Saul L. Miller

Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer's Disease: An Independent Component Analysis

Memory function is likely subserved by multiple distributed neural networks, which are disrupted by the pathophysiological process of Alzheimers disease (AD). In this study, we used multivariate analytic techniques to investigate memory-related functional magnetic resonance imaging (fMRI) activity in 52 individuals across the continuum of normal aging, mild cognitive impairment (MCI), and mild AD. Independent component analyses revealed specific memory-related networks that activated or deactivated during an associative memory paradigm. Across all subjects, hippocampal activation and parietal deactivation demonstrated a strong reciprocal relationship. Furthermore, we found evidence of a nonlinear trajectory of fMRI activation across the continuum of impairment. Less impaired MCI subjects showed paradoxical hyperactivation in the hippocampus compared with controls, whereas more impaired MCI subjects demonstrated significant hypoactivation, similar to the levels observed in the mild AD subjects. We found a remarkably parallel curve in the pattern of memory-related deactivation in medial and lateral parietal regions with greater deactivation in less-impaired MCI and loss of deactivation in more impaired MCI and mild AD subjects. Interestingly, the failure of deactivation in these regions was also associated with increased positive activity in a neocortical attentional network in MCI and AD. Our findings suggest that loss of functional integrity of the hippocampal-based memory systems is directly related to alterations of neural activity in parietal regions seen over the course of MCI and AD. These data may also provide functional evidence of the interaction between neocortical and medial temporal lobe pathology in early AD.

Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation

The neural underpinnings of age-related memory impairment remain to be fully elucidated. Using a subsequent memory face–name functional MRI (fMRI) paradigm, young and old adults showed a similar magnitude and extent of hippocampal activation during successful associative encoding. Young adults demonstrated greater deactivation (task-induced decrease in BOLD signal) in medial parietal regions during successful compared with failed encoding, whereas old adults as a group did not demonstrate a differential pattern of deactivation between trial types. The failure of deactivation was particularly evident in old adults who performed poorly on the memory task. These low-performing old adults demonstrated greater hippocampal and prefrontal activation to achieve successful encoding trials, possibly as a compensatory response. Findings suggest that successful encoding requires the coordination of neural activity in hippocampal, prefrontal, and parietal regions, and that age-related memory impairment may be primarily related to a loss of deactivation in medial parietal regions.

Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline

Objective: To use functional MRI (fMRI) to investigate whether hippocampal activation during a memory task can predict cognitive decline in individuals with mild cognitive impairment (MCI). Methods: 25 older individuals with MCI performed a visual scene encoding task during fMRI scanning, and were followed clinically for at least 4 years after scanning. A hypothesis driven analysis of fMRI data was performed. First, fMRI data were analysed at the group level to identify the regions of the hippocampal formation that were engaged by this memory task. Parameter estimates of each subject’s memory related hippocampal activation (% signal change) were extracted and were analysed with a linear regression model to determine whether hippocampal activation predicted the degree or rate of cognitive decline, as measured by change in Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Results: Over 5.9 (1.2) years of follow-up after scanning, subjects varied widely in degree and rate of cognitive decline (change in CDR-SB ranged from 0 to 6, and the rate ranged from 0 to 1 CDR-SB unit/year). Greater hippocampal activation predicted greater degree and rate of subsequent cognitive decline (p<0.05). This finding was present even after controlling for baseline degree of impairment (CDR-SB), age, education and hippocampal volume, as well as gender and apolipoprotein E status. In addition, an exploratory whole brain analysis produced convergent results, demonstrating that the hippocampal formation was the only brain region where activation predicted cognitive decline. Conclusions: In individuals with MCI, greater memory task related hippocampal activation is predictive of a greater degree and rate of cognitive decline subsequent to scanning. fMRI may provide a physiological imaging biomarker useful for identifying the subgroup of MCI individuals at highest risk of cognitive decline for potential inclusion in disease modifying clinical trials.

