Now showing items 1-20 of 1147

    • Overdiagnosis and overtreatment of infectious diseases at the intersection of individual disease diagnosis, treatment, and public health

      Mayer, Dan; Lee, Sangil; Hansen, Malene Plejdrup; Gottlieb, Michael; Brown, Michael; Sinert, Richard; Davis, Joshua (Wiley, 2024-10-18)
    • Association between adolescent alcohol use and cognitive function in young adulthood: A co‐twin comparison study

      Cooke, Megan E.; Stephenson, Mallory; Brislin, Sarah J.; Latvala, Antti; Barr, Peter B.; Piirtola, Maarit; Vuoksimaa, Eero; Rose, Richard J.; Kaprio, Jaakko; Dick, Danielle M.; et al. (Wiley, 2024-08-06)
      Background and aims: Studies on adolescent alcohol use and cognition are often unable to separate the potential causal effects of alcohol use on cognition from shared etiological influences, including genetic influences or other substance use comorbidities also known to be associated with cognition, such as nicotine use. The present study aimed to fill this gap and clarify the relationship between adolescent alcohol use and young adult cognition by accounting for both measured and unmeasured confounders. Design: A random effects model accounting for nesting in families was used to control for measured confounders. Next, co-twin comparisons were conducted within the full sample and in monozygotic twin pairs (MZ) to control for unmeasured genetic and environmental confounders shared by co-twins. Participants/setting: Participants were 812 individuals (58.6% female, 361 complete pairs, 146 MZ pairs) from the longitudinal FinnTwin12 study in Finland. Measurements: Adolescent alcohol use was indexed with measures of frequency of use and intoxication averaged across ages 14 and 17. Cognitive outcomes were measured at average age 22 and included Trail Making Test, California Stroop test, Wechsler Adult Intelligence subtests (Vocabulary, Block Design, Digit Symbol), Digit Span subtest of Wechsler Memory Scale, Mental Rotation Test and Object Location Memory test. Covariates included sex, parental education, general cognitive ability, current alcohol use and nicotine use. Findings: Greater frequency of alcohol use and frequency of intoxication across adolescence was associated with decreased vocabulary scores in the co-twin control [freq: stnd beta = -0.12, 95% confidence interval (CI) = -0.234, -0.013] and MZ only co-twin control models (freq: stnd beta = -0.305, 95% CI = -0.523, -0.087; intox: stnd beta = -0.301, 95% CI = -0.528, -0.074). Conclusions: In Finland, there appears to be little evidence that adolescent alcohol use causes cognitive deficits in young adulthood, except modest evidence for association of higher adolescent alcohol use with lower young adult vocabulary scores.
    • Single‐cell ionic current phenotyping elucidates non‐canonical features and predictive potential of cardiomyocytes during automated drug experiments

      Clark, Alexander P.; Wei, Siyu; Christini, David J.; Krogh‐Madsen, Trine (Wiley, 2024-05-15)
      All new drugs must go through preclinical screening tests to determine their proarrhythmic potential. While these assays effectively filter out dangerous drugs, they are too conservative, often misclassifying safe compounds as proarrhythmic. In this study, we attempt to address this shortcoming with a novel, medium-throughput drug-screening approach: we use an automated patch-clamp system to acquire optimized voltage clamp (VC) and action potential (AP) data from human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) at several drug concentrations (baseline, 3×, 10× and 20× the effective free plasma concentrations). With our novel method, we show correlations between INa block and upstroke slowing after treatment with flecainide or quinine. Additionally, after quinine treatment, we identify significant reductions in current during voltage steps designed to isolate If and IKs. However, we do not detect any IKr block by either drug, and upon further investigation, do not see any IKr present in the iPSC-CMs when prepared for automated patch experiments (i.e. in suspension) - this is in contrast to similar experiments we have conducted with these cells using the manual patch setup. In this study, we: (1) present a proof-of-concept demonstration of a single-cell medium-throughput drug study, and (2) characterize the non-canonical electrophysiology of iPSC-CMs when prepared for experiments in a medium-throughput setting. KEY POINTS: Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer potential as an in vitro model to study the proarrhythmic potential of drugs, but insights from these cells are often limited by the low throughput of manual patch-clamp. In this study, we use a medium-throughput automated patch-clamp system to acquire action potential (AP) and complex voltage clamp (VC) data from single iPSC-CMs at multiple drug concentrations. A correlation between AP upstroke and INa transients was identified and drug-induced changes in ionic currents found. We also characterize the substantially altered physiology of iPSC-CMs when patched in an automated system, suggesting the need to investigate differences between manual and automated patch experiments.
    • Stem cell‐derived cardiomyocyte heterogeneity confounds electrophysiological insights

