Different methods of 3D QRS area calculation from vectorcardiographic X, Y, and Z Leads.

3DQRSarea is a strong marker for cardiac resynchronization therapy and can be obtained by taking the (i) summation or the (ii) difference of the areas subtended by positive and negative deflections in X, Y, Z vectorcardiographic electrocardiogram (ECG) leads. We correlated both methods with the instantaneous-absolute-3D-voltage-time-integral (VTIQRS-3D). 3DQRSarea consistently underestimated the VTIQRS -3D, but the summation method was a closer and more reliable approximation. The dissimilarity was less apparent in left bundle branch block (r2 summation .996 vs. difference .972) and biventricular paced ECGs (r2 .996 vs. .957) but was more apparent in normal ECGs (r2 .988 vs. .653).

The influence of cortical activity on perception depends on behavioral state and sensory context.

The mechanistic link between neural circuit activity and behavior remains unclear. While manipulating cortical activity can bias certain behaviors and elicit artificial percepts, some tasks can still be solved when cortex is silenced or removed. Here, mice were trained to perform a visual detection task during which we selectively targeted groups of visually responsive and co-tuned neurons in L2/3 of primary visual cortex (V1) for two-photon photostimulation. The influence of photostimulation was conditional on two key factors: the behavioral state of the animal and the contrast of the visual stimulus. The detection of low-contrast stimuli was enhanced by photostimulation, while the detection of high-contrast stimuli was suppressed, but crucially, only when mice were highly engaged in the task. When mice were less engaged, our manipulations of cortical activity had no effect on behavior. The behavioral changes were linked to specific changes in neuronal activity. The responses of non-photostimulated neurons in the local network were also conditional on two factors: their functional similarity to the photostimulated neurons and the contrast of the visual stimulus. Functionally similar neurons were increasingly suppressed by photostimulation with increasing visual stimulus contrast, correlating with the change in behavior. Our results show that the influence of cortical activity on perception is not fixed, but dynamically and contextually modulated by behavioral state, ongoing activity and the routing of information through specific circuits.

Synaptic wiring motifs in posterior parietal cortex support decision-making.

The posterior parietal cortex exhibits choice-selective activity during perceptual decision-making tasks1-10. However, it is not known how this selective activity arises from the underlying synaptic connectivity. Here we combined virtual-reality behaviour, two-photon calcium imaging, high-throughput electron microscopy and circuit modelling to analyse how synaptic connectivity between neurons in the posterior parietal cortex relates to their selective activity. We found that excitatory pyramidal neurons preferentially target inhibitory interneurons with the same selectivity. In turn, inhibitory interneurons preferentially target pyramidal neurons with opposite selectivity, forming an opponent inhibition motif. This motif was present even between neurons with activity peaks in different task epochs. We developed neural-circuit models of the computations performed by these motifs, and found that opponent inhibition between neural populations with opposite selectivity amplifies selective inputs, thereby improving the encoding of trial-type information. The models also predict that opponent inhibition between neurons with activity peaks in different task epochs contributes to creating choice-specific sequential activity. These results provide evidence for how synaptic connectivity in cortical circuits supports a learned decision-making task.

Burnout in early year medical students: experiences, drivers and the perceived value of a reflection-based intervention.

