMW), and other exploratory markers of radiographic shift/compression. Pupil reactivity was measured using an automated infrared pupillometer (NeurOptics®, Inc.), specifically the proprietary algorithm for Neurological Pupil Index® (NPi). We used rank-normalization and linear mixed-effects models, stratified by diagnosis and hemorrhagic conversion, to test associations of radiographic markers of shift and asymmetric pupil reactivity (Diff NPi), adjusting for age, lesion volume, Glasgow Coma Scale, and osmotic medications. Results: Of 53 patients with 74 CT images, 26 (49.1%) were female, and median age was 67 years. MLS-SP and PGS were greater in patients with IPH, compared to patients with ischemic stroke (6.2 v. 4.0 mm, 5.6 v. 3.4 mm, respectively). We found no significant associations between pupil reactivity and the radiographic markers of shift when adjusting for confounders. However, we found potentially relevant relationships between MLS-SP and Diff NPi in our IPH cohort (ß = 0.11, SE 0.04, P = 0.01), and PGS and Diff NPi in the ischemic stroke cohort (ß = 0.16, SE 0.09, P = 0.07). Conclusion: We found the relationship between midline shift and asymmetric pupil reactivity may differ between IPH and ischemic stroke. Our study may serve as necessary preliminary data to guide further prospective investigation into how clinical manifestations of radiographic midline shift differ by diagnosis and proximity to the midbrain.

Vocalization categorization behavior explained by a feature-based auditory categorization model.

Vocal animals produce multiple categories of calls with high between- and within-subject variability, over which listeners must generalize to accomplish call categorization. The behavioral strategies and neural mechanisms that support this ability to generalize are largely unexplored. We previously proposed a theoretical model that accomplished call categorization by detecting features of intermediate complexity that best contrasted each call category from all other categories. We further demonstrated that some neural responses in the primary auditory cortex were consistent with such a model. Here, we asked whether a feature-based model could predict call categorization behavior. We trained both the model and guinea pigs (GPs) on call categorization tasks using natural calls. We then tested categorization by the model and GPs using temporally and spectrally altered calls. Both the model and GPs were surprisingly resilient to temporal manipulations, but sensitive to moderate frequency shifts. Critically, the model predicted about 50% of the variance in GP behavior. By adopting different model training strategies and examining features that contributed to solving specific tasks, we could gain insight into possible strategies used by animals to categorize calls. Our results validate a model that uses the detection of intermediate-complexity contrastive features to accomplish call categorization.

Feasibility and efficacy of a nurse practitioner-and pharmacist-led hypertension clinic.

ABSTRACT: Hypertension (HTN) affects over one third of adults in the United States. Blood pressure (BP) management and patient education are provided by physicians, advanced practice clinicians, pharmacists, and nurses. In the traditional medical/clinic model, physicians have provided and directed HTN care. However, advanced practice nurses and pharmacists are also well trained and positioned to manage HTN. The purpose of this study was to explore the feasibility of an HTN clinic, led by a nurse practitioner (NP) and PharmD, specifically analyzing if targeted HTN can be achieved in this setting. Registry data were used to analyze the initial and the most recent visit BP levels in patients who were seen in an NP/PharmD-led HTN clinic. Measures of central tendency and differences between initial and most recent visit were also compared. A total of 46 patients were included in this analysis. Data showed that there was no statistically significant difference in the first visit (144/86) and the most recent visit (138/84) BP ( p = .26), but that there was a clinical trend in decreasing BP as well as narrowing of BP ranges and interquartile ranges between visit. The NP/PharmD-led clinic is feasible and can help lower BP and narrow ranges toward targeted BP.

A differential of the left eye and right eye neurological pupil index is associated with discharge modified Rankin scores in neurologically injured patients.

BACKGROUND: Automated infrared pupillometry (AIP) and the Neurological Pupil index (NPi) provide an objective means of assessing and trending the pupillary light reflex (PLR) across a broad spectrum of neurological diseases. NPi quantifies the PLR and ranges from 0 to 5; in healthy individuals, the NPi of both eyes is expected to be ≥ 3.0 and symmetric. AIP values demonstrate emerging value as a prognostic tool with predictive properties that could allow practitioners to anticipate neurological deterioration and recovery. The presence of an NPi differential (a difference ≥ 0.7 between the left and right eye) is a potential sign of neurological abnormality. METHODS: We explored NPi differential by considering the modified Rankin Score at discharge (DC mRS) among patients admitted to neuroscience intensive care units (NSICU) of 4 U.S. and 1 Japanese hospitals and for two cohorts of brain injuries: stroke (including subarachnoid hemorrhage, intracerebral hemorrhage, acute ischemic stroke, and aneurysm, 1,200 total patients) and 185 traumatic brain injury (TBI) patients for a total of more than 54,000 pupillary measurements. RESULTS: Stroke patients with at least 1 occurrence of an NPi differential during their NSICU stay have higher DC mRS scores (3.9) compared to those without an NPi differential (2.7; P < .001). Patients with TBI and at least 1 occurrence of an NPi differential during their NSICU stay have higher discharge modified Rankin Scale scores (4.1) compared to those without an NPi differential (2.9; P < .001). When patients experience both abnormalities, abnormal (NPi < 3.0) and an NPi differential, the latter has an anticipatory relationship with respect to the former (P < .001 for z-score skewness analysis). Finally, our analysis confirmed ≥ 0.7 as the optimal cutoff value for the NPi differential (AUC = 0.71, P < .001). CONCLUSION: The NPi differential is an important factor that clinicians should consider when managing critically ill neurological injured patients admitted to the neurocritical care units. TRIAL REGISTRATION: NCT02804438 , Date of Registration: June 17, 2016.

