Zolpidem reduces hippocampal neuronal activity in freely behaving mice: a large scale calcium imaging study with miniaturized fluorescence microscope.

Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics. We visualized these dynamics with and without a systemic administration of Zolpidem, a GABAA agonist that is the most commonly prescribed drug for the treatment of insomnia in the United States. Despite growing concerns about the potential adverse effects of Zolpidem on memory and cognition, it remained unclear whether Zolpidem alters neuronal activity in the hippocampus, a brain area critical for cognition and memory. Zolpidem, when delivered at a dose known to induce and prolong sleep, strongly suppressed CA1 calcium signaling. The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment. To factor out the contribution of changes in locomotor or physiological conditions following Zolpidem treatment, we compared the cellular activity across comparable epochs matched by locomotor and physiological assessments. This analysis revealed significantly depressive effects of Zolpidem regardless of the animal's state. Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem with the majority (∼ 65%) significantly decreasing the rate of calcium transients, and a small subset (3%) showing an unexpected and significant increase. By linking molecular mechanisms with the dynamics of neural circuitry and behavioral states, this approach has the potential to contribute substantially to the development of new therapeutics for the treatment of CNS disorders.

Long-term dynamics of CA1 hippocampal place codes.

Using Ca(2+) imaging in freely behaving mice that repeatedly explored a familiar environment, we tracked thousands of CA1 pyramidal cells' place fields over weeks. Place coding was dynamic, as each day the ensemble representation of this environment involved a unique subset of cells. However, cells in the ∼15-25% overlap between any two of these subsets retained the same place fields, which sufficed to preserve an accurate spatial representation across weeks.

Ergonomic audit of a specially engineered sonic powered toothbrush with unique sensing and control technologies, the Sonicare Flexcare, and the Oral-B Smart Series 5000.

OBJECTIVE: The presence of ergonomic features can impact the marketplace success of a new product. Metaphase Design Group, Inc., in partnership with the Colgate-Palmolive Company, conducted an ergonomic audit on three electric toothbrushes: a specially engineered sonic powered toothbrush with unique sensing and control technologies, the Sonicare FlexCare, and the Oral-B Smart Series 5000. METHODS: The ergonomic audit was conducted by Metaphase Design Groups's ergonomic and usability experts. Two experts used the toothbrushes over a one-week period and assessed the performance of each brush against a set of ergonomic principles. RESULTS: The three toothbrushes have some solid ergonomic features. They each have adequate grip zones, provide grip security with elastomeric materials, and provide easy access to the on/off button. The most distinctive feature is the longitudinal shape of the handle of the specially engineered sonic powered toothbrush with unique sensing and control technologies. This handle angles downward at the top end and provides additional advantages through improved grip security and visibility. Yet all three toothbrushes have different opportunities for improvement. The Sonicare Flex Care toothbrush has a cluttered and complicated user interface that is difficult to read. The disadvantages of the Oral-B Smart Series 5000 toothbrush are related to its physical dimensions and audible feedback. CONCLUSION: The specially engineered sonic powered toothbrush with unique sensing afid control technologies is surprising to use with its changes in speeds, brush movements, and resulting changes in audible feedback.

Usability research study of a specially engineered sonic powered toothbrush with unique sensing and control technologies.

OBJECTIVE: This paper summarizes the results of a longitudinal usability research study of a specially engineered sonic powered toothbrush with unique sensing and control technologies. METHODS: The usability test was conducted with fourteen (14) consumers from the St. Louis, MO, USA area who use manual toothbrushes. The study consisted of consumers using the specially engineered sonic powered toothbrush with unique sensing and control technologies for three weeks. During the study, users participated in four toothbrush trials during weekly visits to the research facility. These trials were videotaped and were analyzed regarding brushing time, behavior, and technique. In addition, the users were required to use the toothbrush twice a day for their at-home brushing. RESULTS: The toothbrush had a positive impact on consumers' tooth brushing behavior. Users spent more time brushing their teeth with this toothbrush as compared to their manual toothbrush. In addition, users spent more time keeping the sonic toothbrush in the recommended angle during use. Finally, users perceived their teeth to be cleaner when using the specially engineered sonic powered toothbrush with unique sensing and control technologies. CONCLUSION: The specially engineered sonic powered toothbrush with unique sensing and control technologies left a positive impression on the users. The users perceived the toothbrush to clean their teeth better than a manual toothbrush.

