Unifying network model links recency and central tendency biases in working memory.

The central tendency bias, or contraction bias, is a phenomenon where the judgment of the magnitude of items held in working memory appears to be biased toward the average of past observations. It is assumed to be an optimal strategy by the brain and commonly thought of as an expression of the brain's ability to learn the statistical structure of sensory input. On the other hand, recency biases such as serial dependence are also commonly observed and are thought to reflect the content of working memory. Recent results from an auditory delayed comparison task in rats suggest that both biases may be more related than previously thought: when the posterior parietal cortex (PPC) was silenced, both short-term and contraction biases were reduced. By proposing a model of the circuit that may be involved in generating the behavior, we show that a volatile working memory content susceptible to shifting to the past sensory experience - producing short-term sensory history biases - naturally leads to contraction bias. The errors, occurring at the level of individual trials, are sampled from the full distribution of the stimuli and are not due to a gradual shift of the memory toward the sensory distribution's mean. Our results are consistent with a broad set of behavioral findings and provide predictions of performance across different stimulus distributions and timings, delay intervals, as well as neuronal dynamics in putative working memory areas. Finally, we validate our model by performing a set of human psychophysics experiments of an auditory parametric working memory task.

During cognitive tasks, our brain needs to temporarily hold and manipulate the information it is processing to decide how best to respond. This ability, known as working memory, is influenced by how the brain represents and processes the sensory world around us, which can lead to biases, such as 'central tendency'. Consider an experiment where you are presented with a metal bar and asked to recall how long it was after a few seconds. Typically, our memories, averaged over many trials of repeating this memory recall test, appear to skew towards an average length, leading to the tendency to mis-remember the bar as being shorter or longer than it actually was. This central tendency occurs in most species, and is thought to be the result of the brain learning which sensory input is the most likely to occur out of the range of possibilities. Working memory is also influenced by short-term history or recency bias, where a recent past experience influences a current memory. Studies have shown that 'turning off' a region of the rat brain called the posterior parietal cortex removes the effects of both recency bias and central tendency on working memory. Here, Boboeva et al. reveal that these two biases, which were thought to be controlled by separate mechanisms, may in fact be related. Building on the inactivation study, the team modelled a circuit of neurons that can give rise to the results observed in the rat experiments, as well as behavioural results in humans and primates. The computational model contained two modules: one of which represented a putative working memory, and another which represented the posterior parietal cortex which relays sensory information about past experiences. Boboeva et al. found that sensory inputs relayed from the posterior parietal cortex module led to recency biases in working memory. As a result, central tendency naturally emerged without needing to add assumptions to the model about which sensory input is the most likely to occur. The computational model was also able to replicate all known previous experimental findings, and made some predictions that were tested and confirmed by psychophysics tests on human participants. The findings of Boboeva et al. provide a new potential mechanism for how central tendency emerges in working memory. The model suggests that to achieve central tendency prior knowledge of how a sensory stimulus is distributed in an environment is not required, as it naturally emerges due to a volatile working memory which is susceptible to errors. This is the first mechanistic model to unify these two sources of bias in working memory. In the future, this could help advance our understanding of certain psychiatric conditions in which working memory and sensory learning are impaired.

Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID.

Background: Long COVID contributes to the global burden of disease. Proposed root cause hypotheses include the persistence of SARS-CoV-2 viral reservoir, autoimmunity, and reactivation of latent herpesviruses. Patients have reported various changes in Long COVID symptoms after COVID-19 vaccinations, leaving uncertainty about whether vaccine-induced immune responses may alleviate or worsen disease pathology. Methods: In this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naïve individuals with Long COVID. Surveys were administered before vaccination and then at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination. Results: Self-report at 12 weeks post-vaccination indicated 10 out of 16 participants had improved health, 3 had no change, 1 had worse health, and 2 reported marginal changes. Significant elevation in SARS-CoV-2-specific TCRs and Spike protein-specific IgG were observed 6 and 12 weeks after vaccination. No changes in reactivities were observed against herpes viruses and self-antigens. Within this dataset, higher baseline sIL-6R was associated with symptom improvement, and the two top features associated with non-improvement were high IFN-ß and CNTF, among soluble analytes. Conclusions: Our study showed that in this small sample, vaccination improved the health or resulted in no change to the health of most participants, though few experienced worsening. Vaccination was associated with increased SARS-CoV-2 Spike protein-specific IgG and T cell expansion in most individuals with Long COVID. Symptom improvement was observed in those with baseline elevated sIL-6R, while elevated interferon and neuropeptide levels were associated with a lack of improvement.

