Effects of estrogen on spatial navigation and memory.

RATIONALE: Animal studies suggest that the so-called "female" hormone estrogen enhances spatial navigation and memory. This contradicts the observation that males generally out-perform females in spatial navigation and tasks involving spatial memory. A closer look at the vast number of studies actually reveals that performance differences are not so clear. OBJECTIVES: To help clarify the unclear performance differences between men and women and the role of estrogen, we attempted to isolate organizational from activational effects of estrogen on spatial navigation and memory. METHODS: In a double-blind, placebo-controlled study, we tested the effects of orally administered estradiol valerate (E2V) in healthy, young women in their low-hormone menstrual cycle phase, compared to healthy, young men. Participants performed several first-person, environmentally rich, 3-D computer games inspired by spatial navigation and memory paradigms in animal research. RESULTS: We found navigation behavior suggesting that sex effects dominated any E2 effects with men performing better with allocentric strategies and women with egocentric strategies. Increased E2 levels did not lead to general improvements in spatial ability in either sex but to behavioral changes reflecting navigation flexibility. CONCLUSION: Estrogen-driven differences in spatial cognition might be better characterized on a spectrum of navigation flexibility rather than by categorical performance measures or skills.

Competition between Associations in Memory.

If two associations share an item, one may be remembered at the expense of the other (BC recalled but not AB). Here, we identify the neural processes by which this competition materializes and is resolved. We analyzed fMRI signal while participants studied sets of pairs that reliably induced pair-to-pair associative interference, but which participants could not fully resolve. Precuneus activity tracked retrieval of previous pairs during study of later overlapping pairs. This retrieval apparently produced interference by diverting study resources from the currently displayed pair. However, when activity in ventromedial prefrontal cortex, as well as anterior subregions of the hippocampus, was present while the earlier pair had been studied, interference was reversed, and both pairs were likely to be recalled. Angular gyrus and mid-frontal activity were related to interference resolution once the participant had seen both pairs. Taken together, associations compete via precuneus-mediated competitive retrieval, but ventromedial prefrontal cortex may neutralize this by ensuring that when the earlier association is remembered while studying the later pair, memories of the two pairs can overcome interference likely via activity in mid-frontal cortex and angular gyrus.

The Assimilation of Novel Information into Schemata and Its Efficient Consolidation.

Schemata enhance memory formation for related novel information. This is true even when this information is neutral with respect to schema-driven expectations. This assimilation of novel information into schemata has been attributed to more effective organizational processing that leads to more referential connections with the activated associative schema network. Animal data suggest that systems consolidation of novel assimilated information is also accelerated. In the current study, we used both multivariate and univariate fMRI analyses to provide further support for these proposals and to elucidate the neural underpinning of these processes. Twenty-eight participants (5 male) overlearned fictitious schemata for 7 weeks and then encoded novel related and control facts in the scanner. These facts were retrieved both immediately and 2 weeks later, also in the scanner. Our results conceptually replicate previous findings with respect to enhanced vmPFC-hippocampus coupling during encoding of novel related information and point to a prior knowledge effect that is distinct from situations where novel information is experienced as congruent or incongruent with a schema. Moreover, the combination of both multivariate and univariate results further specified the proposed contributions of the vmPFC, precuneus and angular gyrus network to the more efficient encoding of schema-related information. In addition, our data provide further evidence for more efficient systems consolidation of such novel schema-related and potentially assimilated information.SIGNIFICANCE STATEMENT Our prior knowledge in a certain domain, often termed schema, heavily influences whether and how we form memories for novel information that can be related to them. The results of the current study show how a ventromedial prefrontal-precuneal-angular network contributes to the more efficient encoding of novel related information. Furthermore, the observed increase in prefrontal-hippocampal coupling during this process points to a critical distinction from the previously described mechanisms supporting the encoding of information that is experienced as congruent with schema-driven expectations. In addition, we find further support for the proposal based on animal data that prior knowledge enhances also the consolidation of schema-related information.

Sex Differences and Exogenous Estrogen Influence Learning and Brain Responses to Prediction Errors.