Scent of a Woman Men’s Testosterone Responses to Olfactory Ovulation Cues

Adaptationist models of human mating provide a useful framework for identifying subtle, biologically based mechanisms influencing cross-gender social interaction. In line with this framework, the current studies examined the extent to which olfactory cues to female ovulation—scents of women at the peak of their reproductive fertility—influence endocrinological responses in men. Men in the current studies smelled T-shirts worn by women near ovulation or far from ovulation (Studies 1 and 2) or control T-shirts not worn by anyone (Study 2). Men exposed to the scent of an ovulating woman subsequently displayed higher levels of testosterone than did men exposed to the scent of a nonovulating woman or a control scent. Hence, olfactory cues signaling women’s levels of reproductive fertility were associated with specific endocrinological responses in men—responses that have been linked to sexual behavior and the initiation of romantic courtship.

Intrasexual Vigilance: The Implicit Cognition of Romantic Rivalry

Four experiments tested the hypothesis that concerns about infidelity would lead people, particularly those displaying high chronic levels of romantic jealousy, to display a functionally coordinated set of implicit cognitive biases aimed at vigilantly processing attractive romantic rivals. Priming concerns about infidelity led people with high levels of chronic jealousy (but not those low in chronic jealousy) to attend vigilantly to physically attractive same-sex targets at an early stage of visual processing (Study 1), to strongly encode and remember attractive same-sex targets (Study 2), and to form implicit negative evaluations of attractive same-sex targets (Studies 3 and 4). In each case, effects were observed only for same-sex targets who were physically attractive-individuals who can pose especially potent threats to a persons own romantic interests. These studies reveal a cascade of implicit, lower order cognitive processes underlying romantic rivalry and identify the individuals most likely to display those processes. At a broader conceptual level, this research illustrates the utility of integrating social cognitive and evolutionary approaches to psychological science.

Submitting to Defeat Social Anxiety, Dominance Threat, and Decrements in Testosterone

Although theory suggests a link between social anxiety and social dominance, direct empirical evidence for this link is limited. The present experiment tested the hypothesis that socially anxious individuals, particularly men, would respond to a social-dominance threat by exhibiting decrements in their testosterone levels, an endocrinological change that typically reflects pronounced social submission in humans and other animals. Participants were randomly assigned to either win or lose a rigged face-to-face competition with a confederate. Although no zero-order relationship between social anxiety and level of testosterone was observed, testosterone levels showed a pronounced drop among socially anxious men who lost the competition. No significant changes were observed in nonanxious men or in women. This research provides novel insight into the nature and consequences of social anxiety, and also illustrates the utility of integrating social psychological theory with endocrinological approaches to psychological science.

Ovulation as a male mating prime: subtle signs of women's fertility influence men's mating cognition and behavior.

Womens reproductive fertility peaks for a few days in the middle of their cycle around ovulation. Because conception is most likely to occur inside this brief fertile window, evolutionary theories suggest that men possess adaptations designed to maximize their reproductive success by mating with women during their peak period of fertility. In this article, we provide evidence from 3 studies that subtle cues of fertility prime mating motivation in men, thus facilitating psychological and behavioral processes associated with the pursuit of a sexual partner. In Study 1, men exposed to the scent of a woman near peak levels of fertility displayed increased accessibility to sexual concepts. Study 2 demonstrated that, among men who reported being sensitive to odors, scent cues of fertility triggered heightened perceptions of womens sexual arousal. Study 3 revealed that, in a face-to-face interaction, high levels of female fertility were associated with a greater tendency for men to make risky decisions and to behaviorally mimic a female partner. Hence, subtle cues of fertility led to a cascade of mating-related processes-from lower order cognition to overt behavior-that reflected heightened mating motivation. Implications for theories of goal pursuit, romantic attraction, and evolutionary psychology are discussed.

