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INTRODUCTION: Health research bodies recommend patient involvement and engagement in research and healthcare planning, although their implementation is not yet widespread. This deficiency extends to progressive pulmonary fibrosis (PPF), where crucial aspects remain unknown, including causal mechanisms, curative treatments and optimal symptom management. This study addresses these gaps by seeking stakeholders' perspectives to guide research and treatment directions. METHOD: A priority-setting partnership was established to explore stakeholders' priorities in the diagnosis, treatment, management and care of PPF, including idiopathic pulmonary fibrosis which is the archetypal PPF. Stakeholders included people living with PPF, their carers, relatives and healthcare professionals involved in their management. RESULTS: Through an online open-ended survey, 2542 responses were collected from 638 stakeholders. Thematic analysis identified 48 specific research questions, which were then cross-referenced with academic literature to pinpoint research gaps. Following the evidence check, 44 unanswered questions were shortlisted by 834 stakeholders in a second online survey. Ultimately, a top 10 priority list was established through consensus.The prioritised research questions include (1) improved diagnosis accuracy and timing, (2) development of new treatments, (3) enhanced accuracy in primary care, (4) optimal timing for drug and non-drug interventions, (5) effective cough treatment, (6) early intervention for PPF, (7) improved survival rates, (8) symptom reduction, (9) impact of interventions on life expectancy and (10) new treatments with reduced side effects. CONCLUSION: Stakeholders' priorities can be summarised into five areas: early diagnosis, drug and non-drug treatments, survival and symptom management. Ideally, these topics should guide funding bodies and health policies.
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Progresión de la Enfermedad , Humanos , Reino Unido , Encuestas y Cuestionarios , Participación de los Interesados , Fibrosis Pulmonar Idiopática/terapia , Fibrosis Pulmonar Idiopática/diagnóstico , Investigación Biomédica , Masculino , Femenino , Fibrosis Pulmonar/terapia , Prioridades en Salud , InvestigaciónRESUMEN
BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.
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Enfermedades Pulmonares Intersticiales , Humanos , Enfermedades Pulmonares Intersticiales/terapia , Progresión de la Enfermedad , Proyectos de Investigación , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVES: Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD. DESIGN: Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded. DATA SYNTHESIS: The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design. RESULTS: A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI -4.00 to 9.88, I2=79.3%; %DLco -2.03, 95% CI -4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence. CONCLUSIONS: There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD. PROSPERO REGISTRATION NUMBER: CRD42023423223.
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Azatioprina , Inmunosupresores , Enfermedades Pulmonares Intersticiales , Ácido Micofenólico , Humanos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Azatioprina/uso terapéutico , Ácido Micofenólico/uso terapéutico , Inmunosupresores/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Capacidad Vital , Estudios Observacionales como AsuntoRESUMEN
INTRODUCTION: Remote monitoring of home physiological measurements has been proposed as a solution to support patients with chronic diseases as well as facilitating virtual consultations and pandemic preparedness for the future. Daily home spirometry and pulse oximetry have been demonstrated to be safe and acceptable to patients with interstitial lung disease (ILD) but there is currently limited evidence to support its integration into clinical practice. AIM: Our aim is to understand the clinical utility of frequent remote physiological measurements in ILD and the impact of integrating these into clinical practice from a patient, clinical and health economic perspective. METHODS AND ANALYSIS: 132 patients with fibrotic ILD will be recruited and randomised to receive either usual care with remote digital monitoring of home spirometry and pulse oximetry or usual care alone for 12 months. All participants will complete health-related quality of life and experience questionnaires.The primary outcome compares the availability of spirometry measurements within the 2 weeks preceding planned clinic appointments. Secondary outcomes will explore other aspects of clinical and cost-effectiveness of the remote monitoring programme. ETHICS AND DISSEMINATION: The study has been approved by the Camden and Kings Cross Research Ethics Committee (22/LO/0309). All participants will provide informed consent.This study is registered with www. CLINICALTRIALS: gov (NCT05662124).The results of the study will be submitted for presentation at regional and national conferences and submitted for peer-reviewed publication. Reports will be prepared for study participants with the support from our public involvement representatives through the charity Action for Pulmonary Fibrosis.
