Sensory processing in external globus pallidus neurons.

Sensory processing is crucial for execution of appropriate behavior. The external globus pallidus (GPe), a nucleus within the basal ganglia, is highly involved in the control of movement and could potentially integrate sensory-motor information. The GPe comprises prototypic and arkypallidal cells, which receive partially overlapping inputs. It is unclear, however, which inputs convey sensory information to them. Here, we used in vivo whole-cell recordings in the mouse GPe and optogenetic silencing to characterize the pathways that shape the response to whisker stimulation in prototypic and arkypallidal cells. Our results show that sensory integration in prototypic cells is controlled by the subthalamic nucleus and indirect pathway medium spiny neurons (MSNs), whereas in arkypallidal cells, it is primarily shaped by direct pathway MSNs. These results suggest that GPe subpopulations receive sensory information from largely different neural populations, reinforcing that the GPe consists of two parallel pathways, which differ anatomically and functionally.

Data-Driven Model of Postsynaptic Currents Mediated by NMDA or AMPA Receptors in Striatal Neurons.

The majority of excitatory synapses in the brain uses glutamate as neurotransmitter, and the synaptic transmission is primarily mediated by AMPA and NMDA receptors in postsynaptic neurons. Here, we present data-driven models of the postsynaptic currents of these receptors in excitatory synapses in mouse striatum. It is common to fit two decay time constants to the decay phases of the current profiles but then compute a single weighted mean time constant to describe them. We have shown that this approach does not lead to an improvement in the fitting, and, hence, we present a new model based on the use of both the fast and slow time constants and a numerical calculation of the peak time using Newton's method. Our framework allows for a more accurate description of the current profiles without needing extra data and without overburdening the comptuational costs. The user-friendliness of the method, here implemented in Python, makes it easily applicable to other data sets.

A tonic nicotinic brake controls spike timing in striatal spiny projection neurons.

Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating α4ß2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feedforward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices from mice we show that upon synchronous optogenetic activation of corticostriatal projections blockade of α4ß2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by 'priming' feedforward inhibition, a process that may shape SPN spike timing, striatal processing, and synaptic plasticity.

Diagnostic accuracy and clinical applicability of the Swedish version of the 4AT assessment test for delirium detection, in a mixed patient population and setting.

BACKGROUND: Delirium is common in older hospitalized patients. It has serious consequences e.g., poor health outcomes, mortality and increased costs. Despite that, many cases are undetected. Early detection of delirium is important in improving outcomes and use of assessment tools improves detection rates. The 4AT is a brief screening tool for delirium detection, which has not previously been translated into Swedish. The study aim was to evaluate diagnostic accuracy and clinical applicability of a Swedish version of the screening tool 4AT for delirium detection. METHOD: This diagnostic test accuracy study used a quantitative and a qualitative approach and evaluated the patients' and the health care professionals' experiences of the tool. Study included 200 patients ≥65 years from a university hospital and a county hospital in two Swedish regions. Medical specialties were geriatric stroke/neurology, geriatric multimorbidity, severe cognitive impairment, orthopaedic, and urology. The translated 4AT was tested against the reference standard DSM-IV-TR criteria, based on the Organic Brain Syndrome scale and patient records. The 4AT was assessed simultaneously and independently by two assessors. Additionally, data was collected through patient record reviews, and questions about applicability to the patients (n = 200) and the assessors (n = 37). Statistical analyses, and qualitative content analyses were conducted. RESULTS: By reference standard 18% had delirium, and by 4AT 19%. The overall percent agreement was 88%, AUROC 0.808, sensitivity 0.70 (95% CI 0.51-0.84) and specificity 0.92 (95% CI 0.87-0.96). In the ward for severe cognitive impairment (n = 63) the 4AT was less sensitive and less specific. In the other wards (n = 132) sensitivity was 0.77 (95% CI 0.50-0.93), specificity 0.93 (95% CI 0.87-0.97), and AUROC 0.848. Interrater reliability (Kappa) was 0.918, p = < 0.001 (n = 144). The 4AT was well tolerated by patients, easy to use for health care professionals, and took a few minutes to conduct. CONCLUSION: The Swedish version of 4AT is an accurate and applicable tool to use in clinical practice for detecting delirium in hospitalized patients across different medical specialities, and to use by different professionals and levels of seniority. To improve patient outcomes, we recommend the 4AT to be incorporated in clinical practice in health care settings in Sweden.

