Development of an automated, GMP compliant FASTlab™ radiosynthesis of [18 F]GE-179 for the clinical study of activated NMDA receptors.

N-(2-chloro-5-(S-2-[18 F]fluoroethyl)thiophenyl)-N'-(3-thiomethylphenyl)-N'-methylguanidine, ([18 F]GE-179), has been identified as a promising positron emission tomography (PET) ligand for the intra-channel phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The radiosynthesis of [18 F]GE-179 has only been performed at low radioactivity levels. However, the manufacture of a GMP compliant product at high radioactivity levels was required for clinical studies. We describe the development of a process using the GE FASTlab™ radiosynthesis platform coupled with HPLC purification. The radiosynthesis is a two-step process, involving the nucleophilic fluorination of ethylene ditosylate, 11, followed by alkylation to the deprotonated thiol precursor, N-(2-chloro-5-thiophenol)-N'-(3-thiomethylphenyl)-N'-methyl guanidine, 8. The crude product was purified by semi-preparative HPLC to give the formulated product in an activity yield (AY) of 7 ± 2% (n = 15) with a total synthesis time of 120 minutes. The radioactive concentration (RAC) and radiochemical purity (RCP) were 328 ± 77 MBq/mL and 96.5 ± 1% respectively and the total chemical content was 2 ± 1 µg. The final formulation volume was 14 mL. The previously described radiosynthesis of [18 F]GE-179 was successfully modified to deliver an process on the FASTlab™ that allows the manufacture of a GMP quality product from high starting radioactivitity (up to 80 GBq) and delivers a product suitable for clinical use.

Imaging in drug development.

Imaging has played an important part in the diagnosis of disease and development of the understanding of the underlying disease mechanisms and is now poised to make an impact in the development of new pharmaceuticals. This chapter discusses the underlying technologies that make the field ready for this challenge. In particular, the potentials of magnetic resonance imaging and functional magnetic resonance imaging are outlined, including the new methods developed to provide additional information from the scans carried out. The field of nuclear medicine has seen a rapid increase in interest as advances in radiochemistry have enabled a wide range of new radiotracers to be synthesised.

Source-constrained retrieval and survival processing.

Three experiments investigated the mnemonic effects of source-constrained retrieval in the survival-processing paradigm. Participants were asked to make survival-based or control decisions (pleasantness or moving judgments) about items prior to a source identification test. The source test was followed by a surprise free recall test for all items processed during the experiment, including the new items (foils) presented during the source test. For the source test itself, when asked about the content of prior processing-did you make a survival or a pleasantness decision about this item?-no differences were found between the survival and control conditions. The final free recall data revealed a different pattern: When participants were asked to decide whether an item had been processed previously for survival, that item was subsequently recalled better than when the source query asked about pleasantness or relevance to a moving scenario. This mnemonic boost occurred across-the-board-for items processed during the initial rating phase and for the new items. These data extend the generality of source-constrained retrieval effects and have implications for understanding the proximate mechanisms that underlie the oft-replicated survival-processing advantage in recall and recognition.

Adaptive memory: animacy effects persist in paired-associate learning.

Recent evidence suggests that animate stimuli are remembered better than matched inanimate stimuli. Two experiments tested whether this animacy effect persists in paired-associate learning of foreign words. Experiment 1 randomly paired Swahili words with matched animate and inanimate English words. Participants were told simply to learn the English "translations" for a later test. Replicating earlier findings using free recall, a strong animacy advantage was found in this cued-recall task. Concerned that the effect might be due to enhanced accessibility of the individual responses (e.g., animates represent a more accessible category), Experiment 2 selected animate and inanimate English words from two more constrained categories (four-legged animals and furniture). Once again, an advantage was found for pairs using animate targets. These results argue against organisational accounts of the animacy effect and potentially have implications for foreign language vocabulary learning.

The Three "Ws" of Episodic Memory: What, When, and Where.

