Functional imaging analyses reveal prototype and exemplar representations in a perceptual single-category task.

Similarity-based categorization can be performed by memorizing category members as exemplars or by abstracting the central tendency of the category - the prototype. In similarity-based categorization of stimuli with clearly identifiable dimensions from two categories, prototype representations were previously located in the hippocampus and the ventromedial prefrontal cortex (vmPFC) and exemplar representations in areas supporting visual memory. However, the neural implementation of exemplar and prototype representations in perceptual similarity-based categorization of single categories is unclear. To investigate these representations, we applied model-based univariate and multivariate analyses of functional imaging data from a dot-pattern paradigm-based task. Univariate prototype and exemplar representations occurred bilaterally in visual areas. Multivariate analyses additionally identified prototype representations in parietal areas and exemplar representations in the hippocampus. Bayesian analyses supported the non-presence of prototype representations in the hippocampus and the vmPFC. We additionally demonstrate that some individuals form both representation types simultaneously, probably granting flexibility in categorization strategies.

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.

Estradiol administration modulates neural emotion regulation.

Variations of sex hormones during the menstrual cycle can lead to changes in emotion processing. The ability to successfully regulate one's emotions is associated with better social abilities and mental health. While women show better performance in fear extinction learning under high estradiol (E2) compared to women under low E2 levels, little is known about the effect of E2 on emotion regulation. We explored whether E2 modulates emotion regulation in a functional magnetic resonance imaging paradigm and administered E2 valerate to 32 young naturally cycling women during their early follicular phase in a double-blind, placebo-controlled within-subject design. This standardized experimental control allowed us to explore the specific effect of E2 on emotion regulation while controlling for other hormones varying throughout the menstrual cycle. Behaviorally, no difference between conditions appeared. However, on the neural level, E2 administration was associated with lower activation in the right lingual- and left calcarine gyrus, right orbitofrontal cortex and left hippocampus relative to placebo. With respect to the main effect of down-regulation higher activation of the right superior frontal gyrus and left dorsomedial prefrontal cortex was seen; which is in accordance to previous literature. An interaction between drug condition and emotion regulation appeared for the left inferior frontal gyrus extending into the middle frontal gyrus indicating lower activation during down-regulation in the E2 condition than the placebo condition. On the behavioral level, women reported less negative affect in the E2 condition. The results fit well to a previously described psychoneuroendocrinological model in which E2 plays an important modulatory role on emotional processes and risk factors of mental health in women.

Probing emotional recognition memory: how different response formats affect response behaviour.

Receiver-operating characteristic curves from confidence ratings and remember/know (R/K) judgments are often used to estimate the contribution of familiarity and recollection to recognition memory. Both coming with specific advantages and disadvantages, which could be reduced by their combination. Little is known how the combination of both methods impacts response behaviour. This could be particularly important for emotional memory research, which is susceptible to variation in meta-mnemonic processes. We obtained reference performance indices from the two methods, instructing individuals to give confidence ratings or R/K judgments in one step. Against these, we contrasted R/K judgments in a two-step format and two combined formats, confidence ratings followed by R/K judgments and vice versa. Regarding reference formats, confidence ratings resulted in more liberal response criteria and false alarm rates than R/K judgments. Two-step R/K judgments and confidence ratings followed by R/K judgments resulted in patterns similar to one-step R/K judgments. Reversing the order resulted in more liberal response biases, higher hit and false alarms rates. Recollection and familiarity were unaffected by response formats. Valence effects did not vary with response formats. The present results suggest that confidence ratings followed by R/K judgments provide the advantages of both without biasing response behaviour.

Prototype-based category learning in autism: A review.

Similarity-based categorization, as an important cognitive skill, can be performed by abstracting a categories' central tendency, the so-called prototype, or by memorizing individual exemplars of a category. The flexible selection of an appropriate strategy is crucial for effective cognitive functioning. The detail-focused cognitive style in individuals with autism spectrum disorders (ASD) has been hypothesized to specifically impair prototype-based categorization but to leave exemplar-based categorization unimpaired. We first give an overview of approaches to investigate prototype-based abstraction in the prototype-distortion task, with an emphasis on model-based approaches suitable to discern the two strategies on the individual level. The second part summarizes literature speaking to prototype-based categorization in ASD using that task. Despite considerable inconsistencies, most studies appear to confirm that autistic individuals have more difficulties to perform prototype-distortion tasks than non-autistic individuals. We highlight how inconsistencies in literature can be resolved by taking the differences in task designs into account. The current review illustrates the need for sensitive computational approaches, suitable to detect hidden individual differences and potential compensatory strategies.

