Effects of repeated cortisol administration on brain potential correlates of episodic memory retrieval

RATIONALE: Neuropsychological impairments in depressive illness may be secondary to hypercortisolaemia. Cortisol administration to healthy subjects impairs episodic memory, though how this is mediated is unknown. OBJECTIVES: To examine the effects of 1 week's administration of cortisol on the neural correlates of episodic memory in healthy subjects. METHODS: Fourteen healthy men were treated with oral cortisol (hydrocortisone 20 mg) or placebo twice daily for 1 week, in a double blind, crossover fashion. Event related potentials (ERPs) were recorded during a well-validated source memory task. Subjects listened to words spoken in a male or female voice. At test, old and new words were presented visually; subjects judged whether words were old or new, and if old, the gender of the voice at study. RESULTS: Response times were significantly speeded by cortisol. A significant reduction in recognition accuracy with cortisol was found for the second study occasion. ERP recordings with placebo showed greater positivity over left parietal and right frontal scalp areas for ERPs to items given correct source judgements versus correctly rejected new items. In comparison, cortisol increased ERP voltage between 500 and 1400 ms post-stimulus and this effect interacted with item type and electrode site, being diffusely distributed for correct rejections but of a lesser magnitude frontally for old items accorded a correct source judgement. CONCLUSIONS: Repeated cortisol administration leads to a qualitative change in the neural correlates of episodic memory retrieval in healthy subjects. This change may contribute to cognitive impairments seen in illnesses characterised by hypercortisolaemia.     

Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study

Rationale Dehydroepiandrosterone (DHEA) has been reported to enhance cognition in rodents, although there are inconsistent findings in humans.Objectives The aim of this study was to investigate the effects of DHEA administration in healthy young men on episodic memory and its neural correlates utilising an event-related potential (ERP) technique.Methods Twenty-four healthy young men were treated with a 7-day course of oral DHEA (150 mg b.d.) or placebo in a double blind, random, crossover and balanced order design. Subjective mood and memory were measured using visual analogue scales (VASs). Cortisol concentrations were measured in saliva samples. ERPs were recorded during retrieval in an episodic memory test. Low-resolution brain electromagnetic tomography (LORETA) was used to identify brain regions involved in the cognitive task.Results DHEA administration led to a reduction in evening cortisol concentrations and improved VAS mood and memory. Recollection accuracy in the episodic memory test was significantly improved following DHEA administration. LORETA revealed significant hippocampal activation associated with successful episodic memory retrieval following placebo. DHEA modified ERPs associated with retrieval and led to a trend towards an early differential activation of the anterior cingulate cortex (ACC).Conclusions DHEA treatment improved memory recollection and mood and decreased trough cortisol levels. The effect of DHEA appears to be via neuronal recruitment of the steroid sensitive ACC that may be involved in pre-hippocampal memory processing. These findings are distinctive, being the first to show such beneficial effects of DHEA on memory in healthy young men.     

Enhanced effects of cortisol administration on episodic and working memory in aging veterans with PTSD.

Though both glucocorticoid alterations and memory impairments have been noted in posttraumatic stress disorder (PTSD), it is not clear if these phenomena are causally linked. As there is emerging evidence that these domains become further altered in PTSD with increasing age, it is of interest to examine these relationships in an older cohort. Aging (mean age, 62.7+/-8.9; range, 52-81) combat veterans with (n=13) and without (n=17) PTSD received an intravenous bolus of 17.5 mg hydrocortisone (cortisol), a naturally occurring glucocorticoid, or placebo in a randomized, double-blind manner, on two mornings approximately 1-2 weeks apart. Neuropsychological testing to evaluate episodic and working memory performance was performed 75 min later. Cortisol enhanced episodic memory performance in both groups of subjects, but enhanced elements of working memory performance only in the PTSD+ group. The preferential effect of cortisol administration on working memory in PTSD may be related to the superimposition of PTSD and age, as cortisol had impairing effects on this task in a previously studied, younger cohort. The findings suggest that there may be opportunities for developing therapeutic strategies using glucocorticoids in the treatment of aging combat veterans.     

