Cortical and Hippocampal Correlates of Deliberation during Model-Based Decisions for Rewards in Humans

How do we use our memories of the past to guide decisions we''ve never had to make before? Although extensive work describes how the brain learns to repeat rewarded actions, decisions can also be influenced by associations between stimuli or events not directly involving reward — such as when planning routes using a cognitive map or chess moves using predicted countermoves — and these sorts of associations are critical when deciding among novel options. This process is known as model-based decision making. While the learning of environmental relations that might support model-based decisions is well studied, and separately this sort of information has been inferred to impact decisions, there is little evidence concerning the full cycle by which such associations are acquired and drive choices. Of particular interest is whether decisions are directly supported by the same mnemonic systems characterized for relational learning more generally, or instead rely on other, specialized representations. Here, building on our previous work, which isolated dual representations underlying sequential predictive learning, we directly demonstrate that one such representation, encoded by the hippocampal memory system and adjacent cortical structures, supports goal-directed decisions. Using interleaved learning and decision tasks, we monitor predictive learning directly and also trace its influence on decisions for reward. We quantitatively compare the learning processes underlying multiple behavioral and fMRI observables using computational model fits. Across both tasks, a quantitatively consistent learning process explains reaction times, choices, and both expectation- and surprise-related neural activity. The same hippocampal and ventral stream regions engaged in anticipating stimuli during learning are also engaged in proportion to the difficulty of decisions. These results support a role for predictive associations learned by the hippocampal memory system to be recalled during choice formation.     

Effects of Methamphetamine Administration on Information Gathering during Probabilistic Reasoning in Healthy Humans

Jumping to conclusions (JTC) during probabilistic reasoning is a cognitive bias repeatedly demonstrated in people with schizophrenia and shown to be associated with delusions. Little is known about the neurochemical basis of probabilistic reasoning. We tested the hypothesis that catecholamines influence data gathering and probabilistic reasoning by administering intravenous methamphetamine, which is known to cause synaptic release of the catecholamines noradrenaline and dopamine, to healthy humans whilst they undertook a probabilistic inference task. Our study used a randomised, double-blind, cross-over design. Seventeen healthy volunteers on three visits were administered either placebo or methamphetamine or methamphetamine preceded by amisulpride. In all three conditions participants performed the “beads” task in which participants decide how much information to gather before making a probabilistic inference, and which measures the cognitive bias towards jumping to conclusions. Psychotic symptoms triggered by methamphetamine were assessed using Comprehensive Assessment of At-Risk Mental States (CAARMS). Methamphetamine induced mild psychotic symptoms, but there was no effect of drug administration on the number of draws to decision (DTD) on the beads task. DTD was a stable trait that was highly correlated within subjects across visits (intra-class correlation coefficients of 0.86 and 0.91 on two versions of the task). The less information was sampled in the placebo condition, the more psychotic-like symptoms the person had after the methamphetamine plus amisulpride condition (p = 0.028). Our results suggest that information gathering during probabilistic reasoning is a stable trait, not easily modified by dopaminergic or noradrenergic modulation.     

Transcranial Direct Current Stimulation of Right Dorsolateral Prefrontal Cortex Does Not Affect Model-Based or Model-Free Reinforcement Learning in Humans

There is broad consensus that the prefrontal cortex supports goal-directed, model-based decision-making. Consistent with this, we have recently shown that model-based control can be impaired through transcranial magnetic stimulation of right dorsolateral prefrontal cortex in humans. We hypothesized that an enhancement of model-based control might be achieved by anodal transcranial direct current stimulation of the same region. We tested 22 healthy adult human participants in a within-subject, double-blind design in which participants were given Active or Sham stimulation over two sessions. We show Active stimulation had no effect on model-based control or on model-free (‘habitual’) control compared to Sham stimulation. These null effects are substantiated by a power analysis, which suggests that our study had at least 60% power to detect a true effect, and by a Bayesian model comparison, which favors a model of the data that assumes stimulation had no effect over models that assume stimulation had an effect on behavioral control. Although we cannot entirely exclude more trivial explanations for our null effect, for example related to (faults in) our experimental setup, these data suggest that anodal transcranial direct current stimulation over right dorsolateral prefrontal cortex does not improve model-based control, despite existing evidence that transcranial magnetic stimulation can disrupt such control in the same brain region.     