INTRODUCTION: According to the 11th Revision of the International Classification of Diseases, burnout is defined as a syndrome resulting from chronic work-related stress that has not been successfully managed. Burnout is increasingly prevalent amongst medical students and has been shown to lead to worsened academic engagement, feelings of inadequacy, poor mental health and increased risk of withdrawal from the course. The aim of this study was to explore the experience of burnout amongst early year medical students and evaluate the perceived impact of a reflection-based intervention on their awareness and experience of burnout. METHODS: The reflection-based intervention comprised two tutorials covering the presentation, drivers, impact and management strategies for burnout syndrome. These were introduced into the second-year medical curriculum at Imperial College London. As part of the reflection-based intervention, students were invited to complete an anonymous Qualtrics form three times during the academic year. This included the Shirom-Melamed Burnout Measure (SMBM) and a free-text question prompting the student to consider their stressors at the time of completing the intervention. The former is composed of 14-questions measuring the extent of feelings or behaviours suggestive of burnout, divided into three categories: physical fatigue, cognitive weariness and emotional exhaustion. At the end of the academic year, students were invited to participate in an online focus group to further explore their experience of burnout and their perceived value of the reflection-based intervention. Results of the SMBM were explored descriptively; free-text questions and the focus group transcript were analysed using inductive thematic analysis. RESULTS: A total of 59 submissions for the reflection-based intervention were analysed: 26 students participated and consented in the first round, 8 in the second and 25 in the third round. Overall median burnout scores were 4 (IQR 3-5), 2 (IQR 1-4) and 3 (IQR 2-5) in each round of the SMBM, respectively. A total of 8 (30.8%) met the threshold for severe burnout (≥ 4.4) in round 1 of the questionnaire, zero in the second round and 4 (16%) in the third round. Physical and cognitive fatigue showed higher median scores than emotional exhaustion in every round. Four students participated in the focus group, which had two sections. The first was reflecting on burnout in medical school and the intervention, which revealed four themes: (1) indicators of burnout (often insidious, but may involve lack of energy and motivation, or changes in perceived personality); (2) perceived drivers of burnout (perceived expectation that medical school is supposed to be challenging and consistent prioritisation of work over wellbeing); (3) working habits of medical students (unachievable self-expectations and feelings of guilt when not working); (4) value of the intervention (the teaching and reflection-based intervention prompted students to identify signs of burnout in themselves and consider management strategies). The second section included considerations for implementing burnout interventions into the medical school curriculum, which revealed three themes: (1) desire to learn about burnout (students hoped to gain insight into burnout and methods of prevention as part of their curriculum); (2) importance of community (group interventions and the involvement of Faculty helped students feel less isolated in their experiences); (3) feasibility of interventions (sustainable interventions are likely to be those that are efficient, such as using multiple-choice questions, and with allocated periods in their timetable). CONCLUSION: Second-year medical students demonstrated symptoms and signs of burnout, including exhaustion, lack of motivation and changes in personality. They also expressed a desire to gain greater awareness of burnout and insight into preventative strategies within the medical curriculum. Whilst certain drivers of burnout can be prevented by students themselves through adequate prevention strategies, many remain systemic issues which require curriculum-level change to be effectively addressed. The students found that the reflection-based intervention was effective at improving their perception of burnout and a convenient tool to use, which could be implemented more widely and continued longer-term throughout medical school.

Electrocardiographic Z-axis QRS-T voltage-time-integral in patients with typical right bundle branch block - Correlation with echocardiographic right ventricular size and function.

BACKGROUND: Right bundle branch block (RBBB) can be benign or associated with right ventricular (RV) functional and structural abnormalities. Our aim was to evaluate QRS-T voltage-time-integral (VTI) compared to QRS duration and lead V1 R' as markers for RV abnormalities. METHODS: We included adults with an ECG demonstrating RBBB and echocardiogram obtained within 3 months of each other, between 2010 and 2020. VTIQRS and VTIQRST were obtained for 12 standard ECG leads, reconstructed vectorcardiographic X, Y, Z leads and root-mean-squared (3D) ECG. Age, sex and BSA-adjusted linear regressions were used to assess associations of QRS duration, amplitudes, VTIs and lead V1 R' duration/VTI with echocardiographic tricuspid annular plane systolic excursion (TAPSE), RV tissue Doppler imaging S', basal and mid diameter, and systolic pressure (RVSP). RESULTS: Among 782 patients (33% women, age 71 ± 14 years) with RBBB, R' duration in lead V1 was modestly associated with RV S', RV diameters and RVSP (all p ≤ 0.03). QRS duration was more strongly associated with RV diameters (both p < 0.0001). AmplitudeQRS-Z was modestly correlated with all 5 RV echocardiographic variables (all p ≤ 0.02). VTIR'-V1 was more strongly associated with TAPSE, RV S' and RVSP (all p ≤ 0.0003). VTIQRS-Z and VTIQRST-Z were among the strongest correlates of the 5 RV variables (all p < 0.0001). VTIQRST-Z.√BSA cutoff of ≥62 µVsm had sensitivity 62.7% and specificity 65.7% for predicting ≥3 of 5 abnormal RV variables (AUC 0.66; men 0.71, women 0.60). CONCLUSION: In patients with RBBB, VTIQRST-Z is a stronger predictor of RV dysfunction and adverse remodeling than QRS duration and lead V1 R'.