Effects of tryptophan depletion on brain potential correlates of episodic memory retrieval

RATIONALE: Neuropsychological impairments in depressive illness may be secondary to proposed serotonergic abnormalities. Acute tryptophan depletion (ATD) in healthy subjects impairs episodic memory, but the mechanism of this is unclear. OBJECTIVES: To examine the effects of ATD on the neural correlates of episodic memory retrieval in healthy subjects. METHODS: Fourteen healthy men were given an amino acid cocktail drink with or without tryptophan, in a double blind, crossover design. Event related potentials (ERPs) were recorded during a well-validated episodic memory task performed 5 h after drink ingestion. Subjects listened to words spoken in a male or female voice. At test, old and new words were presented visually; subjects judged whether words were old or new, and if old, the gender of the voice at study. RESULTS: ATD led to an 84+/-5% reduction in plasma free tryptophan concentrations, and significantly impaired episodic memory recall. ERP recordings demonstrated previously reported left parietal and right frontal "old/new" differences for ERPs to items associated with accurate episodic memory retrieval versus correctly rejected new items. ATD increased ERP voltage between 500 and 1400 ms post-stimulus particularly over posterior regions of the scalp, but there was no interaction with item type. Topographical analysis of the old/new difference revealed no significant treatment by site interaction. CONCLUSIONS: ATD impairs episodic memory recall with no effect on the magnitude or topography of the neural correlates of retrieval in healthy subjects. This suggests that the effects of ATD on recall may reflect an impairment of memory encoding and/or consolidation.     

Working memory performance and cognitive flexibility after dexamethasone or hydrocortisone administration in healthy volunteers

Objective

Several studies have shown that glucocorticoids can impair declarative memory retrieval and working memory (WM) performance. The aim of the present study was to investigate the impact of a high dose of hydrocortisone on WM, as well as to examine the effects of cortisol suppression via treatment with a high dose of dexamethasone (DEX). We hypothesized that hydrocortisone treatment results in an impaired cognitive function compared with placebo. We further expected that dexamethasone treatment is also followed by cognitive impairment, due to the hypothesis that very low levels of cortisol are also associated with alterations in memory performance.

Methods

In a placebo-controlled study with a within-subject design, 16 healthy volunteers received placebo or 120?mg of hydrocortisone (two boluses of 60?mg) directly before neuropsychological testing or 4?mg of DEX the day before testing.

Results

We did not find any effect of hydrocortisone on WM and cognitive flexibility, even though cortisol levels were high at the time of testing. Furthermore, we did not find any effect of DEX treatment on WM and reaction time in a cognitive flexibility test. However, cognitive flexibility was negatively correlated with adrenocorticotropin (ACTH) in the DEX condition.

Conclusions

Our results found no clear effect of hydrocortisone and dexamethasone treatment on WM. These results emphasize the need for further research on the association between hypothalamic?Cpituitary?Cadrenal axis activity and cognition. These studies should investigate the hypotheses of dose-dependent associations in more detail and should also include analyses on ACTH and cognition.     

Effects of elevated plasma tryptophan on brain activation associated with the Stroop task

