Association of CSF Biomarkers With Hippocampal-Dependent Memory in Preclinical Alzheimer Disease.

OBJECTIVE: To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF ß-amyloid (Aß)42/Aß40 and phosopho-tau181 (p-tau181) in cognitively unimpaired older adults (CU). METHODS: CU enrolled in the Stanford Aging and Memory Study (n = 153; age 68.78 ± 5.81 years; 94 female) completed a lumbar puncture and memory assessments. CSF Aß42, Aß40, and p-tau181 were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied "target" objects, novel "foil" objects, and perceptually similar "lure" objects. Analyses examined cross-sectional relationships among memory performance, age, and CSF measures, controlling for sex and education. RESULTS: Age and lower Aß42/Aß40 were independently associated with elevated p-tau181. Age, Aß42/Aß40, and p-tau181 were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aß42/Aß40 on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF Aß42 was not significantly associated with p-tau181 or memory. CONCLUSIONS: Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying CU with preclinical AD pathology.

Hippocampal and cortical mechanisms at retrieval explain variability in episodic remembering in older adults.

Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

Accurate expectancies diminish perceptual distraction during visual search.

The load theory of visual attention proposes that efficient selective perceptual processing of task-relevant information during search is determined automatically by the perceptual demands of the display. If the perceptual demands required to process task-relevant information are not enough to consume all available capacity, then the remaining capacity automatically and exhaustively "spills-over" to task-irrelevant information. The spill-over of perceptual processing capacity increases the likelihood that task-irrelevant information will impair performance. In two visual search experiments, we tested the automaticity of the allocation of perceptual processing resources by measuring the extent to which the processing of task-irrelevant distracting stimuli was modulated by both perceptual load and top-down expectations using behavior, functional magnetic resonance imaging, and electrophysiology. Expectations were generated using a trial-by-trial cue that provided information about the likely load of the upcoming visual search task. When the cues were valid, behavioral interference was eliminated and the influence of load on frontoparietal and visual cortical responses was attenuated relative to when the cues were invalid. In conditions in which task-irrelevant information interfered with performance and modulated visual activity, individual differences in mean blood oxygenation level dependent responses measured from the left intraparietal sulcus were negatively correlated with individual differences in the severity of distraction. These results are consistent with the interpretation that a top-down biasing mechanism interacts with perceptual load to support filtering of task-irrelevant information.

Both memory and attention systems contribute to visual search for targets cued by implicitly learned context.

Environmental context learned without awareness can facilitate visual processing of goal-relevant information. According to one view, the benefit of implicitly learned context relies on the neural systems involved in spatial attention and hippocampus-mediated memory. While this view has received empirical support, it contradicts traditional models of hippocampal function. The purpose of the present work was to clarify the influence of spatial context on visual search performance and on brain structures involved memory and attention. Event-related functional magnetic resonance imaging revealed that activity in the hippocampus as well as in visual and parietal cortex was modulated by learned visual context even though participants' subjective reports and performance on a post-experiment recognition task indicated no explicit knowledge of the learned context. Moreover, the magnitude of the initial selective hippocampus response predicted the magnitude of the behavioral benefit due to context observed at the end of the experiment. The results suggest that implicit contextual learning is mediated by attention and memory and that these systems interact to support search of our environment.

Interactions between visual attention and episodic retrieval: dissociable contributions of parietal regions during gist-based false recognition.

The interaction between episodic retrieval and visual attention is relatively unexplored. Given that systems mediating attention and episodic memory appear to be segregated, and perhaps even in competition, it is unclear how visual attention is recruited during episodic retrieval. We investigated the recruitment of visual attention during the suppression of gist-based false recognition, the tendency to falsely recognize items that are similar to previously encountered items. Recruitment of visual attention was associated with activity in the dorsal attention network. The inferior parietal lobule, often implicated in episodic retrieval, tracked veridical retrieval of perceptual detail and showed reduced activity during the engagement of visual attention, consistent with a competitive relationship with the dorsal attention network. These findings suggest that the contribution of the parietal cortex to interactions between visual attention and episodic retrieval entails distinct systems that contribute to different components of the task while also suppressing each other.