Superposition of Automatic and Voluntary Aspects of Grip Force Control in Humans during Object Manipulation

When moving grasped objects, people automatically modulate grip force (GF) with movement-dependent load force (LF) in order to prevent object slip. However, GF can also be modulated voluntarily as when squeezing an object. Here we investigated possible interactions between automatic and voluntary GF control. Participants were asked to generate horizontal cyclic movements (between 0.6 and 2.0 Hz) of a hand-held object that was restrained by an elastic band such that the load force (LF) reached a peak once per movement cycle, and to simultaneously squeeze the object at each movement reversal (i.e., twice per cycle). Participants also performed two control tasks in which they either only moved (between 0.6 and 2.0 Hz) or squeezed (between 1.2 and 4.0 Hz) the object. The extent to which GF modulation in the simultaneous task could be predicted from the two control tasks was assessed using power spectral analyses. At all frequencies, the GF power spectra from the simultaneous task exhibited two prominent components that occurred at the cycle frequency (ƒ) and at twice this frequency (2ƒ), whereas the spectra from the movement and squeeze control task exhibited only single peaks at ƒ and 2ƒ, respectively. At lower frequencies, the magnitudes of both frequency components in the simultaneous task were similar to the magnitudes of the corresponding components in the control tasks. However, as frequency increased, the magnitudes of both components in the simultaneous task were greater than the magnitudes of the corresponding control task components. Moreover, the phase relationship between the ƒ components of GF and LF began to drift from the value observed in the movement control task. Overall these results suggest that, at lower movement frequencies, voluntary and automatic GF control processes operate at different hierarchical levels. Several mechanisms are discussed to account for interaction effects observed at higher movement frequencies.     

Tissue Metallothionein Concentrations in Mice and Humans with Hyperglycemia

Besides participating in tissue zinc homeostasis and protecting against heavy metal toxicities, metallothionein (MT) is known as an antioxidant. Increased MT activity can ameliorate diabetic hyperglycemia, and subjects with less MT synthesis are more prone to diabetic complications. However, whether tissue MT status is varied in the subjects with diabetes mellitus remains unclear. This study was undertaken to measure tissue MT levels in laboratory mice (serum, liver, and epididymal adipose tissue) and humans (serum) with hyperglycemia. Tissue MT levels were measured by enzyme-linked immunosorbent assay. The results showed that MT status in serum and adipose tissue did not markedly differ between the subjects with and without hyperglycemia. In addition, streptozotocin- and high-fat-diet-induced hyperglycemic mice had higher while ob/ob mice had lower liver MT levels than that of normal control mice. Furthermore, serum MT levels tended to correlate with glycemia values in mice. The results of this study indicate that serum MT value does not differ in subjects with hyperglycemia and cannot be used as an index to evaluate the susceptibility or progress of diabetes mellitus.     

Adult Neurogenesis in Humans

Adult neurogenesis appears very well conserved among mammals. It was, however, not until recently that quantitative data on the extent of this process became available in humans, largely because of methodological challenges to study this process in man. There is substantial hippocampal neurogenesis in adult humans, but humans appear unique among mammals in that there is no detectable olfactory bulb neurogenesis but continuous addition of new neurons in the striatum.There has been an enormous expansion in the knowledge regarding adult neurogenesis in experimental animals over the last two decades. A strong motivation in this research field has been that similar processes are likely to operate in humans, and that alterations in adult neurogenesis could underlie neurological or psychiatric diseases. Moreover, many have hoped that the potential of resident neural stem cells could be harnessed to promote the generation of new neurons for cell replacement in neurological diseases. A seminal study by Eriksson, Gage and colleagues (Eriksson et al. 1998), in which they were able to show the presence of 5-bromo-2-deoxyuridine (BrdU) in hippocampal neurons of cancer patients who had received the label for diagnostic purposes, established the presence of adult-born neurons in the human hippocampus. This study was exceptionally important in that it provided strong evidence for the presence of adult neurogenesis in humans. However, it did not enable any quantitative estimates, and a lingering question has been whether adult neurogenesis decreased with primate evolution, and whether the extent of this process in humans is sufficient to have any functional impact (Rakic 1985; Kempermann 2012).     

Cardiorespiratory Synchronism in Humans

Cardiorespiratory synchronism manifests itself (generally at respiratory rates higher than the corresponding baseline heart rates) when the heart adjusts itself to the respiratory rhythm and eventually beats at rate equal to the rate of respiration. Its characteristic parameters are the width of the synchronization range, the time needed for its development (measured from the onset of tachypnea), and the difference between the baseline heart rate and the lower and upper limits of the synchronization range. These parameters were determined for 5- to 65-year-old subjects.     