Systematic Review of the Prevalence of Long COVID.

Background: Long COVID occurs in those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whose symptoms persist or develop beyond the acute phase. We conducted a systematic review to determine the prevalence of persistent symptoms, functional disability, or pathological changes in adults or children at least 12 weeks postinfection. Methods: We searched key registers and databases from January 1, 2020 to November 2, 2021, limited to publications in English and studies with at least 100 participants. Studies in which all participants were critically ill were excluded. Long COVID was extracted as prevalence of at least 1 symptom or pathology, or prevalence of the most common symptom or pathology, at 12 weeks or later. Heterogeneity was quantified in absolute terms and as a proportion of total variation and explored across predefined subgroups (PROSPERO ID CRD42020218351). Results: One hundred twenty studies in 130 publications were included. Length of follow-up varied between 12 weeks and 12 months. Few studies had low risk of bias. All complete and subgroup analyses except 1 had I2 ≥90%, with prevalence of persistent symptoms range of 0%-93% (pooled estimate [PE], 42.1%; 95% prediction interval [PI], 6.8% to 87.9%). Studies using routine healthcare records tended to report lower prevalence (PE, 13.6%; PI, 1.2% to 68%) of persistent symptoms/pathology than self-report (PE, 43.9%; PI, 8.2% to 87.2%). However, studies systematically investigating pathology in all participants at follow up tended to report the highest estimates of all 3 (PE, 51.7%; PI, 12.3% to 89.1%). Studies of hospitalized cases had generally higher estimates than community-based studies. Conclusions: The way in which Long COVID is defined and measured affects prevalence estimation. Given the widespread nature of SARS-CoV-2 infection globally, the burden of chronic illness is likely to be substantial even using the most conservative estimates.

Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates.

Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We have evolved adeno-associated virus (AAV9) capsids into vectors that transduce brain endothelial cells specifically and efficiently following systemic administration in wild-type mice with diverse genetic backgrounds, and in rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and in ex vivo human brain slices, although the endothelial tropism is not conserved across species. The capsid modifications translate from AAV9 to other serotypes such as AAV1 and AAV-DJ, enabling serotype switching for sequential AAV administration in mice. We demonstrate that the endothelial-specific mouse capsids can be used to genetically engineer the blood-brain barrier by transforming the mouse brain vasculature into a functional biofactory. We apply this approach to Hevin knockout mice, where AAV-X1-mediated ectopic expression of the synaptogenic protein Sparcl1/Hevin in brain endothelial cells rescued synaptic deficits.

A review of cytokine-based pathophysiology of Long COVID symptoms.

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with "brain fog," arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates.

Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We have evolved adeno-associated virus (AAV9) capsids into vectors that transduce brain endothelial cells specifically and efficiently following systemic administration in wild-type mice with diverse genetic backgrounds and rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and ex vivo human brain slices although the endothelial tropism is not conserved across species. The capsid modifications translate from AAV9 to other serotypes such as AAV1 and AAV-DJ, enabling serotype switching for sequential AAV administration in mice. We demonstrate that the endothelial specific mouse capsids can be used to genetically engineer the blood-brain barrier by transforming the mouse brain vasculature into a functional biofactory. Vasculature-secreted Hevin (a synaptogenic protein) rescued synaptic deficits in a mouse model.