Pilot Study of Neurologic Pupil Index as A Predictor of External Ventricular Drain Clamp Trial Failure After Subarachnoid Hemorrhage.

BACKGROUND: External ventricular drains (EVDs) provide a temporary egress for cerebrospinal fluid (CSF) in patients with symptomatic hydrocephalus following aneurysmal subarachnoid hemorrhage. Before EVD removal, a wean trial, which involves clamping the EVD, is typically attempted to ensure that CSF self-regulation is achieved. Automated infrared pupillometry (AIP) has been shown to detect early neurologic decline. We sought to explore the use of AIP to detect early EVD clamping trial failure. METHODS: This prospective observational pilot study enrolled aneurysmal subarachnoid hemorrhage patients before an EVD clamp trial. On initiating the clamp trial, nurses included hourly AIP assessment in documentation. Clamp trial outcome was based on neurologic examination and neuroimaging. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) models were constructed to explore computed tomography (CT) versus AIP as predictors of clamp trial outcome. RESULTS: Among the 30 subjects enrolled, there were 38 clamping trials and 22 successful EVD removals. CT scan as a predictor of clamp trial was found to have a sensitivity of 68.8% and specificity of 89.5% (PPV = 84.6%, NPV = 77.3%). AIP assessment as a predictor of wean trial outcome was found to have a sensitivity of 58.3% and specificity of 100% (PPV = 100%, NPV = 63.2%). CONCLUSIONS: The pilot study data support that Neurological Pupil index <3 is a potential indicator of early clamp trial failure, but a CT scan has a higher sensitivity and NPV for predicting successful EVD removal. This finding suggests the benefits of including AIP assessments during clamping trials.

Inter-device reliability of the NPi-200 and NPi-300 pupillometers.

The pupillary evaluation is an essential part of the neurological examination. Research suggests that the traditional examination of the pupil with a handheld flashlight has limited interrater reliability. Automated pupillometers were developed to provide an objective scoring of various pupillary parameters. The NPi-200 pupillometer is used for quantitative pupillary examinations, the NPi-300 was launched in July 2021 with enhanced features. The purpose of this study is to compare results from the NPi-200 to the NPi-300 to ensure that data are translatable across both platforms. This study examines the inter-device reliability of the NPi-200 compared to the NPi-300 in two cohorts: 20 patients at risk for cerebral edema and 50 healthy controls. Paired assessments of the devices were made from all participants. Each assessment included bilateral PLR readings within a 5-minute interval. Data showed high agreement between the two devices for the Neurological Pupil Index (NPi) reading (k = 0.94; CI: 0.91-0.99) and for pupil diameter assessment (k = 0.91; CI: 0.87-0.96). There is a very high level of agreement between the NPi-200 and NPi-300 among healthy controls and critically ill patients. Clinicians and researchers can interpret the results from either device equally.

Q-15 Minutes Vital Sign Documentation Is a Poor Surrogate for Assessing Quality of Care After Acute Ischemic Stroke.

OBJECTIVE: Documenting vital signs and National Institutes of Health Stroke Scale (NIHSS) once every 15 minutes after intravenous thrombolytic therapy for acute ischemic stroke is often used as a metric to assess the quality of care. This study explores the association between "once every 15 minutes" documentation and stroke outcomes. METHODS: This is a retrospective study of the first 2 hours of vital signs and NIHSS documentation after thrombolytic stroke therapy. Sociodemographic and clinical data, including NIHSS, temperature, heart rate, systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, and respiratory rate, were abstracted from the medical record. Missing documentation was examined for association with modified Rankin Scale (mRS) scores and neurologic changes. RESULT: Among 84 patients with a mean age of 68.8 years, there were 2276 documented assessments from an expected 3780. There were 104 clinically significant changes in 1 or more index variables. The most commonly missed documentation occurred during interventional radiology. After controlling for admission NIHSS, there was no significant relationship between the completeness of documentation and discharge mRS score (r2 = 0.047, P = .0561), nor between vital sign documentation and discharge mRS (r2 = 0.003, P = .6338). CONCLUSION: Frequency of documentation does not reflect the quality of care during the early phase of acute stroke treatment.

