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Recently there has been an increased interest in the lateral parietal cortex's role in successful memory retrieval. Several theories have been put forth to explain this phenomenon including the idea that this region plays a direct role in memory retrieval, temporarily storing episodic content until a decision can be made. Other explanations report a more indirect role of the parietal cortex during memory retrieval. Some of these theories include modulations of attentional systems that may guide memory retrieval or representations of subjective awareness of one's memories. According to these theories, parietal activations may assist successful memory retrieval, but are not necessary for it to occur. Although this region is consistently found to be active when memories are successfully retrieved, these results were initially difficult to reconcile with reports from neuropsychology, which show a lack of severe memory impairment when damage to this region occurs. These findings are specifically difficult for theories that assume this region is directly related to memory retrieval (i.e. the episodic buffer account), which assume this activity is necessary for successful retrieval to occur. The purpose of the experiments described in this dissertation is to test whether parietal activations are modulated by task demands that should not affect the amount of episodic content retrieved. These task demands include modifying the way retrieval states are operationalized and varying the base rates of studied items presented at test. Although these procedural changes should affect extra-mnemonic cognitive processes, there is no reason to assume they should affect the amount of mnemonic information retrieved. Results from these studies in fact do show a modulation of both dorsal and ventral lateral parietal activations based on these procedural manipulations. These results are difficult to explain with an episodic buffer account of parietal activity. Instead, the results point to a more indirect role of parietal involvement in memory retrieval and are the most in line with the idea of this area representing the subjective awareness that can accompany successful retrieval, particularly during recollection. When these results are compared to results from neuropsychology, an extra-mnemonic role for the parietal cortex, particularly one associated with the subjective experience of retrieved content, appears to be the most parsimonious explanation of the patient findings. However, a subjective awareness account of parietal activity cannot adequately explain all of the findings from the literature, and most likely is only part of the story. The parietal cortex is an extremely heterogeneous area, both in structural and functional connectivity. The full story of the parietal cortex's role in memory retrieval will most likely be explained with a variety of theories. Increased levels of spatial segregation of the parietal cortex into distinct functional sub-regions will most likely reveal a myriad of functional roles that this region is playing during the complex cognitive process that is memory retrieval.

People rely on predicted and remembered emotion to guide important decisions. But how much can they trust their mental representations of emotion to be accurate, and how much do they trust them? In this investigation, participants (N = 957) reported their predicted, experienced, and remembered emotional response to the outcome of the 2016 U.S. presidential election. They also reported how accurate and vivid they perceived their predictions and memories to be, and the importance of the election. Participants remembered their emotional responses more accurately than they predicted them. But, strikingly, they perceived their predictions to be more accurate than their memories. This perception was explained by the greater importance and vividness of anticipated versus remembered experience. We also assessed whether individuals with Highly Superior Autobiographical Memory for personal and public events (N = 33) showed superior ability to predict or remember their emotional responses to events. They did not and, even for this group, predicting emotion was a more intense experience than remembering emotion. These findings reveal asymmetries in the phenomenological experience of predicting and remembering emotion. The vividness of predicted emotion serves as a powerful subjective signal of accuracy even when predictions turn out to be wrong.

Aging causes hippocampal circuit alterations that differentially affect hippocampal subfields and are associated with age-related memory decline. Additionally, functional organization along the longitudinal axis of the hippocampus has revealed distinctions between anterior and posterior (A-P) connectivity. Here, we examined the functional connectivity (FC) differences between young and older adults at high-resolution within the medial temporal lobe network (entorhinal, perirhinal, and parahippocampal cortices), allowing us to explore how hippocampal subfield connectivity across the longitudinal axis of the hippocampus changes with age. Overall, we found reliably greater connectivity for younger adults than older adults between the hippocampus and PHC and PRC. This drop in functional connectivity was more pronounced in the anterior regions of the hippocampus than the posterior ones, consistent for each of the hippocampal subfields. Further, intra-hippocampal connectivity also reflected an age-related decrease in functional connectivity within the anterior hippocampus in older adults that was offset by an increase in posterior hippocampal functional connectivity. Interestingly, the anterior-posterior shift in older adults between hippocampus and PHC was predictive of lure discrimination performance on the MST, suggesting that this shift may reflect a compensation mechanism that preserves memory performance. While age-related dysfunction within the hippocampal subfields has been well-documented, these results suggest that the age-related A-P shift in hippocampal connectivity may also contribute significantly to memory decline in older adults. Significance Statement We examined functional connectivity differences between young and older adults at high-resolution within the medial temporal lobe network allowing us to explore how hippocampal subfield connectivity across the longitudinal axis of the hippocampus changes with age. This drop in functional connectivity was more pronounced in the anterior regions of the hippocampus than the posterior ones, consistent for each of the hippocampal subfields. Further, intra-hippocampal connectivity also reflected an age-related decrease in functional connectivity within the anterior hippocampus in older adults that was offset by an increase in posterior hippocampal functional connectivity. While age-related dysfunction within the hippocampal subfields has been well-documented, these results suggest that the age-related A-P shift in hippocampal connectivity may contribute to memory decline in older adults.