At its core, episodic memory requires the encoding and retention of occurrence information. One needs to remember that a particular item occurred (what) at a particular time (when) in a particular place (where). These task requirements are scale independent, meaning that they hold regardless of whether one is asked to remember over the short or the long-term. In the present article, written to honor the contributions of Alice Healy, I review evidence suggesting that the benchmark phenomena of short-term memory, including bow-shaped serial position curves, symmetric error gradients, and even our limited memory span, actually arise from processes associated with the recovery of occurrence information. Rather than reflecting the properties of a special short-term storage system, these signature empirical patterns are characteristic of remembering over almost any time scale. More generally, I argue that occurrence information can be conceptualized as stored values along largely independent temporal and spatial dimensions. Such a framework provides a useful way of distinguishing between item and order information, although I conclude by suggesting that item memory requires more than simply the recovery of occurrence. Mnemonic representations, once accessed, must be interpreted or "recovered" as well.

Adaptive memory: the mnemonic value of animacy.

Distinguishing between living (animate) and nonliving (inanimate) things is essential for survival and successful reproduction. Animacy is widely recognized as a foundational dimension, appearing early in development, but its role in remembering is currently unknown. We report two studies suggesting that animacy is a critical mnemonic dimension and is one of the most important item dimensions ultimately controlling retention. Both studies show that animate words are more likely to be recalled than inanimate words, even after the stimulus classes have been equated along other mnemonically relevant dimensions (e.g., imageability and meaningfulness). Mnemonic "tunings" for animacy are easily predicted a priori by a functional-evolutionary analysis.

The breadth of animacy in memory: New evidence from prospective memory.

Studies using retrospective memory tasks have revealed that animates/living beings are better remembered than are inanimates/nonliving things (the animacy effect). However, considering that memory is foremost future oriented, we hypothesized that the animacy effect would also occur in prospective memory (i.e., memory for future intentions). Using standard prospective memory (PM) procedures, we explored this hypothesis by manipulating the animacy status of the PM targets. Study 1a reports data collected from an American sample; these results were then replicated with a Portuguese sample (Study 1b). Study 2 employed a new procedure, and data were collected from a broader English-speaking sample. In these three studies, animate (vs. inanimate) targets consistently led to a better PM performance, revealing, for the first time, that the animacy advantage extends to PM. These results strengthen the adaptive approach to memory and stress the need to consider animacy as an important variable in memory studies.

Adaptive Education: Learning and Remembering with a Stone-Age Brain.

Educators generally accept that basic learning and memory processes are a product of evolution, guided by natural selection. Less well accepted is the idea that ancestral selection pressures continue to shape modern memory functioning. In this article, I review evidence suggesting that attention to nature's criterion-the enhancement of fitness-is needed to explain fully how and why people remember. Thinking functionally about memory, and adopting an evolutionary perspective in the laboratory, has led to recent discoveries with clear implications for learning in the classroom. For example, our memory systems appear to be tuned to animacy (the distinction between living and nonliving things) which, in turn, can play a role in enhancing foreign language acquisition. Effective learning management systems need to align with students' prior knowledge, skill, and interest levels, but also with the inherent content biases or "tunings" that are representative of all people.

The Mnemonic Tuning for Contamination: A Replication and Extension Study Using More Ecologically Valid Stimuli.

To face threats posed by pathogens, natural selection designed the Behavioral Immune System, which orchestrates several responses aimed to prevent contact with pathogens. Memory seems to augment this system. Using line drawings of objects, previous studies found that objects described as having been touched by sick people were better remembered than those described as having been touched by healthy people. The current work was designed to replicate and extend these initial studies using more ecologically-valid stimuli-photographs of real objects being held by hands. These photographs were shown along with descriptors (Experiment 1a) or faces (Experiment 1b) denoting the health status of the person whose hands were holding the objects. Experiments 2 and 3 used, as cues of contamination, dirty hands covered with a substance described as being vomit and diarrhea, respectively. Experiment 3 also investigated the need for a fitness-relevant context for the mnemonic effect to occur. In all experiments, stimuli were presented individually on the screen with the "contamination cue." During encoding participants had to identify whether each object had been touched by a sick or a healthy person. The results of the final surprise free recall tasks replicated those previously reported: performance was enhanced for objects encoded as potential sources of contamination. Furthermore, the results of the last study reinstate the importance of fitness-relevance for the effect to occur. These results establish the generality of the contamination effect previously found, now using more ecologically-valid stimuli.

Adaptive memory: ancestral priorities and the mnemonic value of survival processing.