Miniaturized integration of a fluorescence microscope.

The light microscope is traditionally an instrument of substantial size and expense. Its miniaturized integration would enable many new applications based on mass-producible, tiny microscopes. Key prospective usages include brain imaging in behaving animals for relating cellular dynamics to animal behavior. Here we introduce a miniature (1.9 g) integrated fluorescence microscope made from mass-producible parts, including a semiconductor light source and sensor. This device enables high-speed cellular imaging across ∼0.5 mm2 areas in active mice. This capability allowed concurrent tracking of Ca2+ spiking in >200 Purkinje neurons across nine cerebellar microzones. During mouse locomotion, individual microzones exhibited large-scale, synchronized Ca2+ spiking. This is a mesoscopic neural dynamic missed by prior techniques for studying the brain at other length scales. Overall, the integrated microscope is a potentially transformative technology that permits distribution to many animals and enables diverse usages, such as portable diagnostics or microscope arrays for large-scale screens.

In vivo brain imaging using a portable 2.9 g two-photon microscope based on a microelectromechanical systems scanning mirror.

We present a two-photon microscope that is approximately 2.9 g in mass and 2.0 x 1.9 x 1.1 cm(3) in size and based on a microelectromechanical systems (MEMS) laser-scanning mirror. The microscope has a focusing motor and a micro-optical assembly composed of four gradient refractive index lenses and a dichroic microprism. Fluorescence is captured without the detected emissions reflecting off the MEMS mirror, by use of separate optical fibers for fluorescence collection and delivery of ultrashort excitation pulses. Using this microscope we imaged neocortical microvasculature and tracked the flow of erythrocytes in live mice.

Advances in light microscopy for neuroscience.

Since the work of Golgi and Cajal, light microscopy has remained a key tool for neuroscientists to observe cellular properties. Ongoing advances have enabled new experimental capabilities using light to inspect the nervous system across multiple spatial scales, including ultrastructural scales finer than the optical diffraction limit. Other progress permits functional imaging at faster speeds, at greater depths in brain tissue, and over larger tissue volumes than previously possible. Portable, miniaturized fluorescence microscopes now allow brain imaging in freely behaving mice. Complementary progress on animal preparations has enabled imaging in head-restrained behaving animals, as well as time-lapse microscopy studies in the brains of live subjects. Mouse genetic approaches permit mosaic and inducible fluorescence-labeling strategies, whereas intrinsic contrast mechanisms allow in vivo imaging of animals and humans without use of exogenous markers. This review surveys such advances and highlights emerging capabilities of particular interest to neuroscientists.

High-speed, miniaturized fluorescence microscopy in freely moving mice.

A central goal in biomedicine is to explain organismic behavior in terms of causal cellular processes. However, concurrent observation of mammalian behavior and underlying cellular dynamics has been a longstanding challenge. We describe a miniaturized (1.1 g mass) epifluorescence microscope for cellular-level brain imaging in freely moving mice, and its application to imaging microcirculation and neuronal Ca(2+) dynamics.

Physician perspectives of nurse care management located in primary care clinics.

Care management has been suggested as a method to improve management of chronic disease, but its success can depend on the involvement of primary care physicians, especially with referral to care management. Our objective was to identify and characterize physicians' perspectives of care management in order to gain insight into the rationale for referral to care management. The study took place in primary care clinics within an integrated delivery system. Nineteen primary care physicians with varying levels of involvement with care management participated in the study. We performed a qualitative and quantitative analysis ofsemistructured interviews. Four referral patterns emerged that were related to physicians' recognition of care managers' abilities and how care managers were connected to their practice. Results from this study can be used to more effectively implement similar models of chronic disease management, where physician participation is a critical component for successful implementation.