      Clark, Alexander P.; Krogh‐Madsen, Trine; Christini, David J. (Wiley, 2024-05-09)
      Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer potential as an in vitro model for studying drug cardiotoxicity and patient-specific cardiovascular disease. The inherent electrophysiological heterogeneity of these cells limits the depth of insights that can be drawn from well-designed experiments. In this review, we provide our perspective on some sources and the consequences of iPSC-CM heterogeneity. We demonstrate the extent of heterogeneity in the literature and explain how such heterogeneity is exacerbated by patch-clamp experimental artifacts in the manual and automated set-up. Finally, we discuss how this heterogeneity, caused by both intrinsic and extrinsic factors, limits our ability to build digital twins of patient-derived cardiomyocytes.
    • Reevaluating Informed Consent: Integrating Shared Decision-Making into Spinal Surgery for Better Patient Outcomes

      Wang, Jeffrey N.; Elhakeem, Mohamed A.; Mesimer, Matthew J.; Mastrokostas, Paul G.; Ahmad, Salman; Reed, Tim; Klein, Brandon; Bartlett, Lucas E.; Bitterman, Adam D.; Megas, Andrew (SAGE Publications, 2024-10-26)
      Study design: Narrative review. Objectives: The objectives of this study were to answer the following questions: (1) What is the quality of informed consent in spine surgery, including both neurosurgery and orthopaedic spine surgery? (2) What limitations impede the ability of surgeons to engage in effective shared decision-making (SDM) and obtain adequate informed consent? (3) What strategies and solutions may improve the quality of informed consent and SDM? (4) What factors decrease the incidence of litigation in spine surgery? Methods: N/A. Results: SDM is a collaborative process where patients are involved in their treatment choices through open communication about risks, alternatives, and postoperative expectations. Informed consent is a vital component of this process, ensuring that patients are fully informed and empowered to make decisions based on their values and preferences. This review highlights the current state of informed consent within the context of SDM in spine surgery and explores how enhancing this process can improve patient outcomes, reduce dissatisfaction, and decrease litigation. By emphasizing patient autonomy and improving the quality of risk communication, SDM fosters better physician-patient relationships and more positive clinical outcomes. Conclusions: Orthopaedic surgery and neurosurgery are highly litigated specialties, with failure to obtain informed consent frequently cited in lawsuits. These legal challenges are costly and time-consuming for both physicians and patients. Integrating SDM into the informed consent process can help mitigate these issues, leading to improved patient satisfaction and fewer legal disputes.
    • Fostering Inclusivity in the Clinical Learning Environment

      Smith, Teresa Y.; Terhune, Kyla; Caniano, Donna A. (F1000 Research Ltd, 2024-10-15)
      Despite the Supreme Court's decision on race-based admissions, academic medical centers, medical societies, and accreditation bodies remain committed to recruiting a diverse workforce. Many medical schools and graduate medical education programs created initiatives to expand their census of underrepresented in medicine (UIM) as the key to addressing health care disparities. As a result, an influx of an UIM physician workforce has entered clinical learning environments, often without consideration of the inclusivity of these settings. To create inclusive, safe, and comfortable CLEs, we must first recognize the challenges faced by UIM trainees, students, and faculty and the complex ways in which discrimination manifests. Ultimately, having inclusive CLEs allows all learners, especially those from historically excluded identities, to thrive in their training and working environment, making it essential to retain the diverse workforce necessary. Using case examples, we discuss strategies of inclusivity and ways in which we can maintain clinical learning environments where learners feel safe and supported through their training.
    • Real-World Survival Impact and Utilization of Adjuvant Radiation in Advanced Laryngeal Cancer