Evolutionary psychologists often propose that humans carry around "stone-age" brains, along with a toolkit of cognitive adaptations designed originally to solve hunter-gatherer problems. This perspective predicts that optimal cognitive performance might sometimes be induced by ancestrally-based problems, those present in ancestral environments, rather than by adaptive problems faced more commonly in modern environments. This prediction was examined in four experiments using the survival processing paradigm, in which retention is tested after participants process information in terms of its relevance to fitness-based scenarios. In each of the experiments, participants remembered information better after processing its relevance in an ancestral environment (the grasslands), compared to a modern urban environment (a city), despite the fact that all scenarios described similar fitness-relevant problems. These data suggest that our memory systems may be tuned to ancestral priorities.

Adaptive memory: nature's criterion and the functionalist agenda.

Memory researchers traditionally ignore function in favor of largely structural analyses. For example, it is well known that forming a visual image improves retention, and various proximate mechanisms have been proposed to account for the advantage (e.g., elaboration of the memory trace), but next to nothing is known about why memory evolved such sensitivities. Why did nature craft a memory system that is sensitive to imagery or the processing of meaning? Functional analyses are critical to progress in memory research for two main reasons: First, as in applied research, functional analyses provide the necessary criteria for measuring progress; second, there are good reasons to believe that modern cognitive processes continue to bear the imprint of ancestral selection pressures (i.e., cognitive systems are functionally designed). We review empirical evidence supporting the idea that memory evolved to enhance reproductive fitness; as a consequence, to maximize retention in basic and applied settings it is useful to develop encoding techniques that are congruent with the natural design of memory systems.

Adaptive memory: fitness relevance and the hunter-gatherer mind.

Recent studies suggest that human memory systems are "tuned" to remember information that is processed in terms of its fitness value. When people are asked to rate the relevance of words to a survival scenario, performance on subsequent surprise memory tests exceeds that obtained after most other known encoding techniques. The present experiments explored this effect using survival scenarios designed to mimic the division of labor thought to characterize early hunter-gatherer societies. It has been suggested that males and females have different cognitive specializations due to the unique survival tasks (hunting and gathering, respectively) they typically performed during periods of human evolution; the present experiments tested whether such specializations might be apparent in memory for words rated for relevance to these activities. Males and females were asked to rate the relevance of random words to prototypical hunting and gathering scenarios or to matched, non-fitness-relevant control scenarios (gathering food on a scavenger hunt or in a hunting contest). Surprise retention tests revealed superior memory for the words when they were rated for relevance to hunting and gathering scenarios, compared with when they were rated for relevance to the control scenarios, but no sex differences were found in memory performance.

The mnemonic effect of choice.

Making choices during encoding leads to superior memory compared with having the same choices made for you. Evidence also suggests that chosen items might be more memorable than unchosen alternatives. In prior experiments, an incidental memory advantage was found for chosen over unchosen items when participants chose which one of two words would be more useful to a situation. However, it remains uncertain whether this mnemonic benefit is due to the act of choosing or to a better "fit" of chosen items to the encoding situation (congruity). In the present research, we conducted two experiments to dissociate choice and congruity effects. In both experiments, we manipulated choice and congruity and showed mnemonic benefits for chosen words over unchosen words and for congruent words over incongruent words, but these effects did not interact. There is apparently a unique mnemonic benefit for chosen words that cannot be explained by their "fit" to the encoding task.

Presenting new stimuli to study emotion: Development and validation of the Objects-on-Hands Picture Database.

A long-standing goal shared by researchers has been to design optimal experimental procedures, including the selection of appropriate stimuli. Pictures are commonly used in different research fields. However, until recently, researchers have relied mostly on line-drawings, which can have poor ecological validity. We developed a set of high quality standardized photographs of objects from six different categories, recorded under two camera viewpoints, and five presentation conditions (on its own, held by clean hands, and by hands covered with different substances: sauce, chocolate and mud). These various staging conditions can be used to induce different emotional states while maintaining the object of interest constant. We first report normative data on the objects' name agreement and familiarity collected from North American and Portuguese participants. Results showed high name agreement and familiarity in both samples. Next, arousal, disgust and valence ratings were collected for the stimuli under either an emotional-activating or a neutral context. Subjective ratings varied according to the staging condition and the context, confirming that the same items can effectively be used in different emotional conditions. This database allows researchers to select more ecologically-valid stimuli according to their research purposes while considering several variables of interest and avoiding item-selection problems commonly present when comparing responses to neutral and emotional items.

