Greater Neural Differentiation in the Ventral Visual Cortex Is Associated with Youthful Memory in Superaging.

Superagers are older adults who maintain youthful memory despite advanced age. Previous studies showed that superagers exhibit greater structural and intrinsic functional brain integrity, which contribute to their youthful memory. However, no studies, to date, have examined brain activity as superagers learn and remember novel information. Here, we analyzed functional magnetic resonance imaging data collected from 41 young and 40 older adults while they performed a paired associate visual recognition memory task. Superaging was defined as youthful performance on the long delay free recall of the California Verbal Learning Test. We assessed the fidelity of neural representations as participants encoded and later retrieved a series of word stimuli paired with a face or a scene image. Superagers, like young adults, exhibited more distinct neural representations in the fusiform gyrus and parahippocampal gyrus while viewing visual stimuli belonging to different categories (greater neural differentiation) and more similar category representations between encoding and retrieval (greater neural reinstatement), compared with typical older adults. Greater neural differentiation and reinstatement were associated with superior memory performance in all older adults. Given that the fidelity of cortical sensory processing depends on neural plasticity and is trainable, these mechanisms may be potential biomarkers for future interventions to promote successful aging.

Stronger Functional Connectivity in the Default Mode and Salience Networks Is Associated With Youthful Memory in Superaging.

"Superagers" are older adults who, despite their advanced age, maintain youthful memory. Previous morphometry studies revealed multiple default mode network (DMN) and salience network (SN) regions whose cortical thickness is greater in superagers and correlates with memory performance. In this study, we examined the intrinsic functional connectivity within DMN and SN in 41 young (24.5 ± 3.6 years old) and 40 older adults (66.9 ± 5.5 years old). Superaging was defined as youthful performance on a memory recall task, the California Verbal Learning Test (CVLT). Participants underwent a resting-state functional magnetic resonance imaging (fMRI) scan and performed a separate visual-verbal recognition memory task. As predicted, within both DMN and SN, superagers had stronger connectivity compared with typical older adults and similar connectivity compared with young adults. Superagers also performed similarly to young adults and better than typical older adults on the recognition task, demonstrating youthful episodic memory that generalized across memory tasks. Stronger connectivity within each network independently predicted better performance on both the CVLT and recognition task in older adults. Variation in intrinsic connectivity explained unique variance in memory performance, above and beyond youthful neuroanatomy. These results extend our understanding of the neural basis of superaging as a model of successful aging.

Brain network connectivity-behavioral relationships exhibit trait-like properties: Evidence from hippocampal connectivity and memory.

Despite a growing number of studies showing relationships between behavior and resting-state functional MRI measures of large-scale brain network connectivity, no study to our knowledge has sought to investigate whether intrinsic connectivity-behavioral relationships are stable over time. In this study, we investigated the stability of such brain-behavior relationships at two timepoints, approximately 1 week apart. We focused on the relationship between the strength of hippocampal connectivity to posterior cingulate cortex and episodic memory performance. Our results showed that this relationship is stable across samples of a different age and reliable over two points in time. These findings provide the first evidence that the relationship between large-scale intrinsic network connectivity and episodic memory performance is a stable characteristic that varies between individuals.

Oral contraceptive pill use is associated with localized decreases in cortical thickness.

Oral contraceptive pills (OCs), which are used to prevent pregnancy by the majority of women in the United States, contain steroid hormones that may affect the brain's structure and function. In this investigation, we tested the hypothesis that OC use is associated with differences in brain structure using a hypothesis-driven, surface-based approach. In 90 women, (44 OC users, 46 naturally-cycling women), we compared the cortical thickness of brain regions that participate in the salience network and the default mode network, as well as the volume of subcortical regions in these networks. We found that OC use was associated with significantly lower cortical thickness measurements in the lateral orbitofrontal cortex and the posterior cingulate cortex. These regions are believed to be important for responding to rewards and evaluating internal states/incoming stimuli, respectively. Further investigations are needed to determine if cortical thinning in these regions are associated with behavioral changes, and also to identify whether OC use is causally or only indirectly related to these changes in brain morphology.

Semantic Clustering during Verbal Episodic Memory Encoding and Retrieval in Older Adults: One Cognitive Mechanism of Superaging.

