Joseph M. Andreano

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.

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.

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 17β-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.

Youthful Brains in Older Adults: Preserved Neuroanatomy in the Default Mode and Salience Networks Contributes to Youthful Memory in Superaging

Decline in cognitive skills, especially in memory, is often viewed as part of “normal” aging. Yet some individuals “age better” than others. Building on prior research showing that cortical thickness in one brain region, the anterior midcingulate cortex, is preserved in older adults with memory performance abilities equal to or better than those of people 20–30 years younger (i.e., “superagers”), we examined the structural integrity of two large-scale intrinsic brain networks in superaging: the default mode network, typically engaged during memory encoding and retrieval tasks, and the salience network, typically engaged during attention, motivation, and executive function tasks. We predicted that superagers would have preserved cortical thickness in critical nodes in these networks. We defined superagers (60–80 years old) based on their performance compared to young adults (18–32 years old) on the California Verbal Learning Test Long Delay Free Recall test. We found regions within the networks of interest where the cerebral cortex of superagers was thicker than that of typical older adults, and where superagers were anatomically indistinguishable from young adults; hippocampal volume was also preserved in superagers. Within the full group of older adults, thickness of a number of regions, including the anterior temporal cortex, rostral medial prefrontal cortex, and anterior midcingulate cortex, correlated with memory performance, as did the volume of the hippocampus. These results indicate older adults with youthful memory abilities have youthful brain regions in key paralimbic and limbic nodes of the default mode and salience networks that support attentional, executive, and mnemonic processes subserving memory function. SIGNIFICANCE STATEMENT Memory performance typically declines with age, as does cortical structural integrity, yet some older adults maintain youthful memory. We tested the hypothesis that superagers (older individuals with youthful memory performance) would exhibit preserved neuroanatomy in key brain networks subserving memory. We found that superagers not only perform similarly to young adults on memory testing, they also do not show the typical patterns of brain atrophy in certain regions. These regions are contained largely within two major intrinsic brain networks: the default mode network, implicated in memory encoding, storage, and retrieval, and the salience network, associated with attention and executive processes involved in encoding and retrieval. Preserved neuroanatomical integrity in these networks is associated with better memory performance among older adults.

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 womens 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.

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 brains 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. Hum Brain Mapp 36:2644–2654, 2015.

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.

Resting connectivity between salience nodes predicts recognition memory

Abstract 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.

Preserved 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 preserved 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 elderly adults (66.9 ± 5.5 years old). As in prior studies, superaging was defined as youthful performance on a memory recall task, the California Verbal Learning Test (CVLT). Participants underwent a resting state fMRI scan and performed a separate visual-verbal recognition memory task. As predicted, within both DMN and SN, superagers had stronger connectivity compared to typical older adults and similar connectivity compared to 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 preserved neuroanatomy. A post-hoc analysis revealed that DMN and SN nodes were more strongly inversely correlated in superagers than in typical older adults but were similarly correlated in superagers and young adults. Stronger between-network inverse correlations also predicted better memory performance in the entire sample of older adults. These results extend our understanding of the neural basis of superaging as a model of successful aging. SIGNIFICANCE STATEMENT Memory capacity generally declines with age, but a unique group of older adults – ‘superagers’ – have memory capacities rivaling those of younger adults, as well as preserved neuroanatomy in an ensemble of regions contained in two core intrinsic brain networks – the default mode and salience networks. In this study, we assessed the strength of intrinsic connectivity within these networks in superagers and typical older adults compared to young adults. We also expanded the behavioral assessment of memory. As predicted, superagers have intrinsic connectivity within the default mode and salience networks that is stronger than typical older adults and similar to that of young adults. Within older adults, preserved intrinsic connectivity within each network was uniquely associated with better memory performance.

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.