Animal studies show marked sex differences as well as effects of estrogen (E2) in the mesocorticolimbic dopaminergic (DA) pathways, which play a critical role in reward processing and reinforcement learning and are also implicated in drug addiction. In this computational pharmacological fMRI study, we investigate the effects of both factors, sex and estrogen, on reinforcement learning and the dopaminergic system in humans; 67 male and 64 naturally cycling female volunteers, the latter in their low-hormone phase, were randomly assigned, double-blind, to take E2 or placebo. They completed a reinforcement learning task in the MRI scanner for which we have previously shown reward prediction error (RPE)-related activity to be dopaminergic. We found RPE-related brain activity to be enhanced in women compared with men and to a greater extent when E2 levels were elevated in both sexes. However, both factors, female sex and E2, slowed adaptation to RPEs (smaller learning rate). This discrepancy of larger RPE-related activity yet smaller learning rates can be explained by organizational sex differences and activational effects of circulating E2, which both affect DA release differently to DA receptor binding capacities.

Region-specific effects of acute haloperidol in the human midbrain, striatum and cortex.

D2 autoreceptors provide an important regulatory mechanism of dopaminergic neurotransmission. However, D2 receptors are also expressed as heteroreceptors at postsynaptic membranes. The expression and the functional characteristics of both, D2 auto- and heteroreceptors, differ between brain regions. Therefore, one would expect that also the net response to a D2 antagonist, i.e. whether and to what degree overall neural activity increases or decreases, varies across brain areas. In the current study we systematically tested this hypothesis by parametrically increasing haloperidol levels (placebo, 2 and 3 mg) in healthy volunteers and measuring brain activity in the three major dopaminergic pathways. In particular, activity was assessed using fMRI while participants performed a working memory and a reinforcement learning task. Consistent with the hypothesis, across brain regions activity parametrically in- and decreased. Moreover, even within the same area there were function-specific concurrent de- and increases of activity, likely caused by input from upstream dopaminergic regions. In the ventral striatum, for instance, activity during reinforcement learning decreased for outcome processing while prediction error related activity increased. In conclusion, the current study highlights the intricacy of D2 neurotransmission which makes it difficult to predict the function-specific net response of a given area to pharmacological manipulations.

Burden of dry eye disease in Germany: a retrospective observational study using German claims data.

PURPOSE: To evaluate the clinical and economic burden of dry eye disease (DED) among affected patients in Germany. METHODS: Adult patients (≥18 years) with ≥1 confirmed diagnosis of DED during the study period (2008-2015) were identified from the medical claims of ~3.6 million insured patients from Betriebskrankenkassen, a German statutory health insurance database. Prevalence (per 1000 patients) and incidence (per 1000 person-years at risk) were estimated, and demographic and clinical characteristics, treatment history (excluding over-the-counter tear supplements), healthcare resource use (HCRU) and costs were assessed. RESULTS: In this population, the prevalence of DED increased from 20.24 in 2008 to 23.13 per 1000 patients in 2014. Overall incidence was 6.24 per 1000 person-years at risk (2008-2015). Prevalence and incidence increased with age and were higher in women. Mean age at index was 63.4 years (incident cohort, n = 35 026). The most common ocular comorbidity was cataract (48.5%), and ~36% of patients were dispensed a reimbursed DED-specific medication during the postindex period - most commonly, corticosteroids alone (13.2%) or in combination with anti-infectives (21.8%). HCRU was high in patients with DED, mostly due to comorbidities. HCRU and associated costs were highest in patients ≥60 years. Total costs during the postindex period were higher in the DED cohort than among matched controls (€117 million versus €107 million; p < 0.001). CONCLUSION: This retrospective database analysis provides a better understanding of the epidemiology, clinical characteristics, real-world treatment patterns, HCRU and costs associated with DED in patients living in Germany.

A Real-World Data Study to Evaluate Treatment Patterns, Clinical Characteristics and Survival Outcomes for First- and Second-Line Treatment in Locally Advanced and Metastatic Urothelial Cancer Patients in Germany.

