Impaired free recall of neutral but not negative material tested 105 min after cortisol administration.

Pharmacological studies have consistently shown memory retrieval impairment after administration of cortisol, particularly pronounced for emotional laboratory material (i.e. list of emotional words). However, it is unclear how pharmacological elevation of cortisol affects memory retrieval of ecologically-relevant emotional material (i.e. similar to a newspaper article about an emotional event). In the present study, we aimed to explore whether cortisol administration affects the recall of ecologically-relevant emotional and neutral material, and when memory retrieval occurs after a longer delay (105 min). In this double-blind, pseudo-randomized, placebo-control study, 79 participants learned a negative text and a neutral text. Twenty-four hours later, they were administrated either 10 mg of hydrocortisone or placebo. After 105 min, participants engaged in free recall of both texts. The group with cortisol administration showed significantly reduced free recall compared to the placebo group. Interestingly, this memory retrieval impairment was driven by significantly lower recall after cortisol vs. placebo administration for neutral texts, but not negative texts. The current finding suggests that cortisol administration impairs neutral ecologically-relevant material while leaving emotional material unaffected. These divergent findings, compared to existing literature, emphasize the necessity of employing more ecologically validated material to gain a more comprehensive understanding of the intricate interplay between cortisol administration and memory for ecological material.

Distinct hemodynamic and functional connectivity features of fatigue in clinically isolated syndrome and multiple sclerosis: accounting for the confounding effect of concurrent depression symptoms.

PURPOSE: This study aims to identify common and distinct hemodynamic and functional connectivity (FC) features for self-rated fatigue and depression symptoms in patients with clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RR-MS). METHODS: Twenty-four CIS, 29 RR-MS patients, and 39 healthy volunteers were examined using resting-state fMRI (rs-fMRI) to obtain whole-brain maps of (i) hemodynamic response patterns (through time shift analysis), (ii) FC (via intrinsic connectivity contrast maps), and (iii) coupling between hemodynamic response patterns and FC. Each regional map was correlated with fatigue scores, controlling for depression, and with depression scores, controlling for fatigue. RESULTS: In CIS patients, the severity of fatigue was associated with accelerated hemodynamic response in the insula, hyperconnectivity of the superior frontal gyrus, and evidence of reduced hemodynamics-FC coupling in the left amygdala. In contrast, depression severity was associated with accelerated hemodynamic response in the right limbic temporal pole, hypoconnectivity of the anterior cingulate gyrus, and increased hemodynamics-FC coupling in the left amygdala. In RR-MS patients, fatigue was associated with accelerated hemodynamic response in the insula and medial superior frontal cortex, increased functional role of the left amygdala, and hypoconnectivity of the dorsal orbitofrontal cortex, while depression symptom severity was linked to delayed hemodynamic response in the medial superior frontal gyrus; hypoconnectivity of the insula, ventromedial thalamus, dorsolateral prefrontal cortex, and posterior cingulate; and decreased hemodynamics-FC coupling of the medial orbitofrontal cortex. CONCLUSION: There are distinct FC and hemodynamic responses, as well as different magnitude and topography of hemodynamic connectivity coupling, associated with fatigue and depression in early and later stages of MS.

IL-6 Enhances the Negative Impact of Cortisol on Cognition among Community-Dwelling Older People without Dementia.

There is growing evidence that high basal cortisol levels and systemic inflammation independently contribute to cognitive decline among older people without dementia. The present cross-sectional study examined (a) the potential synergistic effect of cortisol levels and systemic inflammation on executive function and (b) whether this effect is more prominent among older people with mild cognitive impairment (MCI). A sub-sample of 99 patients with MCI and 84 older people without cognitive impairment (CNI) (aged 73.8 ± 7.0 years) were recruited from a large population-based cohort in Crete, Greece, and underwent comprehensive neuropsychiatric and neuropsychological evaluation and a single morning measurement of cortisol and IL-6 plasma levels. Using moderated regression models, we found that the relation between cortisol and executive function in the total sample was moderated by IL-6 levels (b = -0.994, p = 0.044) and diagnostic group separately (b = -0.632, p < 0.001). Moreover, the interaction between cortisol and IL-6 levels was significant only among persons with MCI (b = -0.562, p < 0.001). The synergistic effect of stress hormones and systemic inflammation on cognitive status appears to be stronger among older people who already display signs of cognitive decline. Targeting hypercortisolemia and inflammation may be a promising strategy toward improving the course of cognitive decline.

Chronic Mild Traumatic Brain Injury: Aberrant Static and Dynamic Connectomic Features Identified Through Machine Learning Model Fusion.