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Enfermedades Pulmonares Intersticiales , Calidad de Vida , Humanos , Análisis Costo-Beneficio , Resultado del Tratamiento , Enfermedades Pulmonares Intersticiales/diagnóstico , Oximetría , Espirometría , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
OBJECTIVES: We aimed to assess the available evidence for corticosteroids in fibrotic interstitial lung disease (fILD) to inform the randomised embedded multifactorial adaptive platform ILD. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched Embase, Medline, Cochrane CENTRAL and Web of Science databases from inception to April 17 2023. ELIGIBILITY CRITERIA: We included studies that compared corticosteroids with standard care, placebo or no treatment in adult patients with fILD. DATA EXTRACTION AND SYNTHESIS: We report on the change in forced vital capacity (FVC) and mortality. We used random-effects meta-analysis to estimate relative risk (RR) for dichotomous outcomes, and mean difference (MD) and standardised MDs for continuous outcomes, with 95% CIs. RESULTS: Of the 13 229 unique citations identified, we included 10 observational studies comprising 1639 patients. Corticosteroids had an uncertain effect on mortality compared with no treatment (RR 1.03 (95% CI 0.85 to 1.25); very low certainty evidence). The effect of corticosteroids on the rate of decline in FVC (% predicted) was uncertain when compared with no treatment (MD 4.29% (95% CI -8.26% to 16.83%); very low certainty evidence). However, corticosteroids might reduce the rate of decline in FVC in patients with non-idiopathic pulmonary fibrosis (IPF) fILD (MD 10.89% (95% CI 5.25% to 16.53%); low certainty evidence), while an uncertain effect was observed in patients with IPF (MD -3.80% (95% CI -8.94% to 1.34%); very low certainty evidence). CONCLUSIONS: The current evidence on the efficacy and safety of corticosteroids in fILD is limited and of low certainty. Randomised trials are needed to address this significant research gap.
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Corticoesteroides , Enfermedades Pulmonares Intersticiales , Adulto , Humanos , Corticoesteroides/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Capacidad VitalRESUMEN
Multisensory integration depends on causal inference about the sensory signals. We tested whether implicit causal-inference judgements pertain to entire objects or focus on task-relevant object features. Participants in our study judged virtual visual, haptic and visual-haptic surfaces with respect to two features-slant and roughness-against an internal standard in a two-alternative forced-choice task. Modelling of participants' responses revealed that the degree to which their perceptual judgements were based on integrated visual-haptic information varied unsystematically across features. For example, a perceived mismatch between visual and haptic roughness would not deter the observer from integrating visual and haptic slant. These results indicate that participants based their perceptual judgements on a feature-specific selection of information, suggesting that multisensory causal inference proceeds not at the object level but at the level of single object features. This article is part of the theme issue 'Decision and control processes in multisensory perception'.
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Percepción del Tacto , Humanos , Percepción del Tacto/fisiología , Percepción Visual/fisiología , JuicioRESUMEN
OBJECTIVES: To establish packed cell volume (PCV) ranges for non-pregnant, pregnant and post-partum bitches from day 10 of proestrus, investigating any relationship with parity and litter size. METHODS: This prospective cohort study used 37 healthy breeding bitches to examine PCV counts from routine blood samples collected every 4 weeks, from day 10 of proestrus, as part of routine PCV monitoring. RESULTS: For pregnant (n = 19) and non-pregnant (n = 18) bitches, PCV decreased until week 8 (corresponding to 8.5 ± 1.1 days before whelping for pregnant bitches) and recovered by 16-20 weeks after the initial sample; bitches that whelped average and large litters showed greater declines. PCV began to recover sooner for bitches that had previously whelped one or two litters compared to bitches that had previously whelped three or more litters. There was a significant three-way interaction between time after the onset of proestrus, litter size and the number of previous litters which demonstrated that the large decrease in PCV for bitches that had previously whelped three or more litters only occurred in bitches that were expecting an average or large sized litter. CLINICAL SIGNIFICANCE: Chronological variation in PCV for pregnant and non-pregnant bitches was established during the reproductive cycle. There was no evidence to suggest that routine PCV measurement for normal, healthy bitches would be beneficial. However, knowledge from this study may be useful when deciding whether to prospectively monitor a bitch where there is a history of previous pregnancy-related anaemia, when performing a caesarean section due to the anticipated blood loss during surgery, or when examining blood profiles for post-litter bitches.