Background: Worldwide, urothelial carcinoma (UC) is a common cause of morbidity and mortality. In particular, the incidence of bladder cancer varies widely across Europe; Germany has the ninth highest international age-standardized incidence. For advanced UC or metastatic UC (mUC), platinum-based combination chemotherapy is the standard first-line (1L) treatment; however, there is wide heterogeneity of second-line (2L) treatments, ranging from vinflunine in parts of Europe to taxanes and other agents elsewhere in Europe, in the United States and globally. Limited data exist on treatment patterns and outcomes in patients with advanced UC or mUC in the routine clinical setting in Germany. The objective of this study was to describe clinical characteristics, treatment patterns and subsequent outcomes in this setting. Methods: This retrospective observational cohort analysis evaluated 1L and 2L treatment patterns and overall survival (OS) in patients aged ≥18 years with advanced UC or mUC (T4b, N2-3 and/or M1) at office-based urology and academic as well as nonacademic urology clinics throughout Germany between 1 November 2009 and 2 June 2016. Data were obtained through the GermanOncology database and additional treatment centers using similar electronic case report forms. Results: Among the 435 patients included in the analysis, 435 received 1L treatment and 125 received 2L treatment. Median age at start of 1L treatment was 69 years, 75% of patients were male, 75% were current or ex-smokers, 15% had hemoglobin <10 g/dL and 44% had creatinine clearance<60 mL/min/1.73; proportions were similar with 2L treatment. Cardiovascular disease was the most frequently reported comorbidity (65%), followed by diabetes (19%). Most patients (77%) received 1L platinum-based combination treatment (most commonly gemcitabine + cisplatin, 83%). Of those treated with 2L treatment, 66% received a single agent (most commonly vinflunine, 71%). Median OS (95% CI) with 1L treatment was 16.1 months (13.7-19.2) overall and 17.7 months (14.4-24.2) with 1L cisplatin + gemcitabine. In the 1L setting, 12-month OS was 61%, 24-month OS was 39% and 36-month OS was 26%. Median (95% CI) OS with 2L treatment was 9.2 months (5.5-11.6) overall and 5.9 months (4.1-12.6) with 2L vinflunine. In the 2L setting, OS rates for the same time periods were 40%, 22% and 8%, respectively. Median (95% CI) progression-free survival was 7 months (6.4-8.1) and 4 months (3.0-4.8), respectively, in the 1L and 2L settings. Objective response rates were 34% in the 1L setting and 14% in the 2L setting. No difference in OS by sex or smoking status was noted. Patients with or without renal impairment had a 12-month OS of 54% or 69%, respectively. OS at 12 months was 63% among patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 vs 53% among patients with an ECOG PS of ≥2. Cox regression analysis found no difference in OS between vinflunine and other 2L treatments (P = 0.69). Conclusions: This study provides a contemporary multicenter assessment of real-world treatment patterns and outcomes among palliatively treated patients with UC in Germany. The findings were generally consistent with the poor treatment outcomes observed globally, underscoring the need for effective 1L and 2L treatment for advanced UC or mUC.

Cued Memory Reactivation During SWS Abolishes the Beneficial Effect of Sleep on Abstraction.

Study Objectives: Extracting regularities from stimuli in our environment and generalizing these to new situations are fundamental processes in human cognition. Sleep has been shown to enhance these processes, possibly by facilitating reactivation-triggered memory reorganization. Here, we assessed whether cued reactivation during slow wave sleep (SWS) promotes the beneficial effect of sleep on abstraction of statistical regularities. Methods: We used an auditory statistical learning task, in which the benefit of sleep has been firmly established. Participants were exposed to a probabilistically determined sequence of tones and subsequently tested for recognition of novel short sequences adhering to this same statistical pattern in both immediate and delayed recall sessions. In different groups, the exposure stream was replayed during SWS in the night between the recall sessions (SWS-replay group), in wake just before sleep (presleep replay group), or not at all (control group). Results: Surprisingly, participants who received replay in sleep performed worse in the delayed recall session than the control and the presleep replay group. They also failed to show the association between SWS and task performance that has been observed in previous studies and was present in the controls. Importantly, sleep structure and sleep quality did not differ between groups, suggesting that replay during SWS did not impair sleep but rather disrupted or interfered with sleep-dependent mechanisms that underlie the extraction of the statistical pattern. Conclusions: These findings raise important questions about the scope of cued memory reactivation and the mechanisms that underlie sleep-related generalization.

Cued Reactivation of Motor Learning during Sleep Leads to Overnight Changes in Functional Brain Activity and Connectivity.

Sleep plays a role in memory consolidation. This is demonstrated by improved performance and neural plasticity underlying that improvement after sleep. Targeted memory reactivation (TMR) allows the manipulation of sleep-dependent consolidation through intentionally biasing the replay of specific memories in sleep, but the underlying neural basis of these altered memories remains unclear. We use functional magnetic resonance imaging (fMRI) to show a change in the neural representation of a motor memory after targeted reactivation in slow-wave sleep (SWS). Participants learned two serial reaction time task (SRTT) sequences associated with different auditory tones (high or low pitch). During subsequent SWS, one sequence was reactivated by replaying the associated tones. Participants were retested on both sequences the following day during fMRI. As predicted, they showed faster reaction times for the cued sequence after targeted memory reactivation. Furthermore, increased activity in bilateral caudate nucleus and hippocampus for the cued relative to uncued sequence was associated with time in SWS, while increased cerebellar and cortical motor activity was related to time in rapid eye movement (REM) sleep. Functional connectivity between the caudate nucleus and hippocampus was also increased after targeted memory reactivation. These findings suggest that the offline performance gains associated with memory reactivation are supported by altered functional activity in key cognitive and motor networks, and that this consolidation is differentially mediated by both REM sleep and SWS.