      Cooper, Dylan J.; Davies, Camron; Putnam, Paul; Tansey, James B.; Gleysteen, John; Sansoni, Eugene R.; Schwartz, David L.; Wood, Carey Burton (SAGE Publications, 2024-10-23)
      Background: Optimal treatment of locally advanced cancer of the larynx is controversial. In this study, we aim to compare outcomes in patients with T3-4N0-1 cancer of the larynx who underwent surgery alone versus surgery followed by radiation therapy (RT). Materials and Methods: A total of 1820 patients with advanced laryngeal cancer were identified from the national Surveillance, Epidemiology, and End Results Database and stratified based on postoperative RT status, and clinical outcomes were compared between these 2 groups. Propensity score matching was conducted to balance baseline characteristics. Results: The majority of patients (53.4%) received adjuvant RT. N0 patients who received laryngectomy and who did not undergo adjuvant radiation had a 47% higher risk of cancer-specific death than patients receiving adjuvant RT (adj. HR 1.47, 95% CI 1.18-1.84). N1 patients who did not undergo adjuvant radiation had a 90% higher risk of cancer-specific death than patients receiving RT after surgery (adj. HR 1.90, 95% CI 1.27-2.84). After adjusting for propensity scores, adjuvant RT carried a significant overall survival benefit (HR 0.73, 95% CI 0.60-0.87). Conclusions: This study provides real-world support for adjuvant radiation in patients with T3-4N0-1 laryngeal carcinoma. Nearly half of patients did not receive RT, indicating a need for national provider education and process improvement strategies to improve utilization.
    • Optical images of visible and invisible percepts in the primary visual cortex of primates

      Macknik, Stephen L.; Haglund, Michael M. (Proceedings of the National Academy of Sciences, 1999-12-21)
      We optically imaged a visual masking illusion in primary visual cortex (area V-1) of rhesus monkeys to ask whether activity in the early visual system more closely reflects the physical stimulus or the generated percept. Visual illusions can be a powerful way to address this question because they have the benefit of dissociating the stimulus from perception. We used an illusion in which a flickering target (a bar oriented in visual space) is rendered invisible by two counter-phase flickering bars, called masks, which flank and abut the target. The target and masks, when shown separately, each generated correlated activity on the surface of the cortex. During the illusory condition, however, optical signals generated in the cortex by the target disappeared although the image of the masks persisted. The optical image thus was correlated with perception but not with the physical stimulus.
    • How the visual system prevents the world from fading

      Martinez-Conde, Susana; Macknick, Stephen (2000-12)
      Our visual system contains a built-in contradiction: when we fixate our gaze on an object of interest, our eyes are never still. Instead we produce, several times each second, small eye movements of which we are unaware, called “microsaccades”. Amazingly, if we eliminate these eye movements in the laboratory, our visual perception fades. By knowing the brain activity that occurs as result of a microsaccade, we can know the type of activity that is important for keeping objects visible. To address this, we trained macaque monkeys to fixate their eyes on a small spot and we correlated their neuronal activity with their eye movements. We learned that microsaccades increase the activity of neurons in the primary visual cortex (area V1). This increased activity tends to occur in clumps, also called “bursts”. Bursts of neuronal impulses would seem to be the type of activity most effective in sustaining a visible image.
    • The function of bursts of spikes during visual fixation in the awake primate lateral geniculate nucleus and primary visual cortex

