Significance It is widely recognized that studying the detailed anatomy of the human brain is of great importance for neuroscience and medicine. The principal means for achieving this goal is ...presently diffusion magnetic resonance imaging (dMRI) tractography, which uses the local diffusion of water throughout the brain to estimate the course of long-range anatomical projections. Such projections connect gray matter regions through axons that travel in the deep white matter. The present study combines dMRI tractography with histological analysis to investigate where in the brain this method succeeds and fails. We conclude that certain superficial white matter systems pose challenges for measuring cortical connections that must be overcome for accurate determination of detailed neuroanatomy in humans.
In vivo tractography based on diffusion magnetic resonance imaging (dMRI) has opened new doors to study structure–function relationships in the human brain. Initially developed to map the trajectory of major white matter tracts, dMRI is used increasingly to infer long-range anatomical connections of the cortex. Because axonal projections originate and terminate in the gray matter but travel mainly through the deep white matter, the success of tractography hinges on the capacity to follow fibers across this transition. Here we demonstrate that the complex arrangement of white matter fibers residing just under the cortical sheet poses severe challenges for long-range tractography over roughly half of the brain. We investigate this issue by comparing dMRI from very-high-resolution ex vivo macaque brain specimens with histological analysis of the same tissue. Using probabilistic tracking from pure gray and white matter seeds, we found that ∼50% of the cortical surface was effectively inaccessible for long-range diffusion tracking because of dense white matter zones just beneath the infragranular layers of the cortex. Analysis of the corresponding myelin-stained sections revealed that these zones colocalized with dense and uniform sheets of axons running mostly parallel to the cortical surface, most often in sulcal regions but also in many gyral crowns. Tracer injection into the sulcal cortex demonstrated that at least some axonal fibers pass directly through these fiber systems. Current and future high-resolution dMRI studies of the human brain will need to develop methods to overcome the challenges posed by superficial white matter systems to determine long-range anatomical connections accurately.
Advantageous foraging choices benefit from an estimation of two aspects of a resource’s value: its current desirability and availability. Both orbitofrontal and ventrolateral prefrontal areas ...contribute to updating these valuations, but their precise roles remain unclear. To explore their specializations, we trained macaque monkeys on two tasks: one required updating representations of a predicted outcome’s desirability, as adjusted by selective satiation, and the other required updating representations of an outcome’s availability, as indexed by its probability. We evaluated performance on both tasks in three groups of monkeys: unoperated controls and those with selective, fiber-sparing lesions of either the OFC or VLPFC. Representations that depend on the VLPFC but not the OFC play a necessary role in choices based on outcome availability; in contrast, representations that depend on the OFC but not the VLPFC play a necessary role in choices based on outcome desirability.
•The VLPFC is necessary for updating stimulus-outcome probability estimates•The OFC is necessary for updating stimulus-outcome values based on current needs•The VLPFC is necessary for both contingent and noncontingent learning
Rudebeck et al. show that the orbitofrontal cortex (OFC) and ventrolateral prefrontal cortex (VLPFC) make dissociable contributions to decision-making. The VLPFC, but not the OFC, is critical for updating stimulus-outcome availability, whereas the OFC, but not the VLPFC, is vital for updating stimulus-outcome desirability.
Purpose
Polypharmacy—the use of multiple medications by a single patient—is an important issue associated with various adverse clinical outcomes and rising costs. It is also a topic rarely addressed ...by clinical guidelines. We used routine Scottish health records to address the lack of data on the prevalence of polypharmacy in the broader, adult primary care population, particularly in relation to long-term conditions.
Methods
We conducted a cross-sectional analysis of adult electronic primary healthcare records and used linear regression models to examine the association between the number of medicines prescribed regularly and both multimorbidity and specific clinical conditions, adjusting for age, gender and socioeconomic deprivation.