Specialized structure of neural population codes in parietal cortex outputs.

Do cortical neurons that send axonal projections to the same target area form specialized population codes for transmitting information? We used calcium imaging in mouse posterior parietal cortex (PPC), retrograde labeling, and statistical multivariate models to address this question during a delayed match-to-sample task. We found that PPC broadcasts sensory, choice, and locomotion signals widely, but sensory information is enriched in the output to anterior cingulate cortex. Neurons projecting to the same area have elevated pairwise activity correlations. These correlations are structured as information-limiting and information-enhancing interaction networks that collectively enhance information levels. This network structure is unique to sub-populations projecting to the same target and strikingly absent in surrounding neural populations with unidentified projections. Furthermore, this structure is only present when mice make correct, but not incorrect, behavioral choices. Therefore, cortical neurons comprising an output pathway form uniquely structured population codes that enhance information transmission to guide accurate behavior.

A cell-type-specific error-correction signal in the posterior parietal cortex.

Neurons in the posterior parietal cortex contribute to the execution of goal-directed navigation1 and other decision-making tasks2-4. Although molecular studies have catalogued more than 50 cortical cell types5, it remains unclear what distinct functions they have in this area. Here we identified a molecularly defined subset of somatostatin (Sst) inhibitory neurons that, in the mouse posterior parietal cortex, carry a cell-type-specific error-correction signal for navigation. We obtained repeatable experimental access to these cells using an adeno-associated virus in which gene expression is driven by an enhancer that functions specifically in a subset of Sst cells6. We found that during goal-directed navigation in a virtual environment, this subset of Sst neurons activates in a synchronous pattern that is distinct from the activity of surrounding neurons, including other Sst neurons. Using in vivo two-photon photostimulation and ex vivo paired patch-clamp recordings, we show that nearby cells of this Sst subtype excite each other through gap junctions, revealing a self-excitation circuit motif that contributes to the synchronous activity of this cell type. These cells selectively activate as mice execute course corrections for deviations in their virtual heading during navigation towards a reward location, for both self-induced and experimentally induced deviations. We propose that this subtype of Sst neurons provides a self-reinforcing and cell-type-specific error-correction signal in the posterior parietal cortex that may help with the execution and learning of accurate goal-directed navigation trajectories.

The Tyr Phenomenon: A Hypocalcemic Response in High-Volume Treatment Responders to 177Lu-Prostate-Specific Membrane Antigen Therapy.

177Lu-prostate-specific membrane antigen (PSMA) is an effective treatment for metastatic castration-resistant prostate cancer. Rarer treatment-related adverse events have not yet been described. Methods: We present case reviews of 2 men with a marked hypocalcemic osteosclerotic response to 177Lu-PSMA-I&T therapy. A clinical dataset of 177Lu-PSMA-I&T therapy was evaluated to estimate the incidence and clinical association with hypocalcemia. Results: Forty-one of the 127 men (32%) had a serum calcium drop, and 6 (5%) developed clinical hypocalcemia during 177Lu-PSMA therapy. The baseline total tumor volume was significantly higher in those who developed hypocalcemia (median, 3,249 cm3 [interquartile range, 1,856-3,852] vs. 465 [interquartile range 135-1,172]; P = 0.002). The mean prostate-specific antigen response in those with hypocalcemia was 78% (SD, 24%). Conclusion: Hypocalcemia may occur in response to 177Lu-PSMA-I&T, particularly with both high-volume bone metastases and a significant prostate-specific antigen response, and may be severe, requiring corticosteroids. Further evaluation of 177Lu-PSMA-induced hypocalcemia is required to better understand mechanisms, optimal treatments, and repercussions from any subsequent osteosclerotic response.

Electrocardiographic prediction of left ventricular hypertrophy in women and men with left bundle branch block - Comparison of QRS duration, amplitude and voltage-time-integral.