Symptoms and Well-Being in Older Hospitalized Patients with Cognitive Impairment, As Self-Reported and Reported in Patient Records: A Quantitative Exploratory Subgroup Analysis.

INTRODUCTION: Given the aging population and the high prevalence of cognitive impairment in older hospitalized patients, it is essential to provide good fundamental care to these vulnerable patients, who easily might be affected by poor outcomes as delirium. Risk factors for delirium are, for example, cognitive impairment, old age, pain, and sleep deprivation. Different symptoms are often unidentified in hospitals, and associated with poor well-being, but this is rarely studied in older patients with cognitive impairment. The study aim was to examine symptoms and sense of well-being in older hospitalized patients with cognitive impairment, as self-reported and reported in patient records. METHODS: Exploratory quantitative subgroup (n = 25) analysis of a point-prevalence study (n = 210). Inclusion criteria were age ≥65, and cognitive impairment. Data were collected through structured interviews, validated instruments, and patient records. Associations between well-being and symptoms, and concordance between the occurrence of self-reported symptoms and symptoms reported in patient records were analyzed. RESULTS: The patients reported severe and distressing symptoms that were sparsely reported (14%) in their records. As well were cognitive impairment, and the patients' own descriptions of their well-being. Some symptoms and the total symptom burden were associated with poor well-being. DISCUSSION/CONCLUSION: To our knowledge, this hypothesis-generating study is one of few studies that describe both symptoms and well-being as self-reported and reported in patient records, in vulnerable patients due to old age, cognitive impairment, and hospitalization. Despite the limited sample size, the results indicate that symptoms were more insufficient alleviated in these patients compared to patients with normal cognitive function in other studies. To our knowledge, this has not been shown previously. Additionally, patients' own experiences were sparsely reported in their records. A larger sample size and longitudinal design has the potential to determine if symptom alleviation differs between patients with and without cognitive impairment, and if a total symptom burden increases the risk of poor outcomes as delirium in vulnerable patients.

The microcircuits of striatum in silico.

The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, soma-dendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.

The Functional Organization of Cortical and Thalamic Inputs onto Five Types of Striatal Neurons Is Determined by Source and Target Cell Identities.

To understand striatal function, it is essential to know the functional organization of the numerous inputs targeting the diverse population of striatal neurons. Using optogenetics, we activated terminals from ipsi- or contralateral primary somatosensory cortex (S1) or primary motor cortex (M1), or thalamus while obtaining simultaneous whole-cell recordings from pairs or triplets of striatal medium spiny neurons (MSNs) and adjacent interneurons. Ipsilateral corticostriatal projections provided stronger excitation to fast-spiking interneurons (FSIs) than to MSNs and only sparse and weak excitation to low threshold-spiking interneurons (LTSIs) and cholinergic interneurons (ChINs). Projections from contralateral M1 evoked the strongest responses in LTSIs but none in ChINs, whereas thalamus provided the strongest excitation to ChINs but none to LTSIs. In addition, inputs varied in their glutamate receptor composition and their short-term plasticity. Our data revealed a highly selective organization of excitatory striatal afferents, which is determined by both pre- and postsynaptic neuronal identity.

Referral and admission to intensive care: A qualitative study of doctors' practices in a Tanzanian university hospital.

BACKGROUND: Intensive care is care for critically ill patients with potentially reversible conditions. Patient selection for intensive care should be based on potential benefit but since demand exceeds availability, rationing is needed. In Tanzania, the availability of Intensive Care Units (ICUs) is very limited and the practices for selecting patients for intensive care are not known. The aim of this study was to explore doctors' experiences and perceptions of ICU referral and admission processes in a university hospital in Tanzania. METHODS: We performed a qualitative study using semi-structured interviews with fifteen doctors involved in the recent care of critically ill patients in university hospital in Tanzania. Inductive conventional content analysis was applied for the analysis of interview notes to derive categories and sub-categories. RESULTS: Two main categories were identified, (i) difficulties with the identification of critically ill patients in the wards and (ii) a lack of structured triaging to the ICU. A lack of critical care knowledge and communication barriers were described as preventing identification of critically ill patients. Triaging to the ICU was affected by a lack of guidelines for admission, diverging ideas about ICU indications and contraindications, the lack of bed capacity in the ICU and non-medical factors such as a fear of repercussions. CONCLUSION: Critically ill patients may not be identified in general wards in a Tanzanian university hospital and the triaging process for the admission of patients to intensive care is convoluted and not explicit. The findings indicate a potential for improved patient selection that could optimize the use of scarce ICU resources, leading to better patient outcomes.