Results
Overall, 16.9 % of the adults assessed were receiving four to nine medications, and 4.6 % were receiving ten or more medications, increasing with age (28.6 and 7.4 %, respectively, in those aged 60–69 years; 51.8 and 18.6 %, respectively, in those aged ≥80 years), but relatively unaffected by gender or deprivation. Of those patients with two clinical conditions, 20.8 % were receiving four to nine medications, and 1.1 % were receiving ten or more medications; in those patients with six or more comorbidities, these values were 47.7 and 41.7 %, respectively. The number of medications varied considerably between clinical conditions, with cardiovascular conditions associated with the greatest number of additional medications. The accumulation of additional medicines was less with concordant conditions.
Conclusions
Polypharmacy is common in UK primary care. The main factor associated with this is multimorbidity, although considerable variation exists between different conditions. The impact of clinical conditions on the number of medicines is generally less in the presence of co-existing concordant conditions.
We present an investigation of the optical spectra of 264 low-redshift (z < 0.2) Type Ia supernovae (SNe Ia) discovered by the Palomar Transient Factory, an untargeted transient survey. We focus on ...velocity and pseudo-equivalent width measurements of the Si ii 4130, 5972, and 6355 Å lines, as well those of the Ca ii near-infrared (NIR) triplet, up to +5 days relative to the SN B-band maximum light. We find that a high-velocity component of the Ca ii NIR triplet is needed to explain the spectrum in ∼95 per cent of SNe Ia observed before −5 days, decreasing to ∼80 per cent at maximum. The average velocity of the Ca ii high-velocity component is ∼8500 km s−1 higher than the photospheric component. We confirm previous results that SNe Ia around maximum light with a larger contribution from the high-velocity component relative to the photospheric component in their Ca ii NIR feature have, on average, broader light curves and lower Ca ii NIR photospheric velocities. We find that these relations are driven by both a stronger high-velocity component and a weaker contribution from the photospheric Ca ii NIR component in broader light curve SNe Ia. We identify the presence of C ii in very-early-time SN Ia spectra (before −10 days), finding that >40 per cent of SNe Ia observed at these phases show signs of unburnt material in their spectra, and that C ii features are more likely to be found in SNe Ia having narrower light curves.
To study how the interaction between orbitofrontal (OFC) and rhinal (Rh) cortices influences the judgment of reward size, we reversibly disconnected these regions using hM4Di-DREADD (designer ...receptor exclusively activated by designer drug). Repeated inactivation reduced sensitivity to differences in reward size in two monkeys. These results suggest that retrieval of relative stimulus values from memory depends on the interaction between Rh and OFC.
Two ideas have dominated neuropsychology concerning the orbitofrontal cortex (OFC). One holds that OFC regulates emotion and enhances behavioral flexibility through inhibitory control. The other ...ascribes to OFC a role in updating valuations on the basis of current motivational states. Neuroimaging, neurophysiological and clinical observations are consistent with either or both hypotheses. Although these hypotheses are compatible in principle, we present results supporting the latter view of OFC function and arguing against the former. We found that excitotoxic, fiber-sparing lesions confined to OFC in monkeys did not alter either behavioral flexibility, as measured by object reversal learning, or emotion regulation, as assessed by fear of snakes. A follow-up experiment indicated that a previously reported loss of inhibitory control resulted from damage to nearby fiber tracts and not from OFC dysfunction. Thus, OFC has a more specialized role in reward-guided behavior and emotion than has been thought, a function that includes value updating.
Opioid use disorder (OUD) is associated with substantial morbidity and mortality for women, especially during the perinatal period. Opioid overdose has become a significant cause of maternal death in ...the United States, with rates highest in the immediate postpartum year. While pregnancy is a time of high motivation for healthcare engagement, unique challenges exist for pregnant women with OUD seeking both substance use treatment and maternity care, including managing change after birth. How women successfully navigate these barriers, engage in treatment, and abstain from substance use during pregnancy and postpartum is poorly understood. The aim of this study is to explore the experiences of postpartum women with OUD who successfully engaged in both substance use treatment and maternity care during pregnancy, to understand factors contributing to their ability to access care and social support.
We conducted semi-structured, in-depth interviews with postpartum women in sustained recovery (n = 10) engaged in a substance use treatment program in northern New England. Interviews were analyzed using grounded theory methodology.