      Martinez-Conde, Susana; Macknik, Stephen L.; Hubel, David H. (Proceedings of the National Academy of Sciences, 2002-10-02)
      When images are stabilized on the retina, visual perception fades. During voluntary visual fixation, however, constantly occurring small eye movements, including microsaccades, prevent this fading. We previously showed that microsaccades generated bursty firing in the primary visual cortex (area V-1) in the presence of stationary stimuli. Here we examine the neural activity generated by microsaccades in the lateral geniculate nucleus (LGN), and in the area V-1 of the awake monkey, for various functionally relevant stimulus parameters. During visual fixation, microsaccades drove LGN neurons by moving their receptive fields across a stationary stimulus, offering a likely explanation of how microsaccades block fading during normal fixation. Bursts of spikes in the LGN and area V-1 were associated more closely than lone spikes with preceding microsaccades, suggesting that bursts are more reliable than are lone spikes as neural signals for visibility. In area V-1, microsaccade-generated activity, and the number of spikes per burst, was maximal when the bar stimulus centered over a receptive field matched the cell's optimal orientation. This suggested burst size as a neural code for stimuli optimality (and not solely stimuli visibility). As expected, burst size did not vary with stimulus orientation in the LGN. To address the effectiveness of microsaccades in generating neural activity, we compared activity correlated with microsaccades to activity correlated with flashing bars. Onset responses to flashes were about 7 times larger than the responses to the same stimulus moved across the cells' receptive fields by microsaccades, perhaps because of the relative abruptness of flashes.
    • Visibility, visual awareness, and visual masking of simple unattended targets are confined to areas in the occipital cortex beyond human V1/V2

      Tse, Peter U.; Martinez-Conde, Susana; Schlegel, Alexander A.; Macknik, Stephen L. (Proceedings of the National Academy of Sciences, 2005-11-10)
      In visual masking, visible targets are rendered invisible by modifying the context in which they are presented, but not by modifying the targets themselves. Here, we localize the neuronal correlates of visual awareness in the human brain by using visual masking illusions. We compare monoptic visual masking activation, which we find within all retinotopic visual areas, with dichoptic masking activation, which we find only in those retinotopic areas downstream of V2. Because monoptic and dichoptic masking are equivalent in magnitude perceptually, the present results establish a lower bound for maintenance of visual awareness of simple unattended targets. Moreover, we find that awareness-correlated circuits for simple targets are restricted to the occipital lobe. This finding provides evidence of an upper boundary in the visual hierarchy for visual awareness of simple unattended targets, thus constraining the location of circuits that maintain the visibility of simple targets to occipital areas beyond V1/V2.
    • Microsaccades Counteract Visual Fading during Fixation

      Martinez-Conde, Susana; Macknik, Stephen L.; Troncoso, Xoana G.; Dyar, Thomas A. (Elsevier BV, 2006-01)
      Our eyes move continually, even while we fixate our gaze on an object. If fixational eye movements are counteracted, our perception of stationary objects fades completely, due to neural adaptation. Some studies have suggested that fixational microsaccades refresh retinal images, thereby preventing adaptation and fading. However, other studies disagree, and so the role of microsaccades remains unclear. Here, we correlate visibility during fixation to the occurrence of microsaccades. We asked subjects to indicate when Troxler fading of a peripheral target occurs, while simultaneously recording their eye movements with high precision. We found that before a fading period, the probability, rate, and magnitude of microsaccades decreased. Before transitions toward visibility, the probability, rate, and magnitude of microsaccades increased. These results reveal a direct link between suppression of microsaccades and fading and suggest a causal relationship between microsaccade production and target visibility during fixation.
    • The role of feedback in visual masking and visual processing