Reasoning in bioethics

It is striking that some arguments in the bioethical literature seem implausible, counterintuitive, and even ridiculous when reported to competent moral agents. When examined, these arguments bear uncanny resemblances to the discourse of patients with debilitating mental disorders. I examine the kinds of irrationality involved, and discuss the fact that such irrationality is worrying in a discipline that purports to serve as a guide for real-life practical reasoning. I offer some thoughts about correctives that we might use to temper some of the odd opinions that bedevil our subject in the name of ethical analysis. It seems that one ought to be suspicious of neatly rational arguments that produce counterintuitive conclusions, but the alternative seems to be that we explore new constructions of old problems in Bioethics such that our discussion of them does justice to what we regard as of fundamental significance to our lives together as human beings.     

Cholesterol from Degenerating Nerve Myelin Becomes Associated with Lipoproteins Containing Apolipoprotein E

Apolipoprotein E is synthesized and secreted by rat sciatic nerve consequent to several types of injury. It has been proposed that endoneurial apolipoprotein E, in analogy to its role in systemic cholesterol transport, is involved in the salvage and reutilization of myelin cholesterol during degeneration and regeneration. To test this hypothesis, nerve lipids were prelabeled via intraneural injection of [3H]acetate. Four weeks later the nerves were crushed. From 1 to 12 weeks later, crushed nerves were examined for extracellular lipoprotein-bound cholesterol label. By 2 weeks after injury, 10% of the endoneurial lipid label was in a soluble form that was releasable into incubation medium. This released fraction was enriched in labeled cholesterol, and its labeled lipid composition was constant, in contrast to the changing distribution of label in the nerve with time after injury. On a KBr gradient, the released lipid label cofractionated with the released apolipoprotein E at densities similar to that of lipoproteins. These data indicate that at least some myelin cholesterol in injured nerve becomes associated with apolipoprotein E-containing lipoproteins and thus is available for reutilization via the hypothesized model.     

Muscle Carnosine Is Associated with Cardiometabolic Risk Factors in Humans

BackgroundCarnosine is a naturally present dipeptide abundant in skeletal muscle and an over-the counter food additive. Animal data suggest a role of carnosine supplementation in the prevention and treatment of obesity, insulin resistance, type 2 diabetes and cardiovascular disease but only limited human data exists.ConclusionOur data shows that higher carnosine content in human skeletal muscle is positively associated with insulin resistance and fasting metabolic preference for glucose. Moreover, it is negatively associated with HDL-cholesterol and basal energy expenditure. Intervention studies targeting insulin resistance, metabolic and cardiovascular disease risk factors are necessary to evaluate its putative role in the prevention and management of type 2 diabetes and cardiovascular disease.     

Hypocretin Deficiency in Narcoleptic Humans Is Associated with Abdominal Obesity

Objective: To determine the prevalence of obesity among patients with narcolepsy, to estimate associated long‐term health risks on the basis of waist circumference, and to distinguish the impact of hypocretin deficiency from that of increased daytime sleepiness (i.e., reduced physical activity) on these anthropometric measures. Research Methods and Procedures: A cross‐sectional, case‐control study was conducted. Patients with narcolepsy (n = 138) or idiopathic hypersomnia (IH) (n = 33) were included. Age‐matched, healthy members of the Dutch population (Monitoring Project on Risk Factors for Chronic Diseases and Doetinchem Project; n = 10, 526) were used as controls. BMI and waist circumference were determined. Results: Obesity (BMI ≥ 30 kg/m²) and overweight (BMI 25 to 30 kg/m²) occurred more often among narcolepsy patients [prevalence: 33% (narcoleptics) vs. 12.5% (controls) and 43% (narcoleptics) vs. 36% (controls), respectively; both p < 0.05]. Narcoleptics had a larger waist circumference (mean difference 5 ± 1.4 cm, p < 0.001). The BMI of patients with IH was significantly lower than that of narcolepsy patients (25.6 ± 3.6 vs. 28.5 ± 5.4 kg/m²; p = 0.004). Discussion: Overweight and obesity occur frequently in patients with narcolepsy. Moreover, these patients have an increased waist circumference, indicating excess fat storage in abdominal depots. The fact that patients with IH had a lower BMI than narcoleptics supports the notion that excessive daytime sleepiness (i.e., inactivity) cannot account for excess body fat in narcoleptic patients.     