Sleep Spindle Density Predicts the Effect of Prior Knowledge on Memory Consolidation.

Information that relates to a prior knowledge schema is remembered better and consolidates more rapidly than information that does not. Another factor that influences memory consolidation is sleep and growing evidence suggests that sleep-related processing is important for integration with existing knowledge. Here, we perform an examination of how sleep-related mechanisms interact with schema-dependent memory advantage. Participants first established a schema over 2 weeks. Next, they encoded new facts, which were either related to the schema or completely unrelated. After a 24 h retention interval, including a night of sleep, which we monitored with polysomnography, participants encoded a second set of facts. Finally, memory for all facts was tested in a functional magnetic resonance imaging scanner. Behaviorally, sleep spindle density predicted an increase of the schema benefit to memory across the retention interval. Higher spindle densities were associated with reduced decay of schema-related memories. Functionally, spindle density predicted increased disengagement of the hippocampus across 24 h for schema-related memories only. Together, these results suggest that sleep spindle activity is associated with the effect of prior knowledge on memory consolidation. SIGNIFICANCE STATEMENT: Episodic memories are gradually assimilated into long-term memory and this process is strongly influenced by sleep. The consolidation of new information is also influenced by its relationship to existing knowledge structures, or schemas, but the role of sleep in such schema-related consolidation is unknown. We show that sleep spindle density predicts the extent to which schemas influence the consolidation of related facts. This is the first evidence that sleep is associated with the interaction between prior knowledge and long-term memory formation.

Cued memory reactivation during slow-wave sleep promotes explicit knowledge of a motor sequence.

Memories are gradually consolidated after initial encoding, and this can sometimes lead to a transition from implicit to explicit knowledge. The exact physiological processes underlying this reorganization remain unclear. Here, we used a serial reaction time task to determine whether targeted memory reactivation (TMR) of specific memory traces during slow-wave sleep promotes the emergence of explicit knowledge. Human participants learned two 12-item sequences of button presses (A and B). These differed in both cue order and in the auditory tones associated with each of the four fingers (one sequence had four higher-pitched tones). Subsequent overnight sleep was monitored, and the tones associated with one learned sequence were replayed during slow-wave sleep. After waking, participants demonstrated greater explicit knowledge (p = 0.005) and more improved procedural skill (p = 0.04) for the cued sequence relative to the uncued sequence. Furthermore, fast spindles (13.5-15 Hz) at task-related motor regions predicted overnight enhancement in procedural skill (r = 0.71, p = 0.01). Auditory cues had no effect on post-sleep memory performance in a control group who received TMR before sleep. These findings suggest that TMR during sleep can alter memory representations and promote the emergence of explicit knowledge, supporting the notion that reactivation during sleep is a key mechanism in this process.

Time- but not sleep-dependent consolidation promotes the emergence of cross-modal conceptual representations.

Conceptual knowledge about objects comprises a diverse set of multi-modal and generalisable information, which allows us to bring meaning to the stimuli in our environment. The formation of conceptual representations requires two key computational challenges: integrating information from different sensory modalities and abstracting statistical regularities across exemplars. Although these processes are thought to be facilitated by offline memory consolidation, investigations into how cross-modal concepts evolve offline, over time, rather than with continuous category exposure are still missing. Here, we aimed to mimic the formation of new conceptual representations by reducing this process to its two key computational challenges and exploring its evolution over an offline retention period. Participants learned to distinguish between members of two abstract categories based on a simple one-dimensional visual rule. Underlying the task was a more complex hidden indicator of category structure, which required the integration of information across two sensory modalities. In two experiments we investigated the impact of time- and sleep-dependent consolidation on category learning. Our results show that offline memory consolidation facilitated cross-modal category learning. Surprisingly, consolidation across wake, but not across sleep showed this beneficial effect. By demonstrating the importance of offline consolidation the current study provided further insights into the processes that underlie the formation of conceptual representations.