Optogenetic perturbation of projections from thalamic nucleus reuniens to hippocampus disrupts spatial working memory retrieval more than encoding.

BACKGROUND: Working memory deficits are key cognitive symptoms of schizophrenia. Elevated delta oscillations, which are uniquely associated with the presence of the illness, may be the proximal cause of these deficits. Spatial working memory (SWM) is impaired by elevated delta oscillations projecting from thalamic nucleus reuniens (RE) to the hippocampus (HPC); these findings imply a role of the RE-HPC circuit in working memory deficits in schizophrenia, but questions remain as to whether the affected process is the encoding of working memory, recall, or both. Here, we answered this question by optogenetically inducing delta oscillations in the HPC terminals of RE axons in mice during either the encoding or retrieval phase (or both) of an SWM task. METHODS: We transduced cells in RE to express channelrhodopsin-2 through bilateral injection of adeno-associated virus, and bilaterally implanted optical fibers dorsal to the hippocampus (HPC). While mice performed a spatial memory task on a Y-maze, the RE-HPC projections were optogenetically stimulated at delta frequency during distinct phases of the task. RESULTS: Full-trial stimulation successfully impaired SWM performance, replicating the results of the previous study in a mouse model. Task-phase-specific stimulation significantly impaired performance during retrieval but not encoding. CONCLUSIONS: Our results indicate that perturbations in the RE-HPC circuit specifically impair the retrieval phase of working memory. This finding supports the hypothesis that abnormal delta frequency bursting in the thalamus could have a causal role in producing the WM deficits seen in schizophrenia.

Parametric shift from rational to irrational decisions in mice.

In the classical view of economic choices, subjects make rational decisions evaluating the costs and benefits of options in order to maximize their overall income. Nonetheless, subjects often fail to reach optimal outcomes. The overt value of an option drives the direction of decisions, but covert factors such as emotion and sensitivity to sunk cost are thought to drive the observed deviations from optimality. Many questions remain to be answered as to (1) which contexts contribute the most to deviation from an optimal solution; and (2) the extent of these effects. In order to tackle these questions, we devised a decision-making task for mice, in which cost and benefit parameters could be independently and flexibly adjusted and for which a tractable optimal solution was known. Comparing mouse behavior with this optimal solution across parameter settings revealed that the factor most strongly contributing to suboptimal performance was the cost parameter. The quantification of sensitivity to sunk cost, a covert factor implicated in our task design, revealed it as another contributor to reduced optimality. In one condition where the large reward option was particularly unattractive and the small reward cost was low, the sensitivity to sunk cost and the cost-led suboptimality almost vanished. In this regime and this regime only, mice could be viewed as close to rational (here, 'rational' refers to a state in which an animal makes decisions basing on objective valuation, not covert factors). Taken together, our results suggest that "rationality" is a task-specific construct even in mice.

Significant systemic therapeutic effects of high-LET immunoradiation by 212Pb-trastuzumab against prostatic tumors of androgen-independent human prostate cancer in mice.

The purpose of this study was to determine therapeutic effects and systemic toxicity of 212Pb-trastuzumab in an orthotopic model of human prostate cancer cells in nude mice. TCMC-Trastuzumab was radiolabeled with 212Pb. The 212Pb-trastuzumab generated from the procedure was intact and had high binding affinity with a dissociation constant (of 3.9±0.99 nM. PC-3MM2 cells, which expressed a lower level of HER2 both in culture and in tumors, were used in therapy studies. A single intravenous injection of 212Pb-trastuzumab reduced tumor growth by 60-80%, reduced aortic lymph node metastasis, and prolonged the survival of tumor-bearing mice. Treatment with 212Pb-trastuzumab did not cause significant changes in body weight, serum glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), hematological profiles, and histological morphology of several major organs of tumor-bearing mice. These findings suggest that a systemic delivery of 212Pb-trastuzumab could be an effective modality for management of advanced human prostate cancer.

A modified LAMSTAR neural network and its applications.

This paper describes a modification of the LArge Memory STorage And Retrieval (LAMSTAR) neural network. The purpose of the modification is to allow rare events a larger role in decision-making when they are strongly biased towards a particular decision. As a by-product, the modification also permits the introduction of a confidence measure. This measure allows comparison across different network inputs so that the user may choose the "best" solution. The authors have applied the modified LAMSTAR network to a financial forecasting problem.