Despite multiple barriers, women identified pregnancy as a change point from which they were able to develop self-efficacy and exercise agency in seeking care. A shift in internal motivation enabled women to disclose need for OUD treatment to maternity care providers, a profoundly significant moment. Concurrently, women developed a new capacity for self-care, demonstrated through managing relationships with providers and family members, and overcoming logistical challenges which had previously seemed overwhelming. This transformation was also expressed in making decisions based on pregnancy risk, engaging with and caring for others, and providing peer support. Women developed resilience through the interaction of inner motivation and their ability to positively utilize or transform external factors.
Complex interactions occurred between individual-level changes in treatment motivation due to pregnancy, emerging self-efficacy in accessing resources, and engagement with clinicians and peers. This transformative process was identified by women as a key factor in entering recovery during pregnancy and sustaining it postpartum. Clinicians and policymakers should target the provision of services which promote resilience in pregnant women with OUD.
Understanding the neural code requires understanding how populations of neurons code information. Theoretical models predict that information may be limited by correlated noise in large neural ...populations. Nevertheless, analyses based on tens of neurons have failed to find evidence of saturation. Moreover, some studies have shown that noise correlations can be very small, and therefore may not affect information coding. To determine whether information-limiting correlations exist, we implanted eight Utah arrays in prefrontal cortex (PFC; area 46) of two male macaque monkeys, recording >500 neurons simultaneously. We estimated information in PFC about saccades as a function of ensemble size. Noise correlations were, on average, small (∼10
). However, information scaled strongly sublinearly with ensemble size. After shuffling trials, destroying noise correlations, information was a linear function of ensemble size. Thus, we provide evidence for the existence of information-limiting noise correlations in large populations of PFC neurons.
Recent theoretical work has shown that even small correlations can limit information if they are "differential correlations," which are difficult to measure directly. However, they can be detected through decoding analyses on recordings from a large number of neurons over a large number of trials. We have achieved both by collecting neural activity in dorsal-lateral prefrontal cortex of macaques using eight microelectrode arrays (768 electrodes), from which we were able to compute accurate information estimates. We show, for the first time, strong evidence for information-limiting correlations. Despite pairwise correlations being small (on the order of 10
), they affect information coding in populations on the order of 100 s of neurons.
Learning leads to changes in population patterns of neural activity. In this study we wanted to examine how these changes in patterns of activity affect the dimensionality of neural responses and ...information about choices. We addressed these questions by carrying out high channel count recordings in dorsal-lateral prefrontal cortex (dlPFC; 768 electrodes) while monkeys performed a two-armed bandit reinforcement learning task. The high channel count recordings allowed us to study population coding while monkeys learned choices between actions or objects. We found that the dimensionality of neural population activity was higher across blocks in which animals learned the values of novel pairs of objects, than across blocks in which they learned the values of actions. The increase in dimensionality with learning in object blocks was related to less shared information across blocks, and therefore patterns of neural activity that were less similar, when compared to learning in action blocks. Furthermore, these differences emerged with learning, and were not a simple function of the choice of a visual image or action. Therefore, learning the values of novel objects increases the dimensionality of neural representations in dlPFC.
The search for therapeutic agents that bind specifically to precursor protein conformations and inhibit amyloid assembly is an important challenge. Identifying such inhibitors is difficult because ...many protein precursors of aggregation are partially folded or intrinsically disordered, which rules out structure-based design. Furthermore, inhibitors can act by a variety of mechanisms, including specific or nonspecific binding, as well as colloidal inhibition. Here we report a high-throughput method based on ion mobility spectrometry-mass spectrometry (IMS-MS) that is capable of rapidly detecting small molecules that bind to amyloid precursors, identifying the interacting protein species and defining the mode of inhibition. Using this method we have classified a variety of small molecules that are potential inhibitors of human islet amyloid polypeptide (hIAPP) aggregation or amyloid-beta 1-40 aggregation as specific, nonspecific, colloidal or non-interacting. We also demonstrate the ability of IMS-MS to screen for inhibitory small molecules in a 96-well plate format and use this to discover a new inhibitor of hIAPP amyloid assembly.
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