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Cesárea , Fase Luteínica , Embarazo , Animales , Femenino , Perros , Cesárea/veterinaria , Estudios Prospectivos , Reproducción , Tamaño de la CélulaRESUMEN
Real-world scene perception unfolds remarkably quickly, yet the underlying visual processes are poorly understood. Space-centered theory maintains that a scene's spatial structure (e.g., openness, mean depth) can be rapidly recovered from low-level image statistics. In turn, the statistical relationship between a scene's spatial properties and semantic content allows for semantic identity to be inferred from its layout. We tested this theory by investigating (1) the temporal dynamics of spatial and semantic perception in real-world scenes, and (2) dependencies between spatial and semantic judgments. Participants viewed backward-masked images for 13.3 to 106.7 ms, and identified the semantic (e.g., beach, road) or spatial structure (e.g., open, closed-off) category. We found no temporal precedence of spatial discrimination relative to semantic discrimination. Computational analyses further suggest that, instead of using spatial layout to infer semantic categories, humans exploit semantic information to discriminate spatial structure categories. These findings challenge traditional 'bottom-up' views of scene perception.
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Social isolation is an established risk factor for mental illness and impaired immune function. Evidence suggests that neuroinflammatory processes contribute to mental illness, possibly via cytokine-induced modulation of neural activity. We examined the effects of lipopolysaccharide (LPS) administration and social home cage environment on cognitive performance in the 5-Choice Serial Reaction Time Task (5CSRTT), and their effects on corticosterone and cytokines in serum and brain tissue. Male Long-Evans rats were reared in pairs or in isolation before training on the 5CSRTT. The effects of saline and LPS (150 µg/kg i.p.) administration on sickness behaviour and task performance were then assessed. LPS-induced sickness behaviour was augmented in socially-isolated rats, translating to increased omissions and slower response times in the 5CSRTT. Both social isolation and LPS administration reduced impulsive responding, while discriminative accuracy remained unaffected. With the exception of reduced impulsivity in isolated rats, these effects were not observed following a second administration of LPS, revealing behavioural tolerance to repeated LPS injections. In a separate cohort of animals, social isolation potentiated the ability of LPS to increase serum corticosterone and IL-6, which corresponded to increased IL-6 in the orbitofrontal and medial prefrontal cortices and the nucleus accumbens. Basal IL-4 levels in the nucleus accumbens were reduced in socially-isolated rats. These findings are consistent with the adaptive response of reduced motivational drive following immune challenge, and identify social isolation as an exacerbating factor. Enhanced IL-6 signalling may play a role in mediating the potentiated behavioural response to LPS administration in isolated animals.
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Corticosterona , Lipopolisacáridos , Animales , Cognición/fisiología , Citocinas , Humanos , Interleucina-6 , Lipopolisacáridos/farmacología , Masculino , Ratas , Ratas Long-EvansRESUMEN
Cannabinoid is the most frequently reported illicit drug class in Driving Under the Influence of Drugs (DUID) investigation casework. In recent years, our laboratory observed an increasing rate of overlapping peaks for the cannabinoid confirmation performed using 2D high-performance liquid chromatography (LC)--tandem mass spectrometry (MS-MS). Starting in early 2018, the incidence of unresolved interfering substances increased, contributing to a higher rate of canceled testing that peaked at 3.7% in February 2019. The observed interference demonstrates a distinctive pattern affecting the identification and quantification of both delta-9 tetrahydrocannabinol (THC) and delta-9 carboxy THC. An improved quantitative method was developed and validated to separate delta-8 and -9 isomers and their metabolites in blood. All acceptance criteria were met, with identical measurement ranges from the original method (lower limit of quantitation: 0.5 ng/mL for delta-9 THC, 1.0 ng/mL for 11-hydroxy delta-9 THC and 5.0 ng/mL for delta-9 carboxy THC). Cannabinoids were extracted from whole blood using liquid-liquid extraction, separated in a 2D LC system over a run time of 10 min and detected by an MS-MS system equipped with ESI source operating in positive ionization mode with scheduled multiple reaction mass spectrometric monitoring. The LC system consisted of a pair of Phenomenex® SecurityGuard™ C6 Phenyl (4 × 2 mm) cartridges for extracting the compounds with 5 mM ammonium formate buffer in deionized (DI) water and 0.1% formic acid in methanol as mobile phase, and a Phenomenex® Kinetex C18 column (100 × 3 mm) with 0.1% formic acid in DI water and 0.1% formic acid in methanol for LC separation at 45°C. Each set of isomers was fully resolved by the longer run-time method. To the authors' knowledge, this is the first report of a method that successfully quantitates these primary cannabinoids in blood specimens where significant concentrations of both delta-9 and delta-8 isomers are present.