BACKGROUND: Standard ECG criteria for left ventricular (LV) hypertrophy rely on QRS amplitudes. However, in the setting of left bundle branch block (LBBB), ECG correlates of LV hypertrophy are not well established. We sought to evaluate quantitative ECG predictors of LV hypertrophy in the presence of LBBB. METHODS: We included adult patients with typical LBBB having ECG and transthoracic echocardiogram performed within 3 months of each other in 2010-2020. Orthogonal X, Y, Z leads were reconstructed from digital 12­lead ECGs using Kors's matrix. In addition to QRS duration, we evaluated QRS amplitudes and voltage-time-integrals (VTIs) from all 12 leads, X, Y, Z leads and 3D (root-mean-squared) ECG. We used age, sex and BSA-adjusted linear regressions to predict echocardiographic LV calculations (mass, end-diastolic and end-systolic volumes, ejection fraction) from ECG, and separately generated ROC curves for predicting echocardiographic abnormalities. RESULTS: We included 413 patients (53% women, age 73 ± 12 years). All 4 echocardiographic LV calculations were most strongly correlated with QRS duration (all p < 0.00001). In women, QRS duration ≥ 150 ms had sensitivity/specificity 56.3%/64.4% for increased LV mass and 62.7%/67.8% for increased LV end-diastolic volume. In men, QRS duration ≥ 160 ms had a sensitivity/specificity 63.1%/72.1% for increased LV mass and 58.3%/74.5% for increased LV end-diastolic volume. QRS duration was best able to discriminate eccentric hypertrophy (area under ROC curve 0.701) and increased LV end-diastolic volume (0.681). CONCLUSIONS: In patients with LBBB, QRS duration (≥ 150 in women and ≥ 160 in men) is a superior predictor of LV remodeling esp. eccentric hypertrophy and dilation.

A distributed and efficient population code of mixed selectivity neurons for flexible navigation decisions.

Decision-making requires flexibility to rapidly switch one's actions in response to sensory stimuli depending on information stored in memory. We identified cortical areas and neural activity patterns underlying this flexibility during virtual navigation, where mice switched navigation toward or away from a visual cue depending on its match to a remembered cue. Optogenetics screening identified V1, posterior parietal cortex (PPC), and retrosplenial cortex (RSC) as necessary for accurate decisions. Calcium imaging revealed neurons that can mediate rapid navigation switches by encoding a mixture of a current and remembered visual cue. These mixed selectivity neurons emerged through task learning and predicted the mouse's choices by forming efficient population codes before correct, but not incorrect, choices. They were distributed across posterior cortex, even V1, and were densest in RSC and sparsest in PPC. We propose flexibility in navigation decisions arises from neurons that mix visual and memory information within a visual-parietal-retrosplenial network.

ArMo: An Articulated Mesh Approach for Mouse 3D Reconstruction.

Characterizing animal behavior requires methods to distill 3D movements from video data. Though keypoint tracking has emerged as a widely used solution to this problem, it only provides a limited view of pose, reducing the body of an animal to a sparse set of experimenter-defined points. To more completely capture 3D pose, recent studies have fit 3D mesh models to subjects in image and video data. However, despite the importance of mice as a model organism in neuroscience research, these methods have not been applied to the 3D reconstruction of mouse behavior. Here, we present ArMo, an articulated mesh model of the laboratory mouse, and demonstrate its application to multi-camera recordings of head-fixed mice running on a spherical treadmill. Using an end-to-end gradient based optimization procedure, we fit the shape and pose of a dense 3D mouse model to data-derived keypoint and point cloud observations. The resulting reconstructions capture the shape of the animal’s surface while compactly summarizing its movements as a time series of 3D skeletal joint angles. ArMo therefore provides a novel alternative to the sparse representations of pose more commonly used in neuroscience research.

Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium.

The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31-36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22%-50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organization identical to trimeric spike.

Mechanoreceptor signal convergence and transformation in the dorsal horn flexibly shape a diversity of outputs to the brain.

The encoding of touch in the spinal cord dorsal horn (DH) and its influence on tactile representations in the brain are poorly understood. Using a range of mechanical stimuli applied to the skin, large-scale in vivo electrophysiological recordings, and genetic manipulations, here we show that neurons in the mouse spinal cord DH receive convergent inputs from both low- and high-threshold mechanoreceptor subtypes and exhibit one of six functionally distinct mechanical response profiles. Genetic disruption of DH feedforward or feedback inhibitory motifs, comprised of interneurons with distinct mechanical response profiles, revealed an extensively interconnected DH network that enables dynamic, flexible tuning of postsynaptic dorsal column (PSDC) output neurons and dictates how neurons in the primary somatosensory cortex respond to touch. Thus, mechanoreceptor subtype convergence and non-linear transformations at the earliest stage of the somatosensory hierarchy shape how touch of the skin is represented in the brain.