Retrieval Failure Contributes to Gist-Based False Recognition.

People often falsely recognize items that are similar to previously encountered items. This robust memory error is referred to as gist-based false recognition. A widely held view is that this error occurs because the details fade rapidly from our memory. Contrary to this view, an initial experiment revealed that, following the same encoding conditions that produce high rates of gist-based false recognition, participants overwhelmingly chose the correct target rather than its related foil when given the option to do so. A second experiment showed that this result is due to increased access to stored details provided by reinstatement of the originally encoded photograph, rather than to increased attention to the details. Collectively, these results suggest that details needed for accurate recognition are, to a large extent, still stored in memory and that a critical factor determining whether false recognition will occur is whether these details can be accessed during retrieval.

Memory distortion: an adaptive perspective.

Memory is prone to distortions that can have serious consequences in everyday life. Here we integrate emerging evidence that several types of memory distortions - imagination inflation, gist-based and associative memory errors, and post-event misinformation - reflect adaptive cognitive processes that contribute to the efficient functioning of memory, but produce distortions as a consequence of doing so. We consider recent cognitive and neuroimaging studies that link these distortions with adaptive processes, including simulation of future events, semantic and contextual encoding, creativity, and memory updating. We also discuss new evidence concerning factors that can influence the occurrence of memory distortions, such as sleep and retrieval conditions, as well as conceptual issues related to the development of an adaptive perspective.

The strategic nature of false recognition in the DRM paradigm.

The false memory effect produced by the Deese/Roediger & McDermott (DRM) paradigm is reportedly impervious to warnings to avoid false alarming to the critical lures (D. A. Gallo, H. L. Roediger III, & K. B. McDermott, 2001). This finding has been used as strong evidence against models that attribute the false alarms to a decision process (e.g., M. B. Miller & G. L. Wolford, 1999). In this report, the authors clarify their earlier article and suggest that subjects establish only 2 underlying criteria for a recognition judgment, a liberal criterion for items that seem to be related to 1 of the study list themes and a conservative criterion for items that do not seem to be related. They demonstrate that warnings designed on the basis of these underlying criteria are effective in significantly suppressing the false recognition effect, suggesting that strategic control of the retrieval response does play a role in the DRM paradigm.

Parietal cortex tracks the amount of information retrieved even when it is not the basis of a memory decision.

Although the parietal cortex is not conventionally associated with memory, a large number of recent fMRI studies have suggested that that the parietal cortex may play a role in recognition memory. Activity in the lateral parietal cortex is correlated with the subjective impression that an item is old. It has therefore been proposed that the parietal cortex may be determining the outcome of the decision process. For instance, parietal cortex may be temporally integrating mnemonic information in favor of an "old" response until a decision criterion is reached (mnemonic accumulator hypothesis). Activity in the lateral parietal cortex also increases with the amount of information retrieved. It has thus been proposed that lateral parietal cortex may be acting as a working memory buffer into which retrieved information is transferred (output buffer hypothesis). In previous studies, confidence in an "old" decision and the amount of information retrieved have been confounded, thus making these competing hypotheses difficult to differentiate. We used a frequency discrimination paradigm to dissociate the amount of information retrieved from memory and decision certainty. We found that lateral and medial regions of parietal cortex previously implicated in recognition memory track the absolute amount of information retrieved even when this is not the basis of the recognition decision. Our results present a serious challenge to proposals that the parietal cortex contributes directly to the recognition decision process.

Lateralization of the parietal old/new effect: an event-related fMRI study comparing recognition memory for words and faces.