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.

Test-retest reliability of the emotional enhancement of memory.

Emotionally arousing stimuli are usually better remembered than neutral ones. This effect can be observed immediately after encoding and becomes more robust after a period of consolidation. The magnitude of this effect in an individual has been treated in various research contexts implicitly as reliable and temporally stable. However, we recently observed in 69 participants that an individual's memory advantage for negative over neutral stimuli, whether immediate or delayed, was very weakly correlated with the advantage measured after 3.5 years, albeit with slightly different memory paradigms. In the current study, we tested whether the test-retest reliability of these emotional memory effects might be larger if the temporal lapse between tests was shorter (10 weeks) and more similar memory tests were used. We observed that the better memory for emotional stimuli is highly replicable on the group level. However, the retest reliability on the individual level was very low. We replicated these findings by re-analysing data from a previous study where female participants took emotional memory tests at two different points of their menstrual cycle. We conclude, therefore, that the individual emotional enhancement of memory is not stable or that it cannot be measured reliably with the standard emotional memory paradigm.

Dose-dependent effects of estrogen on prediction error related neural activity in the nucleus accumbens of healthy young women.

RATIONALE: Whereas the effect of the sex steroid 17-beta-estradiol (E2) on dopaminergic (DA) transmission in the nucleus accumbens (NAc) is well evidenced in female rats, studies in humans are inconsistent. Moreover, linear and inverted u-shaped dose response curves have been observed for E2's effects on hippocampal plasticity, but the shape of dose response curves for E2's effects on the NAc is much less characterized. OBJECTIVES: Investigation of dose response curves for E2's effects on DA-related neural activity in the human NAc. METHODS: Placebo or E2 valerate in doses of 2, 4, 6 or 12 mg was orally administered to 125 naturally cycling young women during the low-hormone menstruation phase on two consecutive days using a randomized, double-blinded design. The E2 treatment regimen induced a wide range of E2 levels, from physiological (2- and 4-mg groups; equivalent to cycle peak) to supraphysiological levels (6- and 12-mg groups; equivalent to early pregnancy). This made it possible to study different dose response functions for E2's effects on NAc activity. During E2 peak, participants performed a well-established reversal learning paradigm. We used trial-wise prediction errors (PE) estimated via a computational reinforcement learning model as a proxy for dopaminergic activity. Linear and quadratic regression analyses predicting PE-related NAc activity from salivary E2 levels were calculated. RESULTS: There was a positive linear relationship between PE-associated NAc activity and salivary E2 increases. CONCLUSIONS: The randomized, placebo-controlled elevation of E2 levels stimulates NAc activity in the human brain, likely mediated by dopaminergic processes.

Effects of the experimental administration of oral estrogen on prefrontal functions in healthy young women.

17-Beta-estradiol (E2) stimulates neural plasticity and dopaminergic transmission in the prefrontal cortex, which is critically involved in attentional control, working memory, and other executive functions. Studies investigating E2's actions on prefrontally mediated behavior in the course of the menstrual cycle or during hormone replacement therapy are inconclusive, with numerous null findings as well as beneficial and detrimental effects. The current study focused on the effect of E2 on attentional performance, as animal studies indicate that supraphysiological doses (i.e., above estrous cycle levels) of E2 have beneficial effects on measures of attention in female rodents. To translate these findings to humans, we administered 12 mg E2-valerate or placebo orally to 34 naturally cycling women in the low-hormone early follicular phase using a randomized, double-blinded, pre-post design. Behavioral performance was tested twice during baseline and E2 peak, where E2 levels reached mildly supraphysiological levels in the E2 group. Aside from mainly prefrontally mediated tasks of attention, working memory, and other executive functions, we employed tasks of affectively modulated attention, emotion recognition, and verbal memory. E2 administration had a significant, but subtle negative impact on general processing speed and working memory performance. These effects could be related to an overstimulation of dopaminergic transmission. The negative effect of supraphysiological E2 on working memory connects well to animal literature. There were no effects on attentional performance or any other measure. This could be explained by different E2 levels being optimal for changing behavioral performance in specific tasks, which likely depends on the brain regions involved.