Rationale Central fatigue, such as that found in chronic fatigue syndrome, is a state in which cognition and action require increasing effort and performance is impaired without evidence for reduced peripheral motor responsiveness. Previous studies identified functional changes in subcortical regions in patients who experience central fatigue but did not address neural correlates of the subjective experience of fatigue. Objectives This study investigated responses to acute tryptophan feeding (after administration of 30 mg/kg body mass) using functional magnetic resonance imaging to investigate neural correlates of central fatigue during a cognitively demanding exercise, the counting Stroop task. Materials and methods In a double-blind, cross-over study, eight subjects ingested l-tryptophan (Trp) or placebo (Plac) on two separate test days. Neutral (N) and interference (I) Stroop tasks were carried out. Results Plasma-free tryptophan (p[FT]) increased tenfold after l-Trp administration (P < 0.01). Although reaction times were longer after Trp (mean±SD, Plac-Neut 669 ± 163 ms, I 715 ± 174 ms, P < 0.01; Trp-Neut 712 ± 193 ms, I 761 ± 198 ms, P < 0.05), the Stroop effect was not significantly different between Plac and Trp. l-Trp administration was associated with relatively decreased activation in regions, including the left postcentral, angular, inferior frontal, and the lateral orbital gyri and the inferior frontal sulcus relative to Plac. Relatively increased activation was found after Trp in the left precuneus and in the posterior cingulate gyrus. Conclusions Thus, Trp administration before the Stroop task caused distributed functional changes in primary sensory and in multimodal neocortex, including changes in a brain region, the activity of which has been shown previously to vary with conscious awareness (precuneus). Previous reports suggest that primary mechanisms of central fatigue may be predominantly subcortical. The present results demonstrate that neocortical activity changes are also found. Whether this activity contributes to the primary mechanisms underlying central fatigue or not, the neocortical activity changes may provide an index of the conscious experience.     

The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers

Rationale: Corticosteroids are elevated in certain neuropsychiatric disorders and this may contribute to the neuropsychological impairments reported in these disorders. Objective: To examine the effects of hydrocortisone on learning, memory and executive function. Methods: Hydrocortisone 20 mg was administered twice daily for 10 days to normal male volunteers in a randomized, placebo control, crossover, within-subject design. Learning, memory and executive function were measured using selected subtests from the Cambridge Neuropsychological Test Automated Battery. Results: Hydrocortisone caused impairments of visuo-spatial memory. These included increased within search errors and impaired use of strategies on the spatial working memory subtest. In addition, administration of hydrocortisone was associated with more errors in the paired associate learning subtest, although no effect was found on the Tower of London. Hydrocortisone speeded response latencies in certain tests (pattern and spatial recognition memory). Conclusion: These results indicate that chronic administration of hydrocortisone leads to deficits in certain tests of cognitive function sensitive to frontal lobe dysfunction and may contribute to the cognitive impairment reported in certain neuropsychiatric disorders. Received: 27 July 1998 / Final version: 9 February 1999     

Sex Differences in Cortisol Level and Neurobehavioral Disinhibition in Children of Substance Abusers

SUMMARY

This investigation determined the extent to which cortisol level, an index of HPA axis activity, covaries with neurobehavioral disinhibition. The sample consisted of 369 boys and 91 girls who were assigned to either a high average risk (HAR) group or a low average risk (LAR) group based on the presence or absence of paternal substance use disorder (SUD). Neurobehavioral disinhibition was assessed using a combination of questionnaires and neuropsychological tests. Saliva was collected for cortisol determination during a mild stressor and again 35 minutes after the task. The results indicated that disinhibition was higher and cortisol level lower in boys compared to girls. Cortisol level was negatively correlated with severity of neurobehavioral disinhibition in girls, accounting for 24% of the variance. A similar trend was observed in the boys; however, the correlation did not attain statistical significance. Based on these findings, it is tentatively concluded that boys and girls differ with respect to biochemical indicators of stress reactivity underlying neurobehavioral disinhibition, a putative phenotype associated with the liability for SUD.     

Hydrocortisone impairs working memory in healthy humans, but not in patients with major depressive disorder

Objective

Several studies have shown that stress or the administration of glucocorticoids can impair hippocampus-based declarative memory retrieval and prefrontal dependent working memory performance in healthy subjects. Major Depressive Disorder (MDD) is often characterized by memory impairment and increased cortisol secretion. Studies indicate that the impairing effects of glucocorticoids on declarative memory performance are missing in patients with MDD. The purpose of our study was to investigate whether the finding of missing effects of acute cortisol administration on memory performance in MDD is also seen when examining prefrontal-based working memory.