Normal aging is commonly accompanied by a decline in cognitive abilities, including memory, yet some individuals maintain these abilities as they get older. We hypothesize that semantic clustering, as an effective strategy for improving performance on episodic recall tasks, may contribute to the maintenance of youthful memory in older adults. We investigated the dynamics of spontaneous production and utilization of the semantic clustering strategy in two independent samples of older adults who completed a list learning paradigm (N1 = 40 and N2 = 29, respectively). Specifically, we predicted and observed that older adults who spontaneously used a semantic clustering strategy throughout the encoding process learned more words by the culmination of the encoding trials (Sample 1, R2= 0.53, p < 0.001; Sample 2, R2= 0.51, p < 0.001), and that those who utilized this strategy during retrieval recalled more words, when compared to older adults who did not produce or utilize a semantic clustering strategy during both a short (Sample 1, R2 = 0.81, p < 0.001; Sample 2, R2 = 0.70, p < 0.001) and long delay retrieval (Sample 1, R2 = 0.83, p < 0.001; Sample 2, R2 = 0.77, p < 0.001). We further predicted and observed that older adults who maintained a youthful level of delayed free recall (i.e., "Superagers") produced (Sample 1, F(1, 38) = 17.81, p < 0.0001; Sample 2, F(1, 27) = 14.45, p < 0.0001) and utilized (Sample 1, F(1, 39) = 25.84, p < 0.0001; Sample 2, F(1, 27) = 12.97, p < 0.01) more semantic clustering than did older individuals with normal memory for their age. These results suggest one cognitive mechanism through which Superagers maintain youthful memory function and raise the possibility that older adults may be able to train themselves to use strategies to promote better memory.

Effects of breast cancer treatment on the hormonal and cognitive consequences of acute stress.

BACKGROUND: Cognitive difficulties following treatment for breast cancer are frequently reported. Breast cancer treatments also disrupt the function of ovarian and glucocorticoid hormone systems, both of which can affect cognition. METHODS: To assess the influence of glucocorticoid and ovarian disruption on cognitive dysfunction, survivors of breast cancer treated with the GnRH agonist Lupron were compared with healthy controls on their glucocorticoid response to a physiological stressor, and their performance on various measures of cognition including working memory, verbal paired associate memory, and narrative recall. RESULTS: The results indicated no significant glucocorticoid response to the stressor in Lupron-treated survivors, while the controls showed significantly elevated cortisol levels. Cognitive testing showed a general impairment of narrative recall in breast cancer survivors relative to controls, irrespective of stress treatment. When tested on an emotional narrative, controls exposed to post-training stress showed a significant enhancement of emotional recall and a significant relationship between cortisol release and subsequent memory. In contrast, post-training stress produced no cognitive enhancement in survivors, and memory performance in this group showed no relationship to cortisol levels. CONCLUSIONS: These results suggest that a disruption of the enhancement of memory by stress may contribute to cognitive difficulties following breast cancer treatment.

Progesterone at encoding predicts subsequent emotional memory.

Significant sex differences in the well-documented relationship between stress hormones and memory have emerged in recent studies. The potentiating effects of glucocorticoids on memory vary across the menstrual cycle, suggesting a potential interaction between these stress hormones and endogenously cycling sex hormones. Here, we show that memory for emotional materials changes significantly in accordance with hormonal changes across the menstrual cycle, suggesting that ovarian sex hormones influence the modulation of emotional memories. Sixty healthy, naturally cycling women rated 120 images on arousal and valence. One week later they completed free recall and recognition memory tests. Their menstrual cycle phases were estimated by self-report and confirmed by salivary assay of 17ß-estradiol and progesterone. Memory for emotional items only was significantly better in the high hormone (luteal) phase compared with the low hormone (follicular) phase on the free recall test; on both tests memory correlated positively with progesterone collected at the time of encoding. These findings suggest that emotional memory performance changes across the menstrual cycle, and that this change is in part mediated by endogenous progesterone cycling.

Structural integrity of the anterior mid-cingulate cortex contributes to resilience to delirium in SuperAging.

Despite its devastating clinical and societal impact, approaches to treat delirium in older adults remain elusive, making it important to identify factors that may confer resilience to this syndrome. Here, we investigated a cohort of 93 cognitively normal older patients undergoing elective surgery recruited as part of the Successful Aging after Elective Surgery study. Each participant was classified either as a SuperAger (n = 19) or typically aging older adult (n = 74) based on neuropsychological criteria, where the former was defined as those older adults whose memory function rivals that of young adults. We compared these subgroups to examine the role of preoperative memory function in the incidence and severity of postoperative delirium. We additionally investigated the association between indices of postoperative delirium symptoms and cortical thickness in functional networks implicated in SuperAging based on structural magnetic resonance imaging data that were collected preoperatively. We found that SuperAging confers the real-world benefit of resilience to delirium, as shown by lower (i.e. zero) incidence of postoperative delirium and decreased severity scores compared with typical older adults. Furthermore, greater baseline cortical thickness of the anterior mid-cingulate cortex-a key node of the brain's salience network that is also consistently implicated in SuperAging-predicted lower postoperative delirium severity scores in all patients. Taken together, these findings suggest that baseline memory function in older adults may be a useful predictor of postoperative delirium risk and severity and that superior memory function may contribute to resilience to delirium. In particular, the integrity of the anterior mid-cingulate cortex may be a potential biomarker of resilience to delirium, pointing to this region as a potential target for preventive or therapeutic interventions designed to mitigate the risk or consequences of developing this prevalent clinical syndrome.