Although the parietal cortex is not conventionally thought of as a major component of the neural systems that mediate declarative memory, many fMRI studies of recognition memory have found that correctly identified old items produce greater activation than correctly rejected new items throughout parietal cortex. This effect is usually heavily lateralized to the left. However, the vast majority of previous studies have used verbal materials. Does the left-lateralization of this effect result from the left hemisphere's role in language or does it suggest the possibility of a specialized role for the left hemisphere in recognition memory that applies across stimulus domains? To address this question, we directly compared recognition memory for words and faces in two event-related fMRI experiments with a total of 38 subjects. In the second experiment, we included a manipulation of recognition difficulty. Despite extensive material-specific lateralization in terms of the brain's overall response to stimuli revealed by a direct comparison of words and faces, the parietal old/new effect did not exhibit material-specific lateralization. Rather, the lateralization of the effect depended on the region of parietal cortex in question. In lateral parietal cortex, the effect was left-lateralized. In medial parietal cortex, the effect was bilateral. These findings indicate that the left-lateralization of the parietal old/new effect is unrelated to the left hemisphere's role in language and raises the possibility of a specialized role for the left hemisphere in recognition memory.

Semantic organization of study materials has opposite effects on recognition and recall.

It has been well established for several decades that semantic organization of study materials greatly enhances recall by facilitating access to information during retrieval. However, the effect of organization on recognition, and its relationship to the effect on recall, is in doubt. We report the first direct comparison of the effects of categorically organizing study lists on recognition, cued recall, and free recall. We found that whereas organization improved recall, it impaired recognition. Organization had a larger effect on free recall than on cued recall. Within the categorized lists, recall was superior for items highly associated with the category; the opposite was true of recognition. In recall, organization improved the proportion of categories recalled, but it lowered the proportion of items per category recalled. A simple framework for interpreting the dissociation is offered. Possible mechanisms underlying the detrimental effect of organization on memory and prospects for future research are briefly discussed.

Modulation of neural activity by angle of rotation during imagined spatial transformations.

Imagined spatial transformations of objects (e.g., mental rotation) and the self (e.g., perspective taking) are psychologically dissociable. In mental rotation, the viewer transforms the location or orientation of an object relative to stable egocentric and environmental reference frames. In imagined shifts of perspective, the viewer's egocentric reference frame is transformed with respect to stable objects and environment. Using fMRI, we showed that during mental transformations of objects the right superior parietal cortex exhibited a positive linear relationship between hemodynamic response and degrees of rotation. By contrast, during imagined transformations of the self, the same regions exhibited a negative linear trend. We interpret this finding in terms of the role of parietal cortex in coding the locations of objects in relation to the body.

Theory of mind broad and narrow: reasoning about social exchange engages ToM areas, precautionary reasoning does not.

Baron-Cohen (1995) proposed that the theory of mind (ToM) inference system evolved to promote strategic social interaction. Social exchange--a form of co-operation for mutual benefit--involves strategic social interaction and requires ToM inferences about the contents of other individuals' mental states, especially their desires, goals, and intentions. There are behavioral and neuropsychological dissociations between reasoning about social exchange and reasoning about equivalent problems tapping other, more general content domains. It has therefore been proposed that social exchange behavior is regulated by social contract algorithms: a domain-specific inference system that is functionally specialized for reasoning about social exchange. We report an fMRI study using the Wason selection task that provides further support for this hypothesis. Precautionary rules share so many properties with social exchange rules--they are conditional, deontic, and involve subjective utilities--that most reasoning theories claim they are processed by the same neurocomputational machinery. Nevertheless, neuroimaging shows that reasoning about social exchange activates brain areas not activated by reasoning about precautionary rules, and vice versa. As predicted, neural correlates of ToM (anterior and posterior temporal cortex) were activated when subjects interpreted social exchange rules, but not precautionary rules (where ToM inferences are unnecessary). We argue that the interaction between ToM and social contract algorithms can be reciprocal: social contract algorithms requires ToM inferences, but their functional logic also allows ToM inferences to be made. By considering interactions between ToM in the narrower sense (belief-desire reasoning) and all the social inference systems that create the logic of human social interaction--ones that enable as well as use inferences about the content of mental states--a broader conception of ToM may emerge: a computational model embodying a Theory of Human Nature (ToHN).