In recognition memory experiments participants must discriminate between old and new items, a judgment influenced by response bias. Research has shown substantial individual differences in the extent to which people will strategically adjust their response bias to diagnostic cues such as the prior probability of an old item. Despite this significant between subject variability, shifts in bias have been found to be relatively predictive within individuals across memory tests. Experiment 1 sought to determine whether this predictability extends beyond memory. Results revealed that the amount a subject shifted response bias in a recognition memory task was significantly predictive of shifting in a visual perception task, suggesting that shifting can generalise outside of a specific testing domain. Experiment 2 sought to determine how predictive shifting would be across two manipulations well known to induce shifts in bias: a probability manipulation and a response payoff manipulation. A modest positive relationship between these two methods was observed, suggesting that shifting behaviour is relatively predictive across different manipulations of shifting. Overall, results from both experiments suggest that response bias shifting, like response bias setting, is a relatively stable behaviour within individuals despite changes in test domain and test manipulation.

The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA’s Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as chemical assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in chemical risk assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions.

The current study focused on individuals with Highly Superior Autobiographical Memory (HSAM) and had two main objectives: 1) investigate whether HSAMs have increased recollection performance compared to controls, and 2) investigate whether HSAMs have a reliably different response bias than controls. While previous lab-based recognition tests have shown that HSAMs have normal memory performance, these tests were based on a mixture of both recollection and familiarity. Here, we employed recognition tests specifically designed to separate recollected responses from those based on familiarity. Additionally, we were interested in how HSAMs make their memory decisions. Several studies have shown a great deal of variability between individuals in their response bias. Here, individuals with HSAM and age- matched controls completed a remember/know and a source memory test. HSAMs behaved like controls in both overall and recollection-based memory discrimination. However, HSAMs showed a significantly more liberal response bias, endorsing more items as "old" than controls. These findings contribute to our understanding of how memory processes - especially those related to decision-making - function in those with superior memory abilities and may help elucidate how other (non-HSAM) memory experts make decisions.

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Mounting evidence suggests that the medial temporal lobe (MTL) and striatal learning systems support different forms of learning, which can be competitive or cooperative depending on task demands. We have previously shown how activity in these regions can be modulated in a conditional visuomotor associative learning task based on the consistency of response mappings or reward feedback (Mattfeld & Stark, 2015). Here, we examined the shift in learning towards the MTL and away from the striatum by placing strong demands on pattern separation, a process of orthogonalizing similar inputs into distinct representations. Mnemonically, pattern separation processes have been shown to rely heavily on processing in the hippocampus. Therefore, we predicted modulation of hippocampal activity by pattern separation demands, but no such modulation of striatal activity. Using a variant of the conditional visuomotor associative learning task that we have used previously, we presented participants with two blocked conditions: items with high and low perceptual overlap during functional magnetic resonance imaging (fMRI). As predicted, we observed learning-related activity in the hippocampus, which was greater in the high than the low overlap condition, particularly in the dentate gyrus. In contrast, the associative striatum also showed learning related activity, but it was not modulated by overlap condition. Using functional connectivity analyses, we showed that the correlation between the hippocampus and dentate gyrus with the associative striatum was differentially modulated by high vs. low overlap, suggesting that the coordination between these regions was affected when pattern separation demands were high. These findings contribute to a growing literature that suggests that the hippocampus and striatal network both contribute to the learning of arbitrary associations that are computationally distinct and can be altered by task demands.