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Cannabinoides , Dronabinol , Cannabinoides/análisis , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Dronabinol/análisis , Espectrometría de Masas en TándemRESUMEN
Active implantable neurological devices like deep brain stimulators have been used over the past few decades to treat movement disorders such as those in people with Parkinson's disease and more recently, in psychiatric conditions like obsessive compulsive disorder. Electrode-tissue interfaces that support safe and effective targeting of specific brain regions are critical to success of these devices. Development of directional electrodes that activate smaller volumes of brain tissue requires electrodes to operate safely with higher charge densities. Coatings such as conductive hydrogels (CHs) provide lower impedances and higher charge injection limits (CILs) than standard platinum electrodes and support safer application of smaller electrode sizes. The aim of this study was to examine the chronic in vivo performance of a new low swelling CH coating that supports higher safe charge densities than traditional platinum electrodes. A range of hydrogel blends were engineered and their swelling and electrical performance compared. Electrochemical performance and stability of high and low swelling formulations were compared during insertion into a model brain in vitro and the formulation with lower swelling characteristics was chosen for the in vivo study. CH-coated or uncoated Pt electrode arrays were implanted into the brains of 14 rats, and their electrochemical performance was tested weekly for 8 weeks. Tissue response and neural survival was assessed histologically following electrode array removal. CH coating resulted in significantly lower voltage transient impedance, higher CIL, lower electrochemical impedance spectroscopy, and higher charge storage capacity compared to uncoated Pt electrodes in vivo, and this advantage was maintained over the 8-week implantation. There was no significant difference in evoked potential thresholds, signal-to-noise ratio, tissue response or neural survival between CH-coated and uncoated Pt groups. The significant electrochemical advantage and stability of CH coating in the brain supports the suitability of this coating technology for future development of smaller, higher fidelity electrode arrays with higher charge density requirement.
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An understanding of the pathogenesis and pathophysiology of Lyme disease is key to the ultimate care of patients with Lyme disease. To better understand the various mechanisms underlying the infection caused by Borrelia burgdorferi, the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee was formed to review what is currently known about the pathogenesis and pathophysiology of Lyme disease, from its inception, but also especially about its ability to persist in the host. To that end, the authors of this report were assembled to update our knowledge about the infectious process, identify the gaps that exist in our understanding of the process, and provide recommendations as to how to best approach solutions that could lead to a better means to manage patients with persistent Lyme disease.
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Categorization performance is a popular metric of scene recognition and understanding in behavioral and computational research. However, categorical constructs and their labels can be somewhat arbitrary. Derived from exhaustive vocabularies of place names (e.g., Deng et al., 2009), or the judgements of small groups of researchers (e.g., Fei-Fei, Iyer, Koch, & Perona, 2007), these categories may not correspond with human-preferred taxonomies. Here, we propose clustering by increasing the rand index via coordinate ascent (CIRCA): an unsupervised, data-driven clustering method for deriving ground-truth scene categories. In Experiment 1, human participants organized 80 stereoscopic images of outdoor scenes from the Southampton-York Natural Scenes (SYNS) dataset (Adams et al., 2016) into discrete categories. In separate tasks, images were grouped according to i) semantic content, ii) three-dimensional spatial structure, or iii) two-dimensional image appearance. Participants provided text labels for each group. Using the CIRCA method, we determined the most representative category structure and then derived category labels for each task/dimension. In Experiment 2, we found that these categories generalized well to a larger set of SYNS images, and new observers. In Experiment 3, we tested the relationship between our category systems and the spatial envelope model (Oliva & Torralba, 2001). Finally, in Experiment 4, we validated CIRCA on a larger, independent dataset of same-different category judgements. The derived category systems outperformed the SUN taxonomy (Xiao, Hays, Ehinger, Oliva, & Torralba, 2010) and an alternative clustering method (Greene, 2019). In summary, we believe this novel categorization method can be applied to a wide range of datasets to derive optimal categorical groupings and labels from psychophysical judgements of stimulus similarity.