Aberrant Gene Expression in Humans

Gene expression as an intermediate molecular phenotype has been a focus of research interest. In particular, studies of expression quantitative trait loci (eQTL) have offered promise for understanding gene regulation through the discovery of genetic variants that explain variation in gene expression levels. Existing eQTL methods are designed for assessing the effects of common variants, but not rare variants. Here, we address the problem by establishing a novel analytical framework for evaluating the effects of rare or private variants on gene expression. Our method starts from the identification of outlier individuals that show markedly different gene expression from the majority of a population, and then reveals the contributions of private SNPs to the aberrant gene expression in these outliers. Using population-scale mRNA sequencing data, we identify outlier individuals using a multivariate approach. We find that outlier individuals are more readily detected with respect to gene sets that include genes involved in cellular regulation and signal transduction, and less likely to be detected with respect to the gene sets with genes involved in metabolic pathways and other fundamental molecular functions. Analysis of polymorphic data suggests that private SNPs of outlier individuals are enriched in the enhancer and promoter regions of corresponding aberrantly-expressed genes, suggesting a specific regulatory role of private SNPs, while the commonly-occurring regulatory genetic variants (i.e., eQTL SNPs) show little evidence of involvement. Additional data suggest that non-genetic factors may also underlie aberrant gene expression. Taken together, our findings advance a novel viewpoint relevant to situations wherein common eQTLs fail to predict gene expression when heritable, rare inter-individual variation exists. The analytical framework we describe, taking into consideration the reality of differential phenotypic robustness, may be valuable for investigating complex traits and conditions.     

Pasteurella Septica Infections in Humans

Five instances of infection by Pasteurella septica, an organism which closely resembles H. influenzae on methods of presumptive bacteriology, are reported from an acute treatment general hospital practice over a period of three months. This infection decidedly outnumbers those caused by other Pasteurella species in North America. The organism is apt to be identified as H. influenzae, Friedlander''s bacillus or Mima polymorpha. Unlike these, it shows extreme sensitivity to penicillin, sometimes combined with resistance to antibiotics that inhibit or kill these other organisms.While in the past Pasteurella septica infection was considered to be characterized by persistent local infection following domestic animal scratches or bites, it is clear that it is more often found in cases of respiratory tract infection and peripheral septic disease. In three of the five cases reported, exposure to animals was the source of infection.Because mixed infection with confusingly similar organisms may occur, lack of awareness of extreme penicillin sensitivity of Pasteurella septica may account for persistent failure of antibiotic therapy.     

Mate Choice Copying in Humans

There is substantial evidence that in human mate choice, females directly select males based on male display of both physical and behavioral traits. In non-humans, there is additionally a growing literature on indirect mate choice, such as choice through observing and subsequently copying the mating preferences of conspecifics (mate choice copying). Given that humans are a social species with a high degree of sharing information, long-term pair bonds, and high parental care, it is likely that human females could avoid substantial costs associated with directly searching for information about potential males by mate choice copying. The present study was a test of whether women perceived men to be more attractive when men were presented with a female date or consort than when they were presented alone, and whether the physical attractiveness of the female consort affected women’s copying decisions. The results suggested that women’s mate choice decision rule is to copy only if a man’s female consort is physically attractive. Further analyses implied that copying may be a conditional female mating tactic aimed at solving the problem of informational constraints on assessing male suitability for long-term sexual relationships, and that lack of mate choice experience, measured as reported lifetime number of sex partners, is also an important determinant of copying.     

Mutations in LRPAP1 Are Associated with Severe Myopia in Humans

Myopia is an extremely common eye disorder but the pathogenesis of its isolated form, which accounts for the overwhelming majority of cases, remains poorly understood. There is strong evidence for genetic predisposition to myopia, but determining myopia genetic risk factors has been difficult to achieve. We have identified Mendelian forms of myopia in four consanguineous families and implemented exome/autozygome analysis to identify homozygous truncating variants in LRPAP1 and CTSH as the likely causal mutations. LRPAP1 encodes a chaperone of LRP1, which is known to influence TGF-β activity. Interestingly, we observed marked deficiency of LRP1 and upregulation of TGF-β in cells from affected individuals, the latter being consistent with available data on the role of TGF-β in the remodeling of the sclera in myopia and the high frequency of myopia in individuals with Marfan syndrome who characteristically have upregulation of TGF-β signaling. CTSH, on the other hand, encodes a protease and we show that deficiency of the murine ortholog results in markedly abnormal globes consistent with the observed human phenotype. Our data highlight a role for LRPAP1 and CTSH in myopia genetics and demonstrate the power of Mendelian forms in illuminating new molecular mechanisms that may be relevant to common phenotypes.     

Alcohol-Related Brain Damage in Humans

Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann’s area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin β II, and α- and β-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in α-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in β-spectrin protein levels, and a significant increase in transmembranous α3 (catalytic) subunit of the Na⁺,K⁺-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of α-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic α- and β-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics.     

Continuous Sensory-Motor Responses in Humans

A vast amount of psychological and physiological data has been accumulated on human responses as elementary models of human behavior. The dynamic structure of human responses in time and the characteristics of their sensory and motor components have been described in detail, and their dependence on a wide variety of factors has been revealed. Diverse aspects of the mechanism regulating human motor responses have been studied. (1)