Linear and inverted U-shaped dose-response functions describe estrogen effects on hippocampal activity in young women.

In animals, 17-beta-estradiol (E2) enhances hippocampal plasticity in a dose-dependent, monotonically increasing manner, but this relationship can also exhibit an inverted U-shaped function. To investigate E2's dose-response function in the human hippocampus, we pharmacologically increased E2 levels in 125 naturally cycling women (who were in their low-hormone menstruation phase) to physiological (equivalent to menstrual cycle peak) and supraphysiological (equivalent to levels during early pregnancy) concentrations in a placebo-controlled design. Twenty-four hours after first E2 intake, we measured brain activity during encoding of neutral and negative pictures and then tested recognition memory 24 h after encoding. Here we report that E2 exhibits both a monotonically increasing relationship with hippocampal activity as well as an inverted U-shaped relationship, depending on the hippocampal region. Hippocampal activity exhibiting a U-shaped relationship inflects at supraphysiological E2 levels, suggesting that while E2 within physiological ranges stimulates hippocampal activity, supraphysiological ranges show opposite effects.

Dissociation of immediate and delayed effects of emotional arousal on episodic memory.

Emotionally arousing events are usually better remembered than neutral ones. This phenomenon is in humans mostly studied by presenting mixed lists of neutral and emotional items. An emotional enhancement of memory is observed in these studies often already immediately after encoding and increases with longer delays and consolidation. A large body of animal research showed that the more efficient consolidation of emotionally arousing events is based on an activation of the central noradrenergic system and the amygdala (Modulation Hypothesis; Roozendaal & McGaugh, 2011). The immediately superior recognition of emotional items is attributed primarily to their attraction of attention during encoding which is also thought to be based on the amygdala and the central noradrenergic system. To investigate whether the amygdala and noradrenergic system support memory encoding and consolidation via shared neural substrates and processes a large sample of participants (n = 690) encoded neutral and arousing pictures. Their memory was tested immediately and after a consolidation delay. In addition, they were genotyped in two relevant polymorphisms (α2B-adrenergic receptor and serotonin transporter). Memory for negative and positive emotional pictures was enhanced at both time points where these enhancements were correlated (immediate r = 0.60 and delayed test r = 0.46). Critically, the effects of emotional arousal on encoding and consolidation correlated only very low (negative r = 0.14 and positive r = 0.03 pictures) suggesting partly distinct underlying processes consistent with a functional heterogeneity of the central noradrenergic system. No effect of genotype on either effect was observed.

Visual Complexity and Affect: Ratings Reflect More Than Meets the Eye.

Pictorial stimuli can vary on many dimensions, several aspects of which are captured by the term 'visual complexity.' Visual complexity can be described as, "a picture of a few objects, colors, or structures would be less complex than a very colorful picture of many objects that is composed of several components." Prior studies have reported a relationship between affect and visual complexity, where complex pictures are rated as more pleasant and arousing. However, a relationship in the opposite direction, an effect of affect on visual complexity, is also possible; emotional arousal and valence are known to influence selective attention and visual processing. In a series of experiments, we found that ratings of visual complexity correlated with affective ratings, and independently also with computational measures of visual complexity. These computational measures did not correlate with affect, suggesting that complexity ratings are separately related to distinct factors. We investigated the relationship between affect and ratings of visual complexity, finding an 'arousal-complexity bias' to be a robust phenomenon. Moreover, we found this bias could be attenuated when explicitly indicated but did not correlate with inter-individual difference measures of affective processing, and was largely unrelated to cognitive and eyetracking measures. Taken together, the arousal-complexity bias seems to be caused by a relationship between arousal and visual processing as it has been described for the greater vividness of arousing pictures. The described arousal-complexity bias is also of relevance from an experimental perspective because visual complexity is often considered a variable to control for when using pictorial stimuli.

Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases.

BACKGROUND: Anxiety disorders are more prevalent in women than in men. Despite this sexual dimorphism, most experimental studies are conducted in male participants and studies focusing on sex differences are sparse. In addition, the role of hormonal contraceptives and menstrual cycle phase in fear conditioning and extinction processes remain largely unknown. METHODS: We investigated sex differences in context-dependent fear acquisition and extinction (day 1) and their retrieval/expression (day 2). Skin conductance responses (SCRs), fear and unconditioned stimulus expectancy ratings were obtained. RESULTS: We included 377 individuals (261 women) in our study. Robust sex differences were observed in all dependent measures. Women generally displayed higher subjective ratings but smaller SCRs than men and showed reduced excitatory/inhibitory conditioned stimulus (CS+/CS-) discrimination in all dependent measures. Furthermore, women using hormonal contraceptives showed reduced SCR CS discrimination on day 2 than men and free-cycling women, while menstrual cycle phase had no effect. LIMITATIONS: Possible limitations include the simultaneous testing of up to 4 participants in cubicles, which might have introduced a social component, and not assessing postexperimental contingency awareness. CONCLUSION: The response pattern in women shows striking similarity to previously reported sex differences in patients with anxiety. Our results suggest that pronounced deficits in associative discrimination learning and subjective expression of safety information (CS- responses) might underlie higher prevalence and higher symptom rates seen in women with anxiety disorders. The data call for consideration of biological sex and hormonal contraceptive use in future studies and may suggest that targeting inhibitory learning during therapy might aid precision medicine.

The effect of estrogen synthesis inhibition on hippocampal memory.

17-Beta-estradiol (E2) facilitates long term-potentiation (LTP) and increases spine synapse density in hippocampal neurons of ovariectomized rodents. Consistent with these beneficial effects on the cellular level, E2 improves hippocampus-dependent memory. A prominent approach to study E2 effects in rodents is the inhibition of its synthesis by letrozole, which reduces LTPs and spine synapse density. In the current longitudinal functional magnetic resonance imaging (fMRI) study, we translated this approach to humans and compared the impact of E2 synthesis inhibition on memory performance and hippocampal activity in post-menopausal women taking letrozole (n = 21) to controls (n = 24). In particular, we employed various behavioral memory paradigms that allow the disentanglement of hippocampus-dependent and -independent memory. Consistent with the literature on rodents, E2 synthesis inhibition specifically impaired hippocampus-dependent memory, however, this did not apply to the same degree to all of the employed paradigms. On the neuronal level, E2 depletion tended to decrease hippocampal activity during encoding, whereas it increased activity in the anterior cingulate and the dorsolateral prefrontal cortex. We thus infer that the inhibition of E2 synthesis specifically impairs hippocampal functioning in humans, whereas the increased prefrontal activity presumably reflects a compensatory mechanism, which is already known from studies on cognitive aging and Alzheimer's disease.

Menstrual-cycle dependent fluctuations in ovarian hormones affect emotional memory.

The hormones progesterone and estradiol modulate neural plasticity in the hippocampus, the amygdala and the prefrontal cortex. These structures are involved in the superior memory for emotionally arousing information (EEM effects). Therefore, fluctuations in hormonal levels across the menstrual cycle are expected to influence activity in these areas as well as behavioral memory performance for emotionally arousing events. To test this hypothesis, naturally cycling women underwent functional magnetic resonance imaging during the encoding of emotional and neutral stimuli in the low-hormone early follicular and the high-hormone luteal phase. Their memory was tested after an interval of 48 h, because emotional arousal primarily enhances the consolidation of new memories. Whereas overall recognition accuracy remained stable across cycle phases, recognition quality varied with menstrual cycle phases. Particularly recollection-based recognition memory for negative items tended to decrease from early follicular to luteal phase. EEM effects for both valences were associated with higher activity in the right anterior hippocampus during early follicular compared to luteal phase. Valence-specific modulations were found in the anterior cingulate, the amygdala and the posterior hippocampus. Current findings connect to anxiolytic actions of estradiol and progesterone as well as to studies on fear conditioning. Moreover, they are in line with differential networks involved in EEM effects for positive and negative items.