The Endocrinology of Exclusion Rejection Elicits Motivationally Tuned Changes in Progesterone

Social exclusion can have profound effects on a vast array of motivated psychological processes, from social withdrawal and aggression to prosocial behavior and social affiliation. The current studies examined motivationally tuned endocrinological consequences of exclusion by measuring the release of progesterone, a hormone that reflects an individual’s level of social-affiliative motivation. Results from two experiments indicate that release of progesterone following social exclusion depends on people’s levels of social anxiety and rejection sensitivity. Individuals high in social anxiety displayed a drop in progesterone in response to exclusion, a pattern consistent with a lack of affiliative motivation. In contrast, individuals high in rejection sensitivity displayed an increase in progesterone when given an opportunity to reaffiliate, a change consistent with a desire for compensatory social contact. These findings provide new insight into the immediate biological changes precipitated by social exclusion—changes that could initiate a range of motivated social responses.

Overperceiving Disease Cues: The Basic Cognition of the Behavioral Immune System

The behavioral immune system is designed to promote the detection and avoidance of potential sources of disease. Whereas previous studies of the behavioral immune system have provided insight into the types of heuristic cues used to identify disease carriers, the present research provides an understanding of the basic psychological processes involved in the detection of those cues. Across 4 studies, feeling vulnerable to disease, whether that feeling stemmed from dispositional tendencies or situational primes, facilitated a disease overperception bias--a tendency to overperceive people in the environment displaying heuristic disease cues. This disease overperception bias was observed in the outcomes of 2 cognitive processes: categorization and memory. When concerned about disease, participants set a lenient threshold for categorizing targets as displaying heuristic disease cues (e.g., obesity, old age). Additionally, concerns about disease led participants to set a lenient threshold for reporting on a recognition task that they had previously seen individuals displaying those disease cues. The present research provides insight into the basic cognitive mechanisms underlying the operation of the behavioral immune system.

Relationship of fMRI activation to clinical trial memory measures in Alzheimer disease

Background: Functional MRI (fMRI) has shown promise as a tool to characterize altered brain function in Alzheimer disease (AD) and for use in proof of concept clinical trials. FMRI studies of subjects with AD have demonstrated altered hippocampal and neocortical activation while encoding novel stimuli compared to older controls. However, the relationship between fMRI activation and performance on standardized clinical trial memory measures has not been fully investigated. Objective: To determine whether patterns of activation during an associative-memory fMRI paradigm correlate with performance on memory measures used in AD clinical trials. Methods: Twenty-nine subjects with AD underwent neuropsychological testing, including the AD Assessment Scale (ADAS-Cog), and an associative-encoding fMRI paradigm. Scores were entered as regressors in SPM2 analyses of the differential fMRI activation to novel-vs-repeated (NvR) stimuli. To account for cerebral atrophy, native-space structure-function analyses were performed with subjects’ high-resolution structural images. Results: Performance on the ADAS-Cog verbal memory component, and the ADAS-Cog total score, correlated with NvR activation in left superior temporal (p = 0.0003; r = −0.51) and left prefrontal (p = 0.00001; r = −0.63) cortices. In a subgroup with more extensive neuropsychological testing (n = 14), performance on the Free and Cued Selective Reminding Test was correlated with activation in these same regions. fMRI activation remained correlated with performance even when accounting for atrophy. Conclusions: The relationship between functional MRI (fMRI) activation and standardized memory measures supports the potential use of fMRI to investigate regional mechanisms of treatment response in clinical trials of novel therapies for Alzheimer disease. GLOSSARY: AD = Alzheimer disease; ADAS-Cog = AD Assessment Scale; EPI = echoplanar imaging sequence; FA = flip angle; FCSRT = Free and Cued Selective Reminding Test; FLAME = FMRIB’s Local Analysis of Mixed Effects; fMRI = Functional MRI; FOV = field of view; GLM = general linear model; HRF = hemodynamic response function; LFG = left fusiform gyrus; LPFC = left prefrontal cortex; LSTG = left superior temporal gyrus; MMSE = Mini-Mental State Examination; MTL = medial temporal lobe; NvR = novel-vs-repeated; ROI = region of interest; TE = echo time; TR = repetition time.