A core outcome set for post-COVID-19 condition in adults for use in clinical practice and research: an international Delphi consensus study.

Health consequences that persist beyond the acute infection phase of COVID-19, termed post-COVID-19 condition (also commonly known as long COVID), vary widely and represent a growing global health challenge. Research on post-COVID-19 condition is expanding but, at present, no agreement exists on the health outcomes that should be measured in people living with the condition. To address this gap, we conducted an international consensus study, which included a comprehensive literature review and classification of outcomes for post-COVID-19 condition that informed a two-round online modified Delphi process followed by an online consensus meeting to finalise the core outcome set (COS). 1535 participants from 71 countries were involved, with 1148 individuals participating in both Delphi rounds. Eleven outcomes achieved consensus for inclusion in the final COS: fatigue; pain; post-exertion symptoms; work or occupational and study changes; survival; and functioning, symptoms, and conditions for each of cardiovascular, respiratory, nervous system, cognitive, mental health, and physical outcomes. Recovery was included a priori because it was a relevant outcome that was part of a previously published COS on COVID-19. The next step in this COS development exercise will be to establish the instruments that are most appropriate to measure these core outcomes. This international consensus-based COS should provide a framework for standardised assessment of adults with post-COVID-19 condition, aimed at facilitating clinical care and research worldwide.

Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development.

BACKGROUND: A substantial portion of people with COVID-19 subsequently experience lasting symptoms including fatigue, shortness of breath, and neurological complaints such as cognitive dysfunction many months after acute infection. Emerging evidence suggests that this condition, commonly referred to as long COVID but also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition, could become a significant global health burden. MAIN TEXT: While the number of studies investigating the post-COVID-19 condition is increasing, there is no agreement on how this new disease should be defined and diagnosed in clinical practice and what relevant outcomes to measure. There is an urgent need to optimise and standardise outcome measures for this important patient group both for clinical services and for research and to allow comparing and pooling of data. CONCLUSIONS: A Core Outcome Set for post-COVID-19 condition should be developed in the shortest time frame possible, for improvement in data quality, harmonisation, and comparability between different geographical locations. We call for a global initiative, involving all relevant partners, including, but not limited to, healthcare professionals, researchers, methodologists, patients, and caregivers. We urge coordinated actions aiming to develop a Core Outcome Set (COS) for post-COVID-19 condition in both the adult and paediatric populations.

Characterizing long COVID in an international cohort: 7 months of symptoms and their impact.

BACKGROUND: A significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. Few systematic studies have investigated this population, particularly in outpatient settings. Hence, relatively little is known about symptom makeup and severity, expected clinical course, impact on daily functioning, and return to baseline health. METHODS: We conducted an online survey of people with suspected and confirmed COVID-19, distributed via COVID-19 support groups (e.g. Body Politic, Long COVID Support Group, Long Haul COVID Fighters) and social media (e.g. Twitter, Facebook). Data were collected from September 6, 2020 to November 25, 2020. We analyzed responses from 3762 participants with confirmed (diagnostic/antibody positive; 1020) or suspected (diagnostic/antibody negative or untested; 2742) COVID-19, from 56 countries, with illness lasting over 28 days and onset prior to June 2020. We estimated the prevalence of 203 symptoms in 10 organ systems and traced 66 symptoms over seven months. We measured the impact on life, work, and return to baseline health. FINDINGS: For the majority of respondents (>91%), the time to recovery exceeded 35 weeks. During their illness, participants experienced an average of 55.9+/- 25.5 (mean+/-STD) symptoms, across an average of 9.1 organ systems. The most frequent symptoms after month 6 were fatigue, post-exertional malaise, and cognitive dysfunction. Symptoms varied in their prevalence over time, and we identified three symptom clusters, each with a characteristic temporal profile. 85.9% of participants (95% CI, 84.8% to 87.0%) experienced relapses, primarily triggered by exercise, physical or mental activity, and stress. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 1700 respondents (45.2%) required a reduced work schedule compared to pre-illness, and an additional 839 (22.3%) were not working at the time of survey due to illness. Cognitive dysfunction or memory issues were common across all age groups (~88%). Except for loss of smell and taste, the prevalence and trajectory of all symptoms were similar between groups with confirmed and suspected COVID-19. INTERPRETATION: Patients with Long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden. FUNDING: All authors contributed to this work in a voluntary capacity. The cost of survey hosting (on Qualtrics) and publication fee was covered by AA's research grant (Wellcome Trust/Gatsby Charity via Sainsbury Wellcome center, UCL).