A hypothalamus-habenula circuit controls aversion.

Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively. We found that LHb-projecting LHA neurons, and not the proposed GABA/glutamate co-releasing GPi neurons, are responsible for encoding negative value. Monosynaptic rabies tracing of the presynaptic organization revealed a predominantly limbic input onto LHA Vglut2 neurons, while sensorimotor inputs were more prominent onto GABA/glutamate co-releasing GPi neurons. We further recorded the activity of LHA Vglut2 neurons, by imaging calcium dynamics in response to appetitive versus aversive events in conditioning paradigms. LHA Vglut2 neurons formed activity clusters representing distinct reward or aversion signals, including a population that responded to mild foot shocks and predicted aversive events. We found that the LHb-projecting LHA Vglut2 neurons encode negative valence and rapidly develop a prediction signal for negative events. These findings establish the glutamatergic LHA-LHb circuit as a critical node in value processing.

Delirium in older hospitalized patients-signs and actions: a retrospective patient record review.

BACKGROUND: Delirium is common in older hospitalized patients, and is associated with negative consequences for the patients, next of kin, healthcare professionals and healthcare costs. It is important to understand its clinical features, as almost 40% of all cases in hospitals may be preventable. Yet, delirium in hospitalized patients is often unrecognized and untreated. Few studies describe thoroughly how delirium manifests itself in older hospitalized patients and what actions healthcare professionals take in relation to these signs. Therefore, the aim of this study was to describe signs of delirium in older hospitalized patients and action taken by healthcare professionals, as reported in patient records. METHODS: Patient records from patients aged ≥65 (n = 286) were retrospectively reviewed for signs of delirium, which was found in 78 patient records (27%). Additionally, these records were reviewed for action taken by healthcare professionals in relation to the patients' signs of delirium. The identified text was analyzed with qualitative content analysis in two steps. RESULTS: Healthcare professionals responded only in part to older hospitalized patients' needs of care in relation to their signs of delirium. The patients displayed various signs of delirium that led to a reduced ability to participate in their own care and to keep themselves free from harm. Healthcare professionals met these signs with a variation of actions and the care was adapted, deficient and beyond the usual care. A systematic and holistic perspective in the care of older hospitalized patients with signs of delirium was missing. CONCLUSION: Improved knowledge about delirium in hospitals is needed in order to reduce human suffering, healthcare utilization and costs. It is important to enable older hospitalized patients with signs of delirium to participate in their own care and to protect them from harm. Delirium has to be seen as a preventable adverse event in all hospitals units. To improve the prevention and management of older hospitalized patients with signs of delirium, person-centered care and patient safety may be important issues.

Dopamine Depletion Impairs Bilateral Sensory Processing in the Striatum in a Pathway-Dependent Manner.

Parkinson's disease (PD) is a movement disorder caused by the loss of dopaminergic innervation, particularly to the striatum. PD patients often exhibit sensory impairments, yet the underlying network mechanisms are unknown. Here we examined how dopamine (DA) depletion affects sensory processing in the mouse striatum. We used the optopatcher for online identification of direct and indirect pathway projection neurons (MSNs) during in vivo whole-cell recordings. In control mice, MSNs encoded the laterality of sensory inputs with larger and earlier responses to contralateral than ipsilateral whisker deflection. This laterality coding was lost in DA-depleted mice due to adaptive changes in the intrinsic and synaptic properties, mainly, of direct pathway MSNs. L-DOPA treatment restored laterality coding by increasing the separation between ipsilateral and contralateral responses. Our results show that DA depletion impairs bilateral tactile acuity in a pathway-dependent manner, thus providing unexpected insights into the network mechanisms underlying sensory deficits in PD. VIDEO ABSTRACT.

A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei.

The serotonin system is proposed to regulate physiology and behavior and to underlie mood disorders; nevertheless, the circuitry controlling serotonergic neurons remains uncharacterized. We therefore generated a comprehensive whole-brain atlas defining the monosynaptic inputs onto forebrain-projecting serotonergic neurons of dorsal versus median raphe based on a genetically restricted transsynaptic retrograde tracing strategy. We identified discrete inputs onto serotonergic neurons from forebrain and brainstem neurons, with specific inputs from hypothalamus, cortex, basal ganglia, and midbrain, displaying a greater than anticipated complexity and diversity in cell-type-specific connectivity. We identified and functionally confirmed monosynaptic glutamatergic inputs from prefrontal cortex and lateral habenula onto serotonergic neurons as well as a direct GABAergic input from striatal projection neurons. In summary, our findings emphasize the role of hyperdirect inputs to serotonergic neurons. Cell-type-specific classification of connectivity patterns will allow for further functional analysis of the diverse but specific inputs that control serotonergic neurons during behavior.