Care management dosage.

BACKGROUND: The care of patients with complex illnesses requires careful management, but systems of care management (CM) vary in their structure and effectiveness. OBJECTIVE: To create a framework identifying components of broad-based CM interventions and validate the framework, including using this framework to evaluate the contribution of varying components on outcomes of patients with chronic illness. DESIGN: We create the framework using retrospective information about CM activities and services over 12 months and categorize it using cluster and factor analysis. We then validate this framework through content and criterion techniques. Content validity is assessed through a Delphi study and criterion validity through relationship of the dosage measures and patterns of care to process and outcomes measures. PARTICIPANTS: Patients with diabetes and/or cardiovascular disease receiving CM services in a model known as Care Management Plus implemented in primary care. RESULTS: Six factors of CM activity were identified, including a single dosage summary measure and 5 separate patterns of care. Of these, the overall dosage summary measure, face-to-face time, duration of follow-up, and breadth of services were all related to improved processes for hemoglobin A1c and LDL testing and control. Brief intense patterns of care and high face-to-face care manager time were also related to improved outcomes. CONCLUSIONS: Using this framework, we isolate components of a CM intervention directly related to improved process of care or patient outcomes. Current efforts to structure CM to include face-to-face time and multiple diseases are discussed.

Productivity enhancement for primary care providers using multicondition care management.

OBJECTIVE: To assess the impact of a multicondition care management system on primary care physician efficiency and productivity. STUDY DESIGN: Retrospective controlled repeated-measures design comparing physician productivity with the proportion of patients in the care management system. METHODS: The setting was primary care clinics in Intermountain Healthcare, a large integrated delivery network. The care management system consisted of a trained team with nurses as care managers and specialized information technology. We defined the use of the care management system as a proportion of referrals by the physician to the care manager. Clinic, physician, and patient panel demographics were used to adjust expected visit productivity and were included in a multivariate mixed model with repeated measures comprising work relative value units and system use. RESULTS: The productivity of 120 physicians in 7 intervention clinics and 14 control clinics was compared during 24 months. Clinic, physician, and patient panel characteristics exhibited similar characteristics, although patients in intervention clinics were less likely to be married. Adjusted work relative value units were 8% (range, 5%-12%) higher for intervention clinics vs control clinics. Additional annual revenue was estimated at 99,986 dollars per clinic. These additional revenues outweighed the estimated cost of the program of 92,077 dollars. CONCLUSIONS: Physician productivity increased when more than 2% of patients were seen by a care management team; the increased revenue in our market exceeded the cost of the program. Implications for the creation, structure, and reimbursement of such teams are discussed.

Use of health-related, quality-of-life metrics to predict mortality and hospitalizations in community-dwelling seniors.

OBJECTIVES: To investigate whether health-related quality-of-life (HRQoL) scores in a primary care population can be used as a predictor of future hospital utilization and mortality. DESIGN: Prospective cohort study measuring Short Form 12 (SF-12) scores obtained using a mailed survey. SF-12 scores, age, and a comorbidity score were used to predict hospitalization and mortality rate using multivariable logistic regression and Cox proportional hazards during the ensuing 28-month period for elderly patients. SETTING: Intermountain Health Care, a large integrated-delivery network serving a population of more than 150,000 seniors. PARTICIPANTS: Participants were senior patients who had one or more chronic diseases, were community dwelling, and were initially treated in primary care clinics. MEASUREMENTS: SF-12 survey Version 1. RESULTS: Seven thousand seventy-six surveys were sent to eligible participants; 3,042 (43%) were returned. Of the returned surveys, 2,166 (71%) were complete and scoreable. For the respondent group, a multivariable analysis demonstrated that older age, male sex, higher comorbidity score, and lower mental and physical summary measures of SF-12 predicted higher mortality and hospitalization. On average, nonresponders were older and had higher comorbidity scores and mortality rates than responders. CONCLUSION: The SF-12 survey provided additional predictive ability for future hospitalizations and mortality. Such predictive ability might facilitate preemptive interventions that would change the course of disease in this segment of the population. However, nonresponder bias may limit the utility of mailed SF-12 surveys in certain populations.