Differential modulation of activity related to the anticipation of monetary gains and losses across the menstrual cycle.

Estradiol and progesterone interact with the dopaminergic and other neurotransmitter systems that are involved in the processing of rewards. On the systems level, these hormones modulate responses to stimulants as well as neuronal activity related to the anticipation of monetary gains. As different mechanisms might underlie the processing of gains and losses, the current study aims to investigate whether neural correlates of gain and loss anticipation are differentially modulated by menstrual cycle phases. Therefore, young, naturally cycling women were examined by means of functional neuroimaging during performing a modified version of the 'Monetary Incentive Delay' task in the early follicular and in the luteal menstrual cycle phase. During the low hormone early follicular phase, the anticipation of high vs. low gains and losses was associated with activity in a largely overlapping network of brain areas. However, high hormone levels in the luteal phase affected brain activity in these areas differentially during the anticipation of high vs. low gains and losses. In particular, the orbitofrontal cortex showed a reduced sensitivity to gain magnitude, whereas the ventral striatum and the anterior cingulate showed a reduced sensitivity to loss magnitude. In summary, the high amount of progesterone and estradiol in the luteal phase decreased activity related to the anticipation of monetary gains and losses in different brain areas, suggesting that hormones modulate different processes during the anticipation of gain and loss magnitude.

Estrogen and the male hippocampus: genetic variation in the aromatase gene predicting serum estrogen is associated with hippocampal gray matter volume in men.

The neurosteroid 17-beta estradiol (E2) plays an important role in neuronal plasticity, neurogenesis and neuroprotection of hippocampal neurons in slice cultures and the female brain. While some effects of E2 on hippocampal neurons observed in females were also seen in the male hippocampus, others seem to be specific to females. The current study aimed to further explore the effect of E2 on the male hippocampus by investigating the relationship between genetic variations in E2 synthesis and hippocampal gray matter (GM) volume. We chose a single nucleotide polymorphism (rs700158, SNP) in the gene CYP19A1 coding for the final enzyme (aromatase) in E2 synthesis. Men homozygous for the A allele of rs700518 have repeatedly been shown to have higher E2 serum levels than male carriers of the G allele. Two independent cohorts of healthy young men were genotyped for rs700518 and voxel-based morphometry (VBM) was performed on structural magnetic resonance images to determine genotype dependent group differences. Men homozygous for the A allele of rs700518 had greater bilateral posterior hippocampal GM volumes in both cohorts. Thus, the genotype associated with higher E2 serum levels was also associated with greater hippocampal gray matter.

The impact of acute psychosocial stress on magnetoencephalographic correlates of emotional attention and exogenous visual attention.

Stress-induced acute activation of the cerebral catecholaminergic systems has often been found in rodents. However, little is known regarding the consequences of this activation on higher cognitive functions in humans. Theoretical inferences would suggest increased distractibility in the sense of increased exogenous attention and emotional attention. The present study investigated the influence of acute stress responses on magnetoencephalographic (MEG) correlates of visual attention. Healthy male subjects were presented emotional and neutral pictures in three subsequent MEG recording sessions after being exposed to a TSST-like social stressor, intended to trigger a HPA-response. The subjects anticipation of another follow-up stressor was designed to sustain the short-lived central catecholaminergic stress reactions throughout the ongoing MEG recordings. The heart rate indicates a stable level of anticipatory stress during this time span, subsequent cortisol concentrations and self-report measures of stress were increased. With regard to the MEG correlates of attentional functions, we found that the N1m amplitude remained constantly elevated during stressor anticipation. The magnetic early posterior negativity (EPNm) was present but, surprisingly, was not at all modulated during stressor anticipation. This suggests that a general increase of the influence of exogenous attention but no specific effect regarding emotional attention in this time interval. Regarding the time course of the effects, an influence of the HPA on these MEG correlates of attention seems less likely. An influence of cerebral catecholaminergic systems is plausible, but not definite.