Collicular circuits for flexible sensorimotor routing.

Context-based sensorimotor routing is a hallmark of executive control. Pharmacological inactivations in rats have implicated the midbrain superior colliculus (SC) in this process. But what specific role is this, and what circuit mechanisms support it? Here we report a subset of rat SC neurons that instantiate a specific link between the representations of context and motor choice. Moreover, these neurons encode animals' choice far earlier than other neurons in the SC or in the frontal cortex, suggesting that their neural dynamics lead choice computation. Optogenetic inactivations revealed that SC activity during context encoding is necessary for choice behavior, even while that choice behavior is robust to inactivations during choice formation. Searches for SC circuit models matching our experimental results identified key circuit predictions while revealing some a priori expected features as unnecessary. Our results reveal circuit mechanisms within the SC that implement response inhibition and context-based vector inversion during executive control.

Patient-Led Research Collaborative: embedding patients in the Long COVID narrative.

A large subset of patients with coronavirus disease 2019 (COVID-19) are experiencing symptoms well beyond the claimed 2-week recovery period for mild cases. These long-term sequelae have come to be known as Long COVID. Originating out of a dedicated online support group, a team of patients formed the Patient-Led Research Collaborative and conducted the first research on Long COVID experience and symptoms. This article discusses the history and value of patient-centric and patient-led research; the formation of Patient-Led Research Collaborative as well as key findings to date; and calls for the following: the acknowledgement of Long COVID as an illness, an accurate estimate of the prevalence of Long COVID, publicly available basic symptom management, care, and research to not be limited to those with positive polymerase chain reaction and antibody tests, and aggressive research and investigation into the pathophysiology of symptoms.

Extracting the dynamics of behavior in sensory decision-making experiments.

Decision-making strategies evolve during training and can continue to vary even in well-trained animals. However, studies of sensory decision-making tend to characterize behavior in terms of a fixed psychometric function that is fit only after training is complete. Here, we present PsyTrack, a flexible method for inferring the trajectory of sensory decision-making strategies from choice data. We apply PsyTrack to training data from mice, rats, and human subjects learning to perform auditory and visual decision-making tasks. We show that it successfully captures trial-to-trial fluctuations in the weighting of sensory stimuli, bias, and task-irrelevant covariates such as choice and stimulus history. This analysis reveals dramatic differences in learning across mice and rapid adaptation to changes in task statistics. PsyTrack scales easily to large datasets and offers a powerful tool for quantifying time-varying behavior in a wide variety of animals and tasks.

Lateral orbitofrontal cortex promotes trial-by-trial learning of risky, but not spatial, biases.

Individual choices are not made in isolation but are embedded in a series of past experiences, decisions, and outcomes. The effects of past experiences on choices, often called sequential biases, are ubiquitous in perceptual and value-based decision-making, but their neural substrates are unclear. We trained rats to choose between cued guaranteed and probabilistic rewards in a task in which outcomes on each trial were independent. Behavioral variability often reflected sequential effects, including increased willingness to take risks following risky wins, and spatial 'win-stay/lose-shift' biases. Recordings from lateral orbitofrontal cortex (lOFC) revealed encoding of reward history and receipt, and optogenetic inhibition of lOFC eliminated rats' increased preference for risk following risky wins, but spared other sequential effects. Our data show that different sequential biases are neurally dissociable, and the lOFC's role in adaptive behavior promotes learning of more abstract biases (here, biases for the risky option), but not spatial ones.