ICOS is upregulated on T cells following radiation and agonism combined with radiation results in enhanced tumor control.

Multiple preclinical studies have shown improved outcomes when radiation therapy is combined with immune modulating antibodies. However, to date, many of these promising results have failed to translate to successful clinical studies. This led us to explore additional checkpoint and co-stimulatory pathways that may be regulated by radiation therapy. Here, we demonstrate that radiation increases the expression of inducible T cell co-stimulator (ICOS) on both CD4 and CD8 T cells in the blood following treatment. Moreover, when we combined a novel ICOS agonist antibody with radiation we observed durable cures across multiple tumor models and mouse strains. Depletion studies revealed that CD8 T cells were ultimately required for treatment efficacy, but CD4 T cells and NK cells also partially contributed to tumor control. Phenotypic analysis showed that the combination therapy diminished the increased infiltration of regulatory T cells into the tumor that typically occurs following radiation alone. Finally, we demonstrate in a poorly immunogenic pancreatic tumor model which is resistant to combined radiation and anti-PD1 checkpoint blockade that the addition of this novel ICOS agonist antibody to the treatment regimen results in tumor control. These findings identify ICOS as part of a T cell pathway that is modulated by radiation and targeting this pathway with a novel ICOS antibody results in durable tumor control in preclinical models.

Removal of redox-sensitive Rubisco Activase does not alter Rubisco regulation in soybean.

Rubisco activase (Rca) facilitates the catalytic repair of Rubisco, the CO2-fixing enzyme of photosynthesis, following periods of darkness, low to high light transitions or stress. Removal of the redox-regulated isoform of Rubisco activase, Rca-α, enhances photosynthetic induction in Arabidopsis and has been suggested as a strategy for the improvement of crops, which may experience frequent light transitions in the field; however, this has never been tested in a crop species. Therefore, we used RNAi to reduce the Rca-α content of soybean (Glycine max cv. Williams 82) below detectable levels and then characterized the growth, photosynthesis, and Rubisco activity of the resulting transgenics, in both growth chamber and field conditions. Under a 16 h sine wave photoperiod, the reduction of Rca-α contents had no impact on morphological characteristics, leaf expansion rate, or total biomass. Photosynthetic induction rates were unaltered in both chamber-grown and field-grown plants. Plants with reduced Rca-α content maintained the ability to regulate Rubisco activity in low light just as in control plants. This result suggests that in soybean, Rca-α is not as centrally involved in the regulation of Rca oligomer activity as it is in Arabidopsis. The isoform stoichiometry supports this conclusion, as Rca-α comprises only ~ 10% of the Rubisco activase content of soybean, compared to ~ 50% in Arabidopsis. This is likely to hold true in other species that contain a low ratio of Rca-α to Rca-ß isoforms.

Fos ensembles encode and shape stable spatial maps in the hippocampus.

In the hippocampus, spatial maps are formed by place cells while contextual memories are thought to be encoded as engrams1-6. Engrams are typically identified by expression of the immediate early gene Fos, but little is known about the neural activity patterns that drive, and are shaped by, Fos expression in behaving animals7-10. Thus, it is unclear whether Fos-expressing hippocampal neurons also encode spatial maps and whether Fos expression correlates with and affects specific features of the place code11. Here we measured the activity of CA1 neurons with calcium imaging while monitoring Fos induction in mice performing a hippocampus-dependent spatial learning task in virtual reality. We find that neurons with high Fos induction form ensembles of cells with highly correlated activity, exhibit reliable place fields that evenly tile the environment and have more stable tuning across days than nearby non-Fos-induced cells. Comparing neighbouring cells with and without Fos function using a sparse genetic loss-of-function approach, we find that neurons with disrupted Fos function have less reliable activity, decreased spatial selectivity and lower across-day stability. Our results demonstrate that Fos-induced cells contribute to hippocampal place codes by encoding accurate, stable and spatially uniform maps and that Fos itself has a causal role in shaping these place codes. Fos ensembles may therefore link two key aspects of hippocampal function: engrams for contextual memories and place codes that underlie cognitive maps.