Methods

In a placebo-controlled study, 57 patients with MDD and 56 sex- and age-matched healthy control subjects received either placebo or 10?mg of hydrocortisone orally before memory testing. To test the verbal modality of working memory, the Word Suppression Test was applied with one negative and one neutral test part.

Results

After hydrocortisone intake, healthy subjects showed a significantly poorer working memory performance compared to placebo treatment when negative interference words were administered. In contrast, memory performance of MDD patients was not affected by hydrocortisone treatment.

Conclusions

The missing effects of glucocorticoid administration on working memory in MDD might be interpreted in the context of reduced central glucocorticoid receptor function.     

Noradrenergic Enhancement of Motor Learning,Attention, and Working Memory in Humans

BackgroundNoradrenaline has an important role as a neuromodulator of the central nervous system. Noradrenergic enhancement was recently shown to enhance glutamate-dependent cortical facilitation and long term potentiation-like plasticity. As cortical excitability and plasticity are closely linked to various cognitive processes, here we aimed to explore whether these alterations are associated with respective cognitive performance changes. Specifically, we assessed the impact of noradrenergic enhancement on motor learning (serial reaction time task), attentional processes (Stroop interference task), and working memory performance (n-back letter task).MethodsThe study was conducted in a cross-over design. Twenty-five healthy humans performed the respective cognitive tasks after a single dose of the noradrenaline reuptake inhibitor reboxetine or placebo administration.ResultsThe results show that motor learning, attentional processes, and working memory performance in healthy participants were improved by reboxetine application compared with placebo.ConclusionsThe results of the present study thus suggest that noradrenergic enhancement can improve memory formation and executive functions in healthy humans. The respective changes are in line with related effects of noradrenaline on cortical excitability and plasticity.     

Acute effects of ayahuasca on neuropsychological performance: differences in executive function between experienced and occasional users

Background

Ayahuasca, a South American psychotropic plant tea containing the psychedelic 5-HT_2A receptor agonist N,N-dimethyltryptamine, has been shown to increase regional cerebral blood flow in prefrontal brain regions after acute administration to humans. Despite interactions at this level, neuropsychological studies have not found cognitive deficits in abstinent long-term users.

Objectives

Here, we wished to investigate the effects of acute ayahuasca intake on neuropsychological performance, specifically on working memory and executive function.

Methods

Twenty-four ayahuasca users (11 long-term experienced users and 13 occasional users) were assessed in their habitual setting using the Stroop, Sternberg, and Tower of London tasks prior to and following ayahuasca intake.

Results

Errors in the Sternberg task increased, whereas reaction times in the Stroop task decreased and accuracy was maintained for the whole sample following ayahuasca intake. Interestingly, results in the Tower of London showed significantly increased execution and resolution times and number of movements for the occasional but not the experienced users. Additionally, a correlation analysis including all subjects showed that impaired performance in the Tower of London was inversely correlated with lifetime ayahuasca use.

Conclusions

Acute ayahuasca administration impaired working memory but decreased stimulus–response interference. Interestingly, detrimental effects on higher cognition were only observed in the less experienced group. Rather than leading to increased impairment, greater prior exposure to ayahuasca was associated with reduced incapacitation. Compensatory or neuromodulatory effects associated with long-term ayahuasca intake could underlie preserved executive function in experienced users.     