Psychosocial and physiological correlates of self-reported hearing problems in male and female musicians in symphony orchestras.

Experimental and epidemiological research indicate an association between long-term stress and hearing problems, yet the mechanisms underlying these disorders are not yet fully established. Thus, in order to better understand the pathogenesis of stress-related hearing problems, the present study explored the symptoms and general physiological and psychosocial status of musicians in symphony orchestras. Orchestral musicians are an ideal group to study since physical, psychosocial, work-environmental and acoustic stressors are highly prevalent. The subjects where obtained from two different studies. The first group included 250 participants from 12 orchestras and is entitled "the epidemiological study". The second group, entitled "the longitudinal study", included 47 musicians who were assessed at five occasions (every half year) during two years. Thirty-one of the 47 participants were selected for sampling of physiological variables, i.e. 24-hour ECG to assess heart rate variability to evaluate the synergistic action of the autonomic system as well as saliva cortisol and testosterone levels. The results indicate that self-reported hearing problems are associated with perceived poorer psychosocial environment, as well as mental health symptoms and stress. High-frequency power of heart rate variability (parasympathetic activity) showed a negative relationship to hearing problems, implying a poorer ability to "unwind" from stress. Cortisol levels were not correlated to hearing problems whereas testosterone levels showed a tendency to be lower in subjects with hearing problems than in others. These findings provide evidence for a relationship between long-term stress and self-reported hearing problems and demonstrate a protective role of parasympathetic and anabolic activity on hearing status.

Malnutrition in a home-living older population: prevalence, incidence and risk factors. A prospective study.

AIMS AND OBJECTIVES: To prospectively investigate and describe the prevalence and incidence of malnutrition among home-living older people, related to demographic and medical factors, self-perceived health and health-related quality of life. Another aim was to find predictors for developing risk of malnutrition. BACKGROUND: Risk factors for malnutrition have previously been identified as diseases, several medications, low functional status, symptoms of depression and inadequate nutrient intake. Most studies are cross-sectionally performed at hospitals or in nursing care settings. DESIGN: A prospective study with a sample of 579 home-living older people, randomly selected from a local national register. Examinations were performed at baseline and yearly follow-ups two to four times. METHOD: Questionnaires validated and tested for reliability, to detect risk of malnutrition (Mini Nutritional Assessment), symptoms of depression (Geriatric Depression Scale-20), cognitive function (Mini Mental State Examination), health-related quality of life (Nottingham Health Profile), well-being (Philadelphia Geriatric Center Multilevel Assessment Instrument) self-perceived health, demographic factors, anthropometry and biochemical examinations. Predictors were searched for through multiple logistic regression analysis with the MNA as dependent factor. RESULTS: The prevalence of risk for malnutrition was 14.5%, according to the MNA. Two risk factors for malnutrition were lower handgrip strength and lower self-perceived health. The incidence of risk for malnutrition at follow-ups was between 7.6% and 16.2%. Predictors for developing malnutrition were higher age, lower self-perceived health and more symptoms of depression. Men with symptoms of depression had a higher risk of developing malnutrition. CONCLUSION: Lower self-perceived health had the highest power to predict risk for malnutrition, with increased number of depression symptoms and higher age as second and third predictors. RELEVANCE TO CLINICAL PRACTICE: A regular and combined assessment using the Mini Nutrition Assessment, Geriatric Depression Scale-20 and self-perceived health as a base for identifying people in need, is one way to prevent the development of malnutrition.

Characteristics of disability pensioners returning to work: an interview study among individuals with musculoskeletal disorders.

PURPOSE: To explore adaptation patterns among disability pensioners with musculoskeletal disorders returning to work by means of the Swedish law on 'resting disability pension'. METHOD: Qualitative analyses of interviews with 17 individuals going back to work. RESULTS: Three adaptation patterns were identified: The Go-getter, the Realist and the Indifferent. These differed regarding influence factors, own expectations, motive, morals and mentality. CONCLUSION: Several actors may support a return to work for individuals who received a disability pension due to musculoskeletal disorders. In order to succeed, however, it is essential that the disability pensioner is motivated for a reconstruction of his/her life.