      Macknik, Stephen L.; Martinez-Conde, Susana (University of Economics and Human Sciences in Warsaw, 2008-07-15)
      This paper reviews the potential role of feedback in visual masking, for and against. Our analysis reveals constraints for feedback mecha- nisms that limit their potential role in visual masking, and in all other general brain functions. We propose a feedforward model of visual masking, and provide a hypothesis to explain the role of feedback in visual masking and visual processing in general. We review the anato-my and physiology of feedback mechanisms, and propose that the massive ratio of feedback versus feedforward connections in the visual system may be explained solely by the critical need for top-down attentional modulation. We discuss the merits of visual masking as a tool to discover the neural correlates of consciousness, especially as compared to other popular illusions, such as binocular rivalry. Finally, we propose a new set of neurophysiological standards needed to establish whether any given neuron or brain circuit may be the neural substrate of awareness.
    • Saccades and microsaccades during visual fixation, exploration, and search: Foundations for a common saccadic generator

      Otero-Millan, J.; Troncoso, X. G.; Macknik, S. L.; Serrano-Pedraza, I.; Martinez-Conde, S. (Association for Research in Vision and Ophthalmology (ARVO), 2008-12-01)
      Microsaccades are known to occur during prolonged visual fixation, but it is a matter of controversy whether they also happen during free-viewing. Here we set out to determine: 1) whether microsaccades occur during free visual exploration and visual search, 2) whether microsaccade dynamics vary as a function of visual stimulation and viewing task, and 3) whether saccades and microsaccades share characteristics that might argue in favor of a common saccade-microsaccade oculomotor generator. Human subjects viewed naturalistic stimuli while performing various viewing tasks, including visual exploration, visual search, and prolonged visual fixation. Their eye movements were simultaneously recorded with high precision. Our results show that microsaccades are produced during the fixation periods that occur during visual exploration and visual search. Microsaccade dynamics during free-viewing moreover varied as a function of visual stimulation and viewing task, with increasingly demanding tasks resulting in increased microsaccade production. Moreover, saccades and microsaccades had comparable spatiotemporal characteristics, including the presence of equivalent refractory periods between all pair-wise combinations of saccades and microsaccades. Thus our results indicate a microsaccade-saccade continuum and support the hypothesis of a common oculomotor generator for saccades and microsaccades.
    • Task difficulty modulates the activity of specific neuronal populations in primary visual cortex

      Chen, Yao; Martinez-Conde, Susana; Macknik, Stephen L; Bereshpolova, Yulia; Swadlow, Harvey A; Alonso, Jose-Manuel (Springer Science and Business Media LLC, 2008-07-06)
      Spatial attention enhances our ability to detect stimuli at restricted regions of the visual field. This enhancement is thought to depend on the difficulty of the task being performed, but the underlying neuronal mechanisms for this dependency remain largely unknown. We found that task difficulty modulates neuronal firing rate at the earliest stages of cortical visual processing (area V1) in monkey (Macaca mulatta). These modulations were spatially specific: increasing task difficulty enhanced V1 neuronal firing rate at the focus of attention and suppressed it in regions surrounding the focus. Moreover, we found that response enhancement and suppression are mediated by distinct populations of neurons that differ in direction selectivity, spike width, interspike-interval distribution and contrast sensitivity. Our results provide strong support for center-surround models of spatial attention and suggest that task difficulty modulates the activity of specific populations of neurons in the primary visual cortex.
    • Microsaccades drive illusory motion in the Enigma illusion

      Troncoso, Xoana G.; Macknik, Stephen L.; Otero-Millan, Jorge; Martinez-Conde, Susana (Proceedings of the National Academy of Sciences, 2008-10-14)
      Visual images consisting of repetitive patterns can elicit striking illusory motion percepts. For almost 200 years, artists, psychologists, and neuroscientists have debated whether this type of illusion originates in the eye or in the brain. For more than a decade, the controversy has centered on the powerful illusory motion perceived in the painting Enigma, created by op-artist Isia Leviant. However, no previous study has directly correlated the Enigma illusion to any specific physiological mechanism, and so the debate rages on. Here, we show that microsaccades, a type of miniature eye movement produced during visual fixation, can drive illusory motion in Enigma. We asked subjects to indicate when illusory motion sped up or slowed down during the observation of Enigma while we simultaneously recorded their eye movements with high precision. Before "faster" motion periods, the rate of microsaccades increased. Before "slower/no" motion periods, the rate of microsaccades decreased. These results reveal a direct link between microsaccade production and the perception of illusory motion in Enigma and rule out the hypothesis that the origin of the illusion is purely cortical.
    • Microsaccades counteract perceptual filling-in