Effects of hydrocortisone administration on cognitive function in the elderly

Previous studies have found adverse effects of both acute and chronic elevations of corticosteroids on cognitive function in humans and that cortisol levels may predict cognitive decline in elderly subjects. However, no previous studies have directly investigated the effects of hydrocortisone on cognitive functioning in the healthy elderly. Sixteen healthy elderly subjects took part in a placebo-controlled, double-blind, cross-over trial. Hydrocortisone 20 mg or placebo was administered twice, 12 h and 1 h before cognitive testing. On each occasion, a battery of neuropsychological tests was performed which included tests of attention, working memory, declarative memory and executive function. Salivary cortisol levels at the time of testing were elevated approximately 10-fold following hydrocortisone compared with placebo. No significant effects were found on memory or a range of other cognitive functions. The lack of effect of this regime of hydrocortisone is in contrast to studies in younger subjects. The elderly may be less sensitive to cognitive effects of short-term increases in cortisol levels, possibly due to an age-related downregulation of hippocampal glucocorticoid receptors.     

Effect of sub-chronic hydrocortisone on responses to amphetamine in normal male volunteers

Rationale Enhancement of dopamine (DA) release by corticosteroids may be of aetiological importance in substance misuse.Objectives To examine the effect of sub-chronic administration of hydrocortisone on the response to amphetamine in healthy male volunteers.Methods Following baseline assessment, 20 volunteers were pretreated for 7 days with 20 mg of hydrocortisone or placebo at 0800 hours and 2000 hours in a double-blind, random order, cross-over design prior to receiving 0.15 mg/kg metamphetamine intravenously. Blood samples for cortisol and prolactin were taken every 15 min. Subjects also underwent tests of neuropsychological function including sustained attention using the rapid visual information processing test (RVIP), which has been shown to be sensitive to changes in DA function.Results Metamphetamine produced a substantial reduction in prolactin levels, and increased subjective mood ratings of "mind-race" and "buzz". Sub-chronic hydrocortisone administration had no effect on these neuroendocrine responses, subjective mood changes or neurocognitive performance on a task of sustained attention (RVIP).Conclusions Despite measurable changes in neuroendocrine and affective functioning in response to metamphetamine, pretreatment with hydrocortisone did not significantly affect any of the variables measured. This suggests that this model of DA function is not affected by this regimen of corticosteroid administration.     

Contrasting effects of citalopram and reboxetine on waking salivary cortisol

Rationale. Acute administration of antidepressants which potentiate serotonin (5-HT) and noradrenaline (NA) function stimulates the hypothalamic-pituitary-adrenal (HPA) axis and increases salivary free cortisol in healthy subjects. The effects of repeated antidepressant administration have been less studied, but the ability of such treatment to modulate HPA axis activity may be relevant to therapeutic effects. Objective. The objective of the study was to assess the effect of short-term treatment with two different antidepressant medications on HPA axis activity. Methods. We studied the effect of 6-day treatment with the selective serotonin re-uptake inhibitor (SSRI) citalopram (20 mg daily) and the selective noradrenaline re-uptake inhibitor, reboxetine (8 mg daily), on diurnal salivary cortisol in a parallel group, placebo-controlled, double-blind design. Results. Citalopram significantly enhanced the increase in salivary cortisol produced by waking, while the effect of reboxetine treatment was indistinguishable from placebo. There was no change in basal salivary cortisol levels sampled in a standard pattern throughout the day. Conclusions. Short-term treatment with citalopram and reboxetine produced strikingly different effects on waking salivary cortisol, arguing against a common effect of antidepressant drugs on HPA axis function. Waking salivary cortisol may be a more reliable means of assessing the effects of antidepressant treatment on the HPA axis than a standard regime of basal salivary sampling. Electronic Publication     