Menstrual cycle modulation of medial temporal activity evoked by negative emotion.

Previous studies have indicated phase-related differences in HPA activity and amygdala responsiveness in women, such that the response to negative emotional images is reduced during high-estrogen phases of the menstrual cycle. Other research has indicated an opposite effect of exogenous progesterone, increasing amygdala activity at some doses. However, no study to date has assessed the response of the brain's arousal circuitry to negative images during the luteal phase, when both progesterone and estrogen levels are elevated. To address this question, 17 naturally cycling women were each scanned during the early follicular and mid-luteal phases of the cycle, and response to IAPS images was assessed by fMRI. The results indicated significantly increased activity in hippocampus and amygdala during mid-luteal scans when compared to scans in the early follicular phase. These findings suggest that progesterone-mediated effects dominate during the luteal phase, and further suggest that estrogen and progesterone may play opposing roles in modulating the brain's arousal circuitry.

Sex influences on the neurobiology of learning and memory.

In essentially every domain of neuroscience, the generally implicit assumption that few, if any, meaningful differences exist between male and female brain function is being challenged. Here we address how this development is influencing studies of the neurobiology of learning and memory. While it has been commonly held that males show an advantage on spatial tasks, and females on verbal tasks, there is increasing evidence that sex differences are more widespread than previously supposed. Differing performance between the sexes have been observed on a number of common learning tasks in both the human and animal literature, many neither purely spatial nor verbal. We review sex differences reported in various areas to date, while attempting to identify common features of sexually dimorphic tasks, and to place these differences in a neurobiological context. This discussion focuses on studies of four classes of memory tasks for which sex differences have been frequently reported: spatial, verbal, autobiographical, and emotional memory. We conclude that the female verbal advantage extends into numerous tasks, including tests of spatial and autobiographical abilities, but that a small but significant advantage may exist for general episodic memory. We further suggest that for some tasks, stress evokes sex differences, which are not normally observed, and that these differences are mediated largely by interactions between stress and sex hormones.

Motivation in the Service of Allostasis: The Role of anterior Mid Cingulate Cortex.

In this article, we suggest that motivation serves to anticipate the energy of the body and meet those needs before they arise, called allostasis. We describe motivation as the output of energy computations that include estimates about future energy/metabolic needs and the value of effort required for potential behaviors (i.e., whether the cost of effort is worthwhile). We bring neuroscience evidence to bear to support this hypothesis. We outline a system of brain networks that have been shown to be important for motivation, and focus in on one hub in this network, the anterior mid-cingulate cortex (aMCC), and discuss its importance for establishing motivation in the service of allostasis. We present evidence that the aMCC, positioned at the intersection of multiple brain networks, is wired to integrate signals relating to allostasis with its sensory consequences, termed interoception, as well as with cognitive control processes, sensory and motor functions. This integration guides the nervous system towards the optimal effort required to achieve a desired goal. Across a variety of task domains, we discuss the role of aMCC in motivation, including a) processing of the value of prior and expected rewards, b) assessment of energetic costs in the brain and the body, c) selectively learning and encoding prediction errors (unexpected changes) that are relevant for allostasis, d) computations for monitoring of internal states of the body and e) modulating the internal state of the body to prepare for action. Finally, we discuss the link between individual differences in aMCC processing and variation in two extreme ends of the range of motivational states, tenacity and apathy.

Menstrual cycle modulation of the relationship between cortisol and long-term memory.

Numerous cognitive effects of fluctuations in ovarian hormones across the menstrual cycle have been previously identified. However, the influence of ovarian hormones on learning under stressful conditions is not well understood. In this experiment, the relationship between salivary cortisol and recall performance was assessed in women at hormonally distinct phases of the menstrual cycle at encoding after cortisol levels were elevated using a cold-pressor stress (CPS) procedure. No memory difference was found between control and CPS groups in any of the three menstrual positions tested, nor was any interaction between stress condition and menstrual phase detected. However, significantly different correlations between cortisol and memory were found in the different phases. A positive correlation was found between salivary cortisol levels and recall 1 week post training when encoding occurred during the mid-luteal phase, whereas no significant relationship was found in either the early or the late follicular phase. In addition, cortisol levels were found to be elevated during the mid-luteal phase. These findings suggest that glucocorticoid effects on memory are modulated by sex hormone levels.