      Troncoso, X. G.; Macknik, S. L.; Martinez-Conde, S. (Association for Research in Vision and Ophthalmology (ARVO), 2008-11-01)
      Artificial scotomas positioned within peripheral dynamic noise fade perceptually during visual fixation (that is, the surrounding dynamic noise appears to fill-in the scotoma). Because the scotomas' edges are continuously refreshed by the dynamic noise background, this filling-in effect cannot be explained by low-level adaptation mechanisms (such as those that may underlie classical Troxler fading). We recently showed that microsaccades counteract Troxler fading and drive first-order visibility during fixation (S. Martinez-Conde, S. L. Macknik, X. G. Troncoso, & T. A. Dyar, 2006). Here we set out to determine whether microsaccades may counteract the perceptual filling-in of artificial scotomas and thus drive second-order visibility. If so, microsaccades may not only counteract low-level adaptation but also play a role in higher perceptual processes. We asked subjects to indicate, via button press/release, whether an artificial scotoma presented on a dynamic noise background was visible or invisible at any given time. The subjects' eye movements were simultaneously measured with a high precision video system. We found that increases in microsaccade production counteracted the perception of filling-in, driving the visibility of the artificial scotoma. Conversely, decreased microsaccades allowed perceptual filling-in to take place. Our results show that microsaccades do not solely overcome low-level adaptation mechanisms but they also contribute to maintaining second-order visibility during fixation.
    • Fixational eye movements across vertebrates: Comparative dynamics, physiology, and perception

      Martinez-Conde, S.; Macknik, S. L. (Association for Research in Vision and Ophthalmology (ARVO), 2008-12-01)
      During visual fixation, human eyes are never still. Instead, they constantly produce involuntary "fixational eye movements." Fixational eye movements overcome neural adaptation and prevent visual fading: thus they are an important tool to understand how the brain makes the environment visible. The last decade has seen a growing interest in the analysis of fixational eye movements in humans and primates, as well as in their perceptual and physiological consequences. However, no comprehensive comparison of fixational eye movements across species has been offered. Here we review five decades of fixational eye movement studies in non-human vertebrates, and we discuss the existing evidence concerning their physiological and perceptual effects. We also provide a table that summarizes the physical parameters of the different types of fixational eye movements described in non-human vertebrates.
    • Real magic: future studies of magic should be grounded in neuroscience

      Macknik, Stephen L.; Martinez-Conde, Susana (Springer Science and Business Media LLC, 2009-01-29)
    • The linearity and selectivity of neuronal responses in awake visual cortex

      Chen, Y.; Anand, S.; Martinez-Conde, S.; Macknik, S. L.; Bereshpolova, Y.; Swadlow, H. A.; Alonso, J. M. (Association for Research in Vision and Ophthalmology (ARVO), 2009-08-01)
      Neurons in primary visual cortex (V1) are frequently classified based on their response linearity: the extent to which their visual responses to drifting gratings resemble a linear replica of the stimulus. This classification is supported by the finding that response linearity is bimodally distributed across neurons in area V1 of anesthetized animals. However, recent studies suggest that such bimodal distribution may not reflect two neuronal types but a nonlinear relationship between the membrane potential and the spike output. A main limitation of these previous studies is that they measured response linearity in anesthetized animals, where the distance between the neuronal membrane potential and the spike threshold is artificially increased by anesthesia. Here, we measured V1 response linearity in the awake brain and its correlation with the neuronal spontaneous firing rate, which is related to the distance between membrane potential and threshold. Our results demonstrate that response linearity is bimodally distributed in awake V1 but that it is poorly correlated with spontaneous firing rate. In contrast, the spontaneous firing rate is best correlated to the response selectivity and response latency to stimuli.