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Reconocimiento Visual de Modelos/fisiología , Reconocimiento en Psicología/fisiología , Adolescente , Adulto , Atención/fisiología , Femenino , Humanos , Juicio , Masculino , Psicofísica , Corteza Visual/fisiología , Adulto JovenRESUMEN
Adolescents with Conduct Disorder (CD) show deficits in recognizing facial expressions of emotion, but it is not known whether these difficulties extend to other social cues, such as emotional body postures. Moreover, in the absence of eye-tracking data, it is not known whether such deficits, if present, are due to a failure to attend to emotionally informative regions of the body. Male and female adolescents with CD and varying levels of callous-unemotional (CU) traits (n = 45) and age- and sex-matched typically-developing controls (n = 51) categorized static and dynamic emotional body postures. The emotion categorization task was paired with eye-tracking methods to investigate relationships between fixation behavior and recognition performance. Having CD was associated with impaired recognition of static and dynamic body postures and atypical fixation behavior. Furthermore, males were less likely to fixate emotionally-informative regions of the body than females. While we found no effects of CU traits on body posture recognition, the effects of CU traits on fixation behavior varied according to CD status and sex, with CD males with lower levels of CU traits showing the most atypical fixation behavior. Critically, atypical fixation behavior did not explain the body posture recognition deficits observed in CD. Our findings suggest that CD-related impairments in recognition of body postures of emotion are not due to attentional issues. Training programmes designed to ameliorate the emotion recognition difficulties associated with CD may need to incorporate a body posture component.
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Trastorno de la Conducta , Adolescente , Emociones , Tecnología de Seguimiento Ocular , Expresión Facial , Femenino , Humanos , Masculino , PosturaRESUMEN
Impairments in decision making under uncertainty, as measured by the Iowa Gambling Task (IGT), are observed in persons suffering from temporal lobe epilepsy (TLE), in which seizures originate in the amygdala and hippocampal formations. Gambling disorder is also more prevalent in this population. Individuals with amygdala damage show similar deficits in decision-making, as do rats with lesions restricted to the basolateral amygdala (BLA) performing an analogous rat gambling task (rGT), yet whether hyperstimulation of the BLA impacts risky decision-making has yet to be demonstrated. We therefore investigated whether kindling of the BLA affected rGT performance. In this task, sugar pellet profits are maximised through consistent selection of options associated with smaller per-trial gains but shorter punishing time-outs. Just as in the IGT, subjects must avoid the risky options, as penalties are disproportionately high despite the higher reward available. Most rats adopt the optimal strategy, but some instead make high numbers of risky, disadvantageous choices. Once stable choice preferences had been established on-task, sixteen male Long Evans rats were implanted unilaterally with a bipolar electrode targeting the BLA and stimulated twice daily until three stage five seizures had been elicited. The electrodes revealed to be nearly evenly places in the BLA and the Central Nucleus of the Amygdala (CeA). Kindling transiently increased choice of the option paired with the smallest reward but also the lowest level of punishment- a risk-averse, but suboptimal, choice. Risk-preferring rats also made more premature responses, a marker of motor impulsivity, and were faster to make a choice, whereas these variables were unaffected in optimal decision-makers. These data suggest epileptiform activity originating within the amygdala can impair choice and promote impulsivity, at least in some individuals.
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Complejo Nuclear Basolateral/fisiología , Núcleo Amigdalino Central/fisiología , Conducta de Elección/fisiología , Conducta Impulsiva/fisiología , Excitación Neurológica/fisiología , Asunción de Riesgos , Animales , Conducta Animal/fisiología , Estimulación Eléctrica , Masculino , Ratas , Ratas Long-EvansRESUMEN
Lithium's efficacy in reducing both symptom severity in bipolar disorder (BD) and suicide risk across clinical populations may reflect its ability to reduce impulsivity. Changes in immune markers are associated with BD and suicidality yet their exact role in symptom expression remains unknown. Evidence also suggests that lithium may decrease levels of pro-inflammatory cytokines in the periphery and central nervous system, and that such changes are related to its therapeutic efficacy. However, issues of cause and effect are hard to infer from clinical data alone. Here, we investigated the effects of chronic dietary lithium treatment on rats' performance of the 5-Choice Serial Reaction Time Task (5CSRTT), a well-validated operant behavioural task measuring aspects of impulsivity, attention and motivation. Male Long-Evans rats received a diet supplemented with 0.3% LiCl (n = 13), or the equivalent control diet (n = 16), during behavioural testing. Blood and brain tissue samples were assayed for a wide range of cytokines once any changes in impulsivity became significant. After 12 weeks, chronic lithium treatment reduced levels of motor impulsivity, as indexed by premature responses in the 5CSRTT; measures of sustained attention and motivation were unaffected. Plasma levels of IL-1ß, IL-10 and RANTES (CCL-5) were reduced in lithium-treated rats at this time point. IL-1ß, IL-6 and RANTES were also reduced selectively within the orbitofrontal cortex of lithium-treated rats, whereas cytokine levels in the medial prefrontal cortex and nucleus accumbens were comparable with control subjects. These results are consistent with the hypothesis that lithium may improve impulse control deficits in clinical populations by minimising the effects of pro-inflammatory signalling on neuronal activity, particularly within the orbitofrontal cortex.