Representational drift: Emerging theories for continual learning and experimental future directions.

Recent work has revealed that the neural activity patterns correlated with sensation, cognition, and action often are not stable and instead undergo large scale changes over days and weeks-a phenomenon called representational drift. Here, we highlight recent observations of drift, how drift is unlikely to be explained by experimental confounds, and how the brain can likely compensate for drift to allow stable computation. We propose that drift might have important roles in neural computation to allow continual learning, both for separating and relating memories that occur at distinct times. Finally, we present an outlook on future experimental directions that are needed to further characterize drift and to test emerging theories for drift's role in computation.

Teaching and learning lifestyle medicine during COVID-19: how has living during a pandemic influenced students' understanding and attitudes to self-care and population health? A qualitative analysis.

BACKGROUND: In 2019 a new Lifestyle Medicine (LM) module was introduced to the undergraduate medical curriculum at Imperial College London. Lifestyle Medicine is an emergent discipline which aims to tackle the increasing burden of non-communicable disease. Previous work has suggested that students value clinical teaching over traditional Public Health topics. Taking a constructivist view of learning, this paper assesses changes in medical students' attitudes towards Public Health and LM in response to living through a pandemic. We then make suggestions as to how this lived experience might be useful in teaching LM, and discuss the interaction between teaching, behaviour, and experience with consideration of self-determination theories in learning. METHODS: First-year medical students were surveyed at the end of their first year of teaching and asked if living during the COVID-19 pandemic had changed the value they place on LM and if so, how. Thematic analysis was conducted on responses representing 71% (n = 216) of the year group. RESULTS: Four themes were defined in the data: acknowledging importance; impact on behaviour; health inequalities and the wider determinants; and promoting Public Health and prevention. These themes highlight the distinct levels through which the pandemic has had an impact: from personal behaviour to population health. CONCLUSIONS: This is the first study to look at the impact of living through a pandemic on attitudes to LM. Our results suggest that the pandemic has led to increased reflection on health behaviours. The lived-experience of COVID-19 may facilitate a better understanding of health inequalities and their impact, alongside the opportunities presented by effective LM interventions.

Shared and specialized coding across posterior cortical areas for dynamic navigation decisions.

Animals adaptively integrate sensation, planning, and action to navigate toward goal locations in ever-changing environments, but the functional organization of cortex supporting these processes remains unclear. We characterized encoding in approximately 90,000 neurons across the mouse posterior cortex during a virtual navigation task with rule switching. The encoding of task and behavioral variables was highly distributed across cortical areas but differed in magnitude, resulting in three spatial gradients for visual cue, spatial position plus dynamics of choice formation, and locomotion, with peaks respectively in visual, retrosplenial, and parietal cortices. Surprisingly, the conjunctive encoding of these variables in single neurons was similar throughout the posterior cortex, creating high-dimensional representations in all areas instead of revealing computations specialized for each area. We propose that, for guiding navigation decisions, the posterior cortex operates in parallel rather than hierarchically, and collectively generates a state representation of the behavior and environment, with each area specialized in handling distinct information modalities.

The structures and functions of correlations in neural population codes.

The collective activity of a population of neurons, beyond the properties of individual cells, is crucial for many brain functions. A fundamental question is how activity correlations between neurons affect how neural populations process information. Over the past 30 years, major progress has been made on how the levels and structures of correlations shape the encoding of information in population codes. Correlations influence population coding through the organization of pairwise-activity correlations with respect to the similarity of tuning of individual neurons, by their stimulus modulation and by the presence of higher-order correlations. Recent work has shown that correlations also profoundly shape other important functions performed by neural populations, including generating codes across multiple timescales and facilitating information transmission to, and readout by, downstream brain areas to guide behaviour. Here, we review this recent work and discuss how the structures of correlations can have opposite effects on the different functions of neural populations, thus creating trade-offs and constraints for the structure-function relationships of population codes. Further, we present ideas on how to combine large-scale simultaneous recordings of neural populations, computational models, analyses of behaviour, optogenetics and anatomy to unravel how the structures of correlations might be optimized to serve multiple functions.