Cognitive effects of methylphenidate and levodopa in healthy volunteers

Our previous study showed enhanced declarative memory consolidation after acute methylphenidate (MPH) administration. The primary aim of the current study was to investigate the duration of this effect. Secondary, the dopaminergic contribution of MPH effects, the electrophysiological correlates of declarative memory, and the specificity of memory enhancing effects of MPH to declarative memory were assessed. Effects of 40 mg of MPH on memory performance were compared to 100 mg of levodopa (LEV) in a placebo-controlled crossover study with 30 healthy volunteers. Memory performance testing included a word learning test, the Sternberg memory scanning task, a paired associates learning task, and a spatial working memory task. During the word learning test, event-related brain potentials (ERPs) were measured. MPH failed to enhance retention of words at a 30 min delay, but it improved 24 h delayed memory recall relative to PLA and LEV. Furthermore, during encoding, the P3b and P600 ERP latencies were prolonged and the P600 amplitude was larger after LEV compared to PLA and MPH. MPH speeded response times on the Sternberg Memory Scanning task and improved performance on the Paired Associates Learning task, relative to LEV, but not PLA. Performance on the Spatial working memory task was not affected by the treatments. These findings suggest that MPH and LEV might have opposite effects on memory     

首发型未服药非器质性睡眠障碍患者前瞻性记忆与工作记忆相关分析

目的 探讨首发型未服药非器质性睡眠障碍（NI）患者前瞻性记忆与工作记忆之间的相关性。方法 将2015年1月至2016年1月在安徽省精神卫生中心首次就诊未服药的80例NI患者设为观察组（NI组）,同时期选择与其人口学资料相匹配的80例合肥社区志愿者作为健康对照组（HC组）,采用基于事件前瞻性记忆（EBPM）范式和基于时间前瞻性记忆（TBPM）范式评估两组患者EBPM、TBPM得分,通过客体、语音及空间工作记忆测试评估两组患者的反应时间及错误数,比较两组研究对象EBPM、TBPM得分及客体、语音及空间工作记忆反应时长及错误数。采用Pearson相关分析NI组前瞻性记忆与工作记忆相关性。结果 NI组在EBPM和TBPM得分低于HC组,差异有统计学意义[(1 448.95±294.54)ms比(1 310.20±180.30)ms;(1 485.26±271.59)ms比(1 397.68±268.08)ms,P均<0.05],NI组在工作记忆中客体和空间工作记忆的反应时长均长于HC组,差异均有统计学意义; Pearson相关分析显示,NI组EMPI得分与客体工作记忆反应呈负相关（r=-0.310,P=0.005）。结论 NI患者存前瞻性记忆与工作记忆损伤,前瞻性记忆损伤与工作记忆损伤有一定相关性。     

Detection of the acute effects of hydrocortisone in the hippocampus using pharmacological fMRI

Impaired hippocampal function is believed to be important in the pathogenesis of depression. The hippocampus contains a high concentration of both mineralocorticoid (MR) and glucocorticoid receptors (GR), and the experimental administration of corticosteroids has been reported to mimic memory impairments seen in depression. Using pharmacological functional magnetic resonance imaging (phMRI) we investigated whether hippocampal function is altered after acute administration of hydrocortisone. Changes in BOLD signal following infusion of 100 mg hydrocortisone given as a rapid intravenous bolus were measured in 14 healthy volunteers in a within-subject placebo-controlled crossover design. Subsequently, subjects completed an n-back task during an fMRI scan. Hydrocortisone infusion caused a significant, time-dependent increase in fMRI BOLD signal in hippocampus reaching a maximal effect at 11–19 min. The n-back task increased BOLD signal in prefrontal and parietal cortical areas and decreased it in the hippocampus. After hydrocortisone the left hippocampal decrease in BOLD signal was attenuated with the magnitude of attenuation correlating with the increase seen after hydrocortisone infusion. No difference in behavioural task performance was observed. The results suggest acute hydrocortisone has rapid direct and modulatory influences on hippocampal function, probably acting through non-genomic GR or MR signalling. Hydrocortisone infusion phMRI may be a useful tool to investigate hippocampal corticosteroid receptor function in depression.     