Adaptive memory: The mnemonic power of survival-based generation.

Four experiments investigated the mnemonic effects of generating survival situations. People were given target words and asked to generate survival situations involving that stimulus (e.g., DOOR: "I'm in a house that's on fire, and I can escape through the door"). No constraints were placed on the generation process, other than that it must be survival-related and refer to the target stimulus. Following a series of these generation trials people were given a surprise retention test for the target words. Across four experiments the survival generation task produced significantly better retention than several deep processing controls including: (a) a pleasantness-rating task, (b) an autobiographical retrieval task, and (c) a task that required people to generate unusual uses for the target items. These results demonstrate the power of survival processing in a new way and provide diagnostic information about the proximate mechanisms that may underlie survival processing advantages. They also extend the generality of survival processing beyond the standard relevance-rating procedure that has been used in virtually all prior research. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Adaptive memory: survival processing enhances retention.

The authors investigated the idea that memory systems might have evolved to help us remember fitness-relevant information--specifically, information relevant to survival. In 4 incidental learning experiments, people were asked to rate common nouns for their survival relevance (e.g., in securing food, water, or protection from predators); in control conditions, the same words were rated for pleasantness, relevance to moving to a foreign land, or personal relevance. In surprise retention tests, participants consistently showed the best memory when words were rated for survival; the survival advantage held across recall, recognition, and for both within-subject and between-subjects designs. These findings suggest that memory systems are "tuned" to remember information that is processed for fitness, perhaps as a result of survival advantages accrued in the past.

Adaptive Memory: Remembering Potential Mates.

According to the adaptive memory perspective, memory should function more efficiently in fitness-relevant domains. The current work explored whether there is a mnemonic tuning in a fundamental domain for human evolution: reproduction. In two experiments, female participants assessed how desirable potential male candidates (represented by a face and a short descriptor) would be in the context of a long-term mating relationship or in the context of a long-term work relationship. Then, after a short distractor task, participants performed a recognition task for the faces and a source memory task. Finally, they were asked to recall the descriptors presented during encoding. Experiment 1 used a between-subjects design, whereas Experiment 2 employed a within-subject design. In both experiments, participants remembered the faces best when they were encoded in the mating condition. Also, in Experiment 1, source memory performance was better in the mating condition than in the working condition with the reverse being true for free recall of the descriptors. The latter difference was not observed in Experiment 2. These results suggest a potential mnemonic tuning for the faces of potential mate partners.

A categorical recall strategy does not explain animacy effects in episodic memory.

Animate stimuli are better remembered than matched inanimate stimuli in free recall. Three experiments tested the hypothesis that animacy advantages are due to a more efficient use of a categorical retrieval cue. Experiment 1 developed an "embedded list" procedure that was designed to disrupt participants' ability to perceive category structure at encoding; a strong animacy effect remained. Experiments 2 and 3 employed animate and inanimate word lists consisting of tightly constrained categories (four-footed animals and furniture). Experiment 2 failed to find an animacy advantage when the categorical structure was readily apparent, but the advantage returned in Experiment 3 when the embedded list procedure was employed using the same target words. These results provide strong evidence against an organizational account of the animacy effect, indicating that the animacy effect in episodic memory is probably due to item-specific factors related to animacy.

Adaptive Memory: The Evolutionary Significance of Survival Processing.

A few seconds of survival processing, during which people assess the relevance of information to a survival situation, produces particularly good retention. One interpretation of this benefit is that our memory systems are optimized to process and retain fitness-relevant information. Such a "tuning" may exist, in part, because our memory systems were shaped by natural selection, using a fitness-based criterion. However, recent research suggests that traditional mnemonic processes, such as elaborative processing, may play an important role in producing the empirical benefit. Boundary conditions have been demonstrated as well, leading some to dismiss evolutionary interpretations of the phenomenon. In this article, we discuss the current state of the evolutionary account and provide a general framework for evaluating evolutionary and purportedly nonevolutionary interpretations of mnemonic phenomena. We suggest that survival processing effects are best viewed within the context of a general survival optimization system, designed by nature to help organisms deal with survival challenges. An important component of survival optimization is the ability to simulate activities that help to prevent or escape from future threats which, in turn, depends in an important way on accurate retrospective remembering of survival-relevant information.