There are several factors that contribute to the development of type 2 diabetes, such as obesity, sedentary lifestyle, and family history, which are widely accepted in the medical community. However, the role of environmental contaminants or pollutants in diabetes is not yet well understood. The strongest body of epidemiological evidence is that linking certain persistent organic pollutants (POPs) to diabetes. POPs include dioxins, furans, polychlorinated biphenyls (PCBs) and organochlorine pesticides. A metaanalysis of six studies of dioxins and furans produced a relative risk (RR) of 1.91 (95% CI 1.44–2.54) for diabetes when comparing the highest category versus the lowest category. A metaanalysis of 13 cross-sectional studies of PCBs and diabetes produced an RR of 2.90 (95% CI 2.14–3.92), and a metaanalysis of 8 prospective studies of PCBs and diabetes produced an RR of 1.65 (95% CI 1.16–2.34). Comparing the top versus the bottom tertile, a metaanalysis of any organochlorine pesticide and diabetes in 22 studies found a summary odds ratio of 1.68 (95% CI 1.37–2.07). Bisphenol A (BPA) is an endocrine disrupter that is found in many consumer products; human exposure is believed to be mainly from food product packaging containing BPA. A metaanalysis of BPA and type 2 diabetes, using five studies, produced a summary RR of 1.45 (95% CI 1.13–1.87) comparing the fourth quartile with the first quartile of urinary BPA. Phthalates are chemicals added to plastics to increase their flexibility, transparency, durability, and longevity. A metaanalysis of four studies produced a summary RR of 1.48 (95% CI 0.98–2.25) for diabetes when comparing the highest category of total phthalates with the lowest category. Although this summary RR is not significant, there is evidence that some individual phthalate metabolites are related to diabetes. Other environmental pollutants that have been studied include carbon monoxide, lead, nitrogen dioxide, ozone, particulate matter and sulfur dioxide in air pollution, and toxic heavy metals such as arsenic, cadmium, and mercury. Notably, a metaanalysis of 12 studies of arsenic in drinking water and type 2 diabetes had a pooled RR of 1.75 (95% CI 1.20–2.54). There is growing support for the “developmental obesogen” theory. It promotes the concept that certain chemicals may be capable of disrupting developmental processes related to metabolic homeostasis during early life and thus increasing the risk for obesity and other related metabolic diseases. However, most of the work relating environmental pollutants to obesity has produced inconsistent results. An exception is DDE (dichlorodiphenyldichloroethylene), a metabolite of dichlorodiphenyltrichloroethane. For DDE, there are seven studies showing positive associations with adiposity and two studies having null relationships.

Numerous neuroimaging studies have shown a dissociation within the left posterior parietal cortex (PPC) between recollection and familiarity, with dorsal regions routinely active during familiarity and ventral regions active during recollection. The two most common methods for separating the neural correlates of these retrieval states are the remember/know paradigm and tests probing source memory. While relatively converging results have been found using these methods, the literature is lacking an adequate and direct comparison of the two procedures. We directly compared these two methodologies and found differences in both the magnitude and extent of activation within the left PPC. During familiarity, dorsal PPC regions were more strongly activated by the source test, while the remember/know test led to stronger recollection-related activations within the ventral regions of the PPC. This modulation of PPC activity is particularly important because it suggests that the neural correlates of familiarity and recollection depend on how they are operationalized. Previous assumptions that remember/know and source memory tests are functionally equivalent should therefore be re-evaluated. Additionally, any theories attempting to explain the functional role of the PPC during memory retrieval must take these differences into account.

Magnetic resonance imaging enables the noninvasive mapping of both anatomical white matter connectivity and dynamic patterns of neural activity in the human brain. We examine the relationship between the structural properties of white matter streamlines (structural connectivity) and the functional properties of correlations in neural activity (functional connectivity) within 84 healthy human subjects both at rest and during the performance of attention- and memory-demanding tasks. We show that structural properties, including the length, number, and spatial location of white matter streamlines, are indicative of and can be inferred from the strength of resting-state and task-based functional correlations between brain regions. These results, which are both representative of the entire set of subjects and consistently observed within individual subjects, uncover robust links between structural and functional connectivity in the human brain.