Methylphenidate restores visual memory,but not working memory function in attention deficit-hyperkinetic disorder

Rationale Dysfunction of executive neuropsychological performance, mediated by the prefrontal cortex, has been the central focus of recent attention deficit/hyperkinetic disorder (AD-HKD) research. The role of other potential neuropsychological risk factors, such as recognition memory, remains understudied. Further, the impact of methylphenidate (MPH) on key neuropsychological processes in AD-HKD remains poorly understood.Objectives To compare the performance of boys with AD-HKD on a spatial working memory (SWM) task and on two non-working memory tasks [a simultaneous and delayed matching-to-sample task (DMtS) and a pattern-recognition task] with that of healthy boys, and to investigate the impact of acute and chronic MPH on performance of these tasks.Methods Baseline performance of 75 stimulant-naive boys with AD-HKD was compared with that of 70 healthy boys. The AD-HKD boys were then re-tested following the administration of acute and chronic challenges with MPH (0.3 mg/kg and 0.6 mg/kg) under randomised double-blind placebo controlled conditions.Results Compared with healthy boys, the AD-HKD boys demonstrated performance deficits on all neuropsychological tasks. A single dose of MPH restored performance on the DMtS task but had no impact on the SWM or pattern-recognition tasks. Chronic MPH administration did not alter performance on the SWM task but did improve performance on both the pattern-recognition and DMtS tasks. However, the acute restorative effect of MPH on DMtS diminished with repeated administration.Conclusions Our results suggest that current conceptualisations of the neuropsychological basis of AD-HKD and the proposed therapeutic mechanisms of MPH require broadening.     

Stimulus-Based Extinction Generalization: Neural Correlates and Modulation by Cortisol

BackgroundWhile healthy individuals and patients with anxiety disorders easily generalize fear responses, extinction learning is more stimulus specific. Treatments aiming to generalize extinction learning are urgently needed, since they comprise the potential to overcome stimulus specificity and reduce relapses, particularly in the face of stressful events.MethodsIn the current 3-day functional magnetic resonance imaging fear conditioning paradigm, we aimed to create a generalized extinction memory trace in 60 healthy men and women by presenting multiple sizes of 1 conditioned stimulus during extinction training (CS+G; generalized), whereas the other conditioned stimulus was solely presented in its original size (CS+N; nongeneralized). Recall was tested on the third day after pharmacological administration of either the stress hormone cortisol or placebo.ResultsAfter successful fear acquisition, prolonged activation of the amygdala and insula and deactivation of the ventromedial prefrontal cortex for CS+G compared with CS+N during extinction learning indicated sustained fear to the generalization stimuli. In line with our hypotheses, reduced amygdala activation was observed after extinction generalization on the third day in the contrast CS+G minus CS+N, possibly reflecting an attenuated return of fear. Cortisol administration before recall, however, blocked this effect.ConclusionsTaken together, the findings show that extinction generalization was associated with decreased activation of the fear network during recall after prolonged activation of the fear network during extinction learning. However, the generalization of the extinction memory did not counteract the detrimental effects of stress hormones on recall. Thus, stimulus-based extinction generalization may not be sufficient to reduce relapses after stressful experiences.     

Allopregnanolone impairs episodic memory in healthy women

OBJECTIVE: Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the gamma-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women. MATERIALS AND METHODS: Twenty-eight healthy women were included in the study. The participants were scheduled for the memory tests twice in the follicular phase. During the test sessions, an intravenous allopregnanolone and placebo infusion were administered in a double-blinded, randomized order at intervals of 48 h. Before and 10 min after the allopregnanolone/placebo injections, memory tasks were performed. RESULTS: The study demonstrated that allopregnanolone impaired episodic memory in healthy women. There was a significant difference between pre- and postallopregnanolone injection episodic memory scores (p < 0.05), whereas there was no change in episodic memory performance following the placebo injections. There was also a significant difference between allopregnanolone and placebo postinjection episodic memory scores (p < 0.05). There were no effects of allopregnanolone on the semantic memory task or working memory task. CONCLUSION: Intravenous allopregnanolone impairs episodic memory in healthy women, but there is a high degree of individual variability.