Saliva testosterone and heart rate variability in the professional symphony orchestra after "public faintings" of an orchestra member.

Musicians are sensitive to changes in their work environment. A 2-year longitudinal study with repeated observations was performed in two professional symphony orchestras. A representative sample from each one of them was selected, 15 and 16 members respectively. In one of them a wind player fainted twice in front of the audience shortly preceding and coinciding with the start of the study. Changes in two indicators that reflect regenerative/anabolic and parasympathetic tone, saliva testosterone concentration (STC) and very low-frequency power (VLFP) in heart rate variability were followed in relation to this dramatic change. Saliva samples and 24-h ECG heart rate variability recordings were collected on five occasions every 6 months during a 2-year period. No changes were seen in the control orchestra whereas the levels showed a pronounced rise in the intervention orchestra during the first part of the study, starting from low levels. VLFP showed a similar pattern, with initially low and then rising level in the intervention orchestra and higher stable level in the other group. In the total study group, a rise in STC over the whole observation period was significantly correlated with increase in VLFP and also significantly correlated with a decrease in low/high-frequency power ratio in heart rate variability. The changes observed in the anabolic/regenerative STC and the parasympathetically influenced VLFP may reflect changes in the work environment associated with the faintings.

Work postures and neck-shoulder pain among orchestra musicians.

BACKGROUND: The purpose of the present study was to identify associations between a work posture with elevated arm position, duration of active playing time, and neck-shoulder pain among orchestra musicians. METHODS: In this study, with a cross-sectional study design, a total of 235 subjects from 12 Swedish orchestras were categorized into four exposure groups according to arm position and duration of active playing time. Logistic regression analysis was used to calculate odds ratios (OR) for neck-shoulder pain in the four exposure groups. RESULTS: A higher prevalence of neck-shoulder pain were found in the groups "elevated arm position, <2 hr per workday" [OR 4.15 (1.30-13.22)], and "elevated arm position, >3 hr per workday" [OR 5.35 (1.96-14.62)] compared to the group "neutral arm position, <2 hr per workday". CONCLUSIONS: Musicians working in an elevated arm position (e.g., violinists, violists, flutists, and trumpet players) had a higher prevalence of neck-shoulder pain than those working in a more neutral position.

Self-perceived health among older women living in their own residence.

Aim. The aim was to characterize women who perceived themselves as healthy and to compare them with women who perceived themselves as less healthy with regard to demographical, social, medical and functional factors. Another aim was to describe changes within the healthy group after one year. Background. Self-perceived health is influenced by several factors, of which diseases and illness are only a part. Method and participants. Two hundred and seventy-eight women, 75 and 80 years old, of which 50% (n = 139) perceived themselves as healthy and less healthy, respectively. Data were collected by using the Nottingham Health Profile, Geriatric Depression Scale, Mini Nutritional Assessment, Mini Mental State Examination and Philadelphia Geriatric Center Multilevel Assessment Instrument, in two examinations at intervals of one year. Results. The women in the healthy group were characterized as having no or low depression symptoms (P = 0.016), better physical mobility (P = 0.029) and better physical health (P < 0.001). Furthermore no or less pain, fewer doctor visits, more energy and fewer negative emotional reactions were predictors for self-perceived health in the healthy group at the one-year follow-up. Conclusion. The most important predictors associated with perceiving oneself as healthy were no or few depression symptoms, physical mobility and good physical health. Relevance to clinical practice. Attention has to be paid to women's mood, physical health, mobility, pain and energy to help them stay healthy.

Return to work still possible after several years as a disability pensioner due to musculoskeletal disorders: a population-based study after new legislation in Sweden permitting "resting disability pension".

Different strategies have been used to stimulate a return to work (RTW) among individuals suffering from long-term ailments. In Sweden a new law on "resting disability pension" permits disability pensioners to go back to work without jeopardising their benefits. In this study different variables related to RTW during 2000 by means of this legislation were identified among disability pensioners with musculoskeletal disorders. Individuals in the study group, when compared to a control group, had more often been disability pensioners for several years, had additional education, estimated their previous job to have been physically strenuous to a lesser degree, were more satisfied with the treatment at the social insurance office and had a more positive self-image. This study shows that it may be meaningful to continue/resume rehabilitation efforts and to try to motivate an individual suffering from musculoskeletal disorders to return to work even after several years as a disability pensioner.