Hormonal Cycles, Brain Network Connectivity, and Windows of Vulnerability to Affective Disorder.

The rate of affective disorder is substantially higher in women than in men, and considerable evidence points to the actions of ovarian hormones in mediating this disparity. In this Opinion, we discuss the hypothesis that cyclic changes in ovarian hormone levels produce cyclic alterations in connectivity between the intrinsic networks of the brain. These alterations produce specific temporal windows within the menstrual cycle when internetwork connectivity is increased, associated with increased stress reactivity and better memory for unpleasant, arousing events, leading to increased negative mood and susceptibility to affective disorder. Our windows of vulnerability model offers insights for both treatment of affective disorder and research on sex differences in the brain.

Dissociable Effects of Aging on Salience Subnetwork Connectivity Mediate Age-Related Changes in Executive Function and Affect.

Aging is associated with both changes in affective experience and attention. An intrinsic brain network subserving these functions, the salience network, has not shown clear evidence of a corresponding age-related change. We propose a solution to this discrepancy: that aging differentially affects the connectivity of two dissociated subsystems of the salience network identified in our prior research (Touroutoglou et al., 2012). We examined the age-related changes in intrinsic connectivity between a dorsal and a ventral salience subsystem in a sample of 111 participants ranging in age from 18 years to 81 years old. We predicted that connectivity within the ventral subsystem is relatively preserved with age, while connectivity in the dorsal subsystem declines. Our findings showed that the connectivity within the ventral subsystem was not only preserved but it actually increased with age, whereas the connectivity within the dorsal subsystem decreased with age. Furthermore, age-related increase in arousal experience was partially mediated by age-related increases in ventral salience subsystem, whereas age-related decline in executive function was fully mediated by age-related decreases in dorsal salience subsystem connectivity. These findings explain previously conflicting results on age-related changes in the salience network, and suggest a mechanism for relatively preserved affective function in the elderly.

Resting connectivity between salience nodes predicts recognition memory.

The resting connectivity of the brain's salience network, particularly the ventral subsystem of the salience network, has been previously associated with various measures of affective reactivity. Numerous studies have demonstrated that increased affective arousal leads to enhanced consolidation of memory. This suggests that individuals with greater ventral salience network connectivity will exhibit greater responses to affective experience, leading to a greater enhancement of memory by affect. To test this hypothesis, resting ventral salience connectivity was measured in 41 young adults, who were then exposed to neutral and negative affect inductions during a paired associate memory test. Memory performance for material learned under both negative and neutral induction was tested for correlation with resting connectivity between major ventral salience nodes. The results showed a significant interaction between mood induction (negative vs neutral) and connectivity between ventral anterior insula and pregenual anterior cingulate cortex, indicating that salience node connectivity predicted memory for material encoded under negative, but not neutral induction. These findings suggest that the network state of the perceiver, measured prior to affective experience, meaningfully influences the extent to which affect modulates memory. Implications of these findings for individuals with affective disorder, who show alterations in both connectivity and memory, are considered.

Sex differences in the persistence of the amygdala response to negative material.

Previous studies have indicated that men and women have different amygdala responses to novel (vs familiar) and valenced (positive vs negative) material. It is not known, however, whether these affective sex differences are related. In this study, we tested whether women have more persistent amygdala responses to familiar, negative material than men do. During fMRI, male and female participants viewed evocative images that varied in novelty and valence. Women and men showed equivalent responses to novel negative material, but women showed a sustained amygdala response to familiar negative material relative to men, indicating that women's amygdala responses were more persistent over multiple repetitions of negative material. Individuals with more persistent amygdala responses also reported greater levels of negative effect. These findings have implications for sex differences in the incidence of affective disorders.

Glucocorticoid release and memory consolidation in men and women.

Glucocorticoid hormones have been shown to enhance memory consolidation when applied at low doses posttraining, but are ineffective or impair memory at high doses. In a test of whether this quadratic relationship also exists for endogenously released glucocorticoids, healthy men and women received cold-pressor stress (CPS) or a control procedure immediately after reading a relatively neutral story and were tested for retention 1 week later. Cortisol levels in response to the stressor were assayed from saliva. CPS significantly elevated salivary cortisol in both sexes, but enhanced memory only in male subjects. Among CPS-treated male subjects, there was a significant quadratic correlation between cortisol release posttraining and subsequent memory. Thus, these findings represent the first demonstration of an inverted-U relationship between activity of endogenous stress hormones and human memory.