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Citocinas , Litio , Animales , Conducta Impulsiva , Masculino , Corteza Prefrontal , Ratas , Ratas Long-EvansRESUMEN
Women and men can differ in their propensity to take risks and develop impulse control and addiction disorders. Sexual dimorphisms in behavioral control by the mesolimbic dopaminergic reward system may underlie these phenomena, given its sensitivity to gonadal hormones. However, this is hard to test experimentally using humans. Using the rat gambling task (rGT), we investigated what impact acute inhibition of accumbal dopamine had on decision-making and impulsivity in animals of both sexes. We expressed an inhibitory designer receptor exclusively activated by designer drugs (hM4D[Gi]) in the accumbal dopaminergic efferents of female and male transgenic (Tg) rats, engineered to selectively express cre recombinase in neurons synthesizing tyrosine hydroxylase. We then trained the rats to perform the rGT and assessed the effect of an acute clozapine-n-oxide (0-3 mg/kg) challenge. Chemogenetic inhibition of dopaminergic projections to the accumbens did not affect choice in females, perhaps due to low levels of risky choice in Tg+ animals at baseline, but induced a switch from risky to optimal decision-making in males performing the cued rGT. This manipulation also decreased motor impulsivity but only in females. These data support the hypothesis that cue-driven risky choice is mediated, at least in males, by activity of accumbal dopaminergic neurons. However, motor impulsivity is more sensitive to inhibition of accumbal dopamine neurons in female rats. These data may help explain differences in the manifestation of addictions across gender and reinforce the importance of examining both sexes when seeking to attribute control of behavior to specific monoaminergic pathways. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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Neuronas Dopaminérgicas/fisiología , Conducta Impulsiva/efectos de los fármacos , Conducta Impulsiva/fisiología , Animales , Conducta Adictiva/fisiopatología , Conducta de Elección/fisiología , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Señales (Psicología) , Dopamina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Femenino , Juego de Azar/fisiopatología , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Ratas , Ratas Long-Evans , Ratas Transgénicas , Recompensa , Asunción de Riesgos , Factores SexualesRESUMEN
People are able to perceive the 3D shape of illuminated surfaces using image shading cues. Theories about how we accomplish this often assume that the human visual system estimates a single lighting direction and interprets shading cues in accord with that estimate. In natural scenes, however, lighting can be much more complex than this, with multiple nearby light sources. Here we show that the human visual system can successfully judge 3D surface shape even when the lighting direction varies from place to place over a surface, provided the scale at which these lighting changes occur is similar to, or larger than, the size of the shape features being judged. Furthermore, we show that despite being able to accommodate rapid changes in lighting direction when judging shape, observers are generally unable to detect these changes. We conclude that, rather than relying on a single estimated illumination direction, the human visual system can accommodate illumination that varies substantially and rapidly across a surface.
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Percepción de Forma/fisiología , Iluminación , Femenino , Humanos , Imagenología Tridimensional , Masculino , Estimulación Luminosa/métodos , Adulto JovenRESUMEN
The visual probe (VP) paradigm provides evidence that emotional stimuli attract attention. Such effects have been reported even when stimuli are presented outside of awareness. These findings have shaped the idea that humans possess a processing pathway that detects evolutionarily significant signals independently of awareness. Here, we addressed 2 unresolved questions: First, if emotional stimuli attract attention, is this driven by their affective content, or by low-level image properties (e.g., luminance contrast)? Second, does attentional capture occur under conditions of genuine unawareness? We found that observers preferentially allocated attention to emotional faces under aware viewing conditions. However, this effect was best explained by low-level stimulus properties, rather than emotional content. When stimuli were presented outside of awareness (via continuous flash suppression or masking), we found no evidence that attention was directed toward emotional face stimuli. Finally, observer's awareness of the stimuli (assessed by d') predicted attentional cuing. Our data challenge existing literature: First, we cast doubt on the notion of preferential attention to emotional stimuli in the absence of awareness. Second, we question whether effects revealed by the VP paradigm genuinely reflect emotion-sensitive processes, instead suggesting they can be more parsimoniously explained by low-level variability between stimuli. (PsycINFO Database Record (c) 2019 APA, all rights reserved).