Implementing a multidisease chronic care model in primary care using people and technology.

Management of chronic disease is performed inadequately in the United States in spite of the availability of beneficial, effective therapies. Successful programs to manage patients with these diseases must overcome multiple challenges, including the recognized fragmentation and complexity of the healthcare system, misaligned incentives, a focus on acute problems, and a lack of team-based care. In many successful programs, care is provided in settings or episodes that focus on a single disease. While these programs may allow for streamlined, focused provision of care, comprehensive care for multiple diseases may be more difficult. At Intermountain Healthcare (Intermountain), a generalist model of chronic disease management was formulated to overcome the limitations associated with specialization. In the Intermountain approach, which reflects elements of the Chronic Care Model (CCM), care managers located within multipayer primary care clinics collaborate with physicians, patients, and other members of a primary care team to improve patient outcomes for a variety of conditions. An important part of the intervention is widespread use of an electronic health record (EHR). This EHR provides flexible access to clinical data, individualized decision support designed to encourage best practice for patients with a variety of diseases (including co-occurring ones), and convenient communication between providers. This generalized model is used to treat diverse patients with disparate and coexisting chronic conditions. Early results from the application of this model show improved patient outcomes and improved physician productivity. Success factors, challenges, and obstacles in implementing the model are discussed.

Impact of generalist care managers on patients with diabetes.

OBJECTIVE: To determine how the addition of generalist care managers and collaborative information technology to an ambulatory team affects the care of patients with diabetes. STUDY SETTING: Multiple ambulatory clinics within Intermountain Health Care (IHC), a large integrated delivery network. STUDY DESIGN: A retrospective cohort study comparing diabetic patients treated by generalist care managers with matched controls was completed. Exposure patients had one or more contacts with a care manager; controls were matched on utilization, demographics, testing, and baseline glucose control. Using role-specific information technology to support their efforts, care managers assessed patients' readiness for change, followed guidelines, and educated and motivated patients. DATA COLLECTION: Patient data collected as part of an electronic patient record were combined with care manager-created databases to assess timely testing of glycosylated hemoglobin (HbA1c) and low-density lipoprotein (LDL) levels and changes in LDL and HbA1c levels. PRINCIPAL FINDINGS: In a multivariable model, the odds of being overdue for testing for HbA1c decreased by 21 percent in the exposure group (n=1,185) versus the control group (n=4,740). The odds of being tested when overdue for HbA1c or LDL increased by 49 and 26 percent, respectively, and the odds of HbA1c <7.0 percent also increased by 19 percent in the exposure group. The average HbA1c levels decreased more in the exposure group than in the controls. The effect on LDL was not significant. CONCLUSIONS: Generalist care managers using computer-supported diabetes management helped increase adherence to guidelines for testing and control of HbA1c levels, leading to improved health status of patients with diabetes.

Use and impact of a computer-generated patient summary worksheet for primary care.

Advanced clinical information systems have been proposed to improve patient care in terms of safety, effectiveness, and efficiency. In order to be effective, such systems require detailed patient-specific clinical information in a form easily reviewed by clinicians. We have developed a patient summary worksheet for use in outpatient clinics, which presents a structured overview of patient health information. The worksheet provides patient demographic information, specific problems and conditions, the patient's current medication profile, laboratory test results pertinent to patient problems, and disease-specific or preventive care actionable advisories. Usage has grown from a few hundred to over 25,000 unique patients per month during a two-year period. Diabetic patients for whom the worksheet is accessed are significantly more likely to be in compliance with accepted testing regimens for glycosolated hemoglobin (OR 1.47, 95% CI 1.28, 1.61).