Posterior parietal cortex represents sensory history and mediates its effects on behaviour.

Many models of cognition and of neural computations posit the use and estimation of prior stimulus statistics: it has long been known that working memory and perception are strongly impacted by previous sensory experience, even when that sensory history is not relevant to the current task at hand. Nevertheless, the neural mechanisms and regions of the brain that are necessary for computing and using such prior experience are unknown. Here we report that the posterior parietal cortex (PPC) is a critical locus for the representation and use of prior stimulus information. We trained rats in an auditory parametric working memory task, and found that they displayed substantial and readily quantifiable behavioural effects of sensory-stimulus history, similar to those observed in humans and monkeys. Earlier proposals that the PPC supports working memory predict that optogenetic silencing of this region would impair behaviour in our working memory task. Contrary to this prediction, we found that silencing the PPC significantly improved performance. Quantitative analyses of behaviour revealed that this improvement was due to the selective reduction of the effects of prior sensory stimuli. Electrophysiological recordings showed that PPC neurons carried far more information about the sensory stimuli of previous trials than about the stimuli of the current trial. Furthermore, for a given rat, the more information about previous trial sensory history in the neural firing rates of the PPC, the greater the behavioural effect of sensory history, suggesting a tight link between behaviour and PPC representations of stimulus history. Our results indicate that the PPC is a central component in the processing of sensory-stimulus history, and could enable further neurobiological investigation of long-standing questions regarding how perception and working memory are affected by prior sensory information.

Efficient inference for time-varying behavior during learning.

The process of learning new behaviors over time is a problem of great interest in both neuroscience and artificial intelligence. However, most standard analyses of animal training data either treat behavior as fixed or track only coarse performance statistics (e.g., accuracy, bias), providing limited insight into the evolution of the policies governing behavior. To overcome these limitations, we propose a dynamic psychophysical model that efficiently tracks trial-to-trial changes in behavior over the course of training. Our model consists of a dynamic logistic regression model, parametrized by a set of time-varying weights that express dependence on sensory stimuli as well as task-irrelevant covariates, such as stimulus, choice, and answer history. Our implementation scales to large behavioral datasets, allowing us to infer 500K parameters (e.g., 10 weights over 50K trials) in minutes on a desktop computer. We optimize hyperparameters governing how rapidly each weight evolves over time using the decoupled Laplace approximation, an efficient method for maximizing marginal likelihood in non-conjugate models. To illustrate performance, we apply our method to psychophysical data from both rats and human subjects learning a delayed sensory discrimination task. The model successfully tracks the psychophysical weights of rats over the course of training, capturing day-to-day and trial-to-trial fluctuations that underlie changes in performance, choice bias, and dependencies on task history. Finally, we investigate why rats frequently make mistakes on easy trials, and suggest that apparent lapses can be explained by sub-optimal weighting of known task covariates.

Fronto-parietal Cortical Circuits Encode Accumulated Evidence with a Diversity of Timescales.

Decision-making in dynamic environments often involves accumulation of evidence, in which new information is used to update beliefs and select future actions. Using in vivo cellular resolution imaging in voluntarily head-restrained rats, we examined the responses of neurons in frontal and parietal cortices during a pulse-based accumulation of evidence task. Neurons exhibited activity that predicted the animal's upcoming choice, previous choice, and graded responses that reflected the strength of the accumulated evidence. The pulsatile nature of the stimuli enabled characterization of the responses of neurons to a single quantum (pulse) of evidence. Across the population, individual neurons displayed extensive heterogeneity in the dynamics of responses to pulses. The diversity of responses was sufficiently rich to form a temporal basis for accumulated evidence estimated from a latent variable model. These results suggest that heterogeneous, often transient sensory responses distributed across the fronto-parietal cortex may support working memory on behavioral timescales. VIDEO ABSTRACT.