Traumatic Brain Injury (TBI) is a frequently occurring condition and approximately 90% of TBI cases are classified as mild (mTBI). However, conventional MRI has limited diagnostic and prognostic value, thus warranting the utilization of additional imaging modalities and analysis procedures. The functional connectomic approach using resting-state functional MRI (rs-fMRI) has shown great potential and promising diagnostic capabilities across multiple clinical scenarios, including mTBI. Additionally, there is increasing recognition of a fundamental role of brain dynamics in healthy and pathological cognition. Here, we undertake an in-depth investigation of mTBI-related connectomic disturbances and their emotional and cognitive correlates. We leveraged machine learning and graph theory to combine static and dynamic functional connectivity (FC) with regional entropy values, achieving classification accuracy up to 75% (77, 74 and 76% precision, sensitivity and specificity, respectively). As compared to healthy controls, the mTBI group displayed hypoconnectivity in the temporal poles, which correlated positively with semantic (r = 0.43, p < 0.008) and phonemic verbal fluency (r = 0.46, p < 0.004), while hypoconnectivity in the right dorsal posterior cingulate correlated positively with depression symptom severity (r = 0.54, p < 0.0006). These results highlight the importance of residual FC in these regions for preserved cognitive and emotional function in mTBI. Conversely, hyperconnectivity was observed in the right precentral and supramarginal gyri, which correlated negatively with semantic verbal fluency (r=-0.47, p < 0.003), indicating a potential ineffective compensatory mechanism. These novel results are promising toward understanding the pathophysiology of mTBI and explaining some of its most lingering emotional and cognitive symptoms.

Pharmacologically increased cortisol levels impair recall of associative background context memory in males, but not females.

Laboratory studies have consistently shown that stress impairs memory retrieval of individual parts (items) of a memory. The stress-hormone cortisol has been particularly linked to this impairment. However, it is unclear whether cortisol similarly affects the binding of items to associative context information in memory, i.e. the constituents of episodic memory. Here, we examine memory retrieval of item and associative memory under pharmacologically elevated cortisol vs. normal levels. Given that previous studies have indicated potential sex differences in the stress- and cortisol-induced memory modulation, we additionally assessed whether there may be sex differences for the cortisol effect on memory retrieval. Eighty-four female and male participants were tested in a placebo controlled, double-blind between-subject design, assigned to either a cortisol (10 mg hydrocortisone) or a placebo group. Participants of both groups were presented foreground images of negative and neutral valence on different neutral background scenes. Twenty-four hours later, participants' memory for the images and their associated background scene was tested with a recognition task 20 min after substance administration. Among the 78 participants of both groups included in the final analysis, cortisol levels were higher in the cortisol group in comparison to the placebo group, and female participants had higher cortisol levels after hydrocortisone intake in comparison to male participants. Item memory did not differ between the placebo and cortisol group. In contrast, in males, but not females, associative memory for the background scene of emotional foreground images was lower in the cortisol vs. placebo group. Moreover, the individual cortisol increase during the recognition task was negatively correlated to memory for the background scenes of the emotional foreground images only in male participants of the cortisol group. This study shows that pharmacologically increased cortisol levels distinctly affect associative memory in female and male participants, but have no effect on item memory, indicating a complex interaction for the stress effects on memory.

Basal Cortisol Levels Are Increased in Patients with Mild Cognitive Impairment: Role of Insomnia and Short Sleep Duration.

BACKGROUND: Mild cognitive impairment (MCI) is frequent in elderly and a risk factor for dementia. Both insomnia and increased cortisol levels are risk factors for MCI. OBJECTIVE: We examined cross-sectionally whether increased cortisol levels are associated with short sleep duration (SSD) and/or the insomnia short sleep duration (ISS) phenotype, in elderly with MCI. METHODS: One hundred twenty-four participants with MCI and 84 cognitively non-impaired controls (CNI)≥60 years underwent medical history, physical examination, neuropsychiatric evaluation, neuropsychological testing, 3-day actigraphy, assessment of subjective insomnia symptoms, and a single morning plasma cortisol level. The short sleep phenotypes were defined by sleep efficiency below the median of the entire sample (i.e.,≤81%) with at least one insomnia symptom (ISS) or without (SSD). ANOVA models were used to compare the various sleep phenotypes to those who did not present either short sleep or insomnia symptoms [non-insomnia (NI)]. RESULTS: MCI participants had higher cortisol levels compared to the CNI group (p = 0.009). MCI participants with insomnia (n = 44) or SSD (n = 38) had higher cortisol levels compared to the NI group (n = 42; p = 0.014 and p = 0.045, respectively). Furthermore, MCI participants with ISS phenotype but not those with insomnia with normal sleep duration had higher cortisol levels compared to NI (p = 0.011 and p = 0.4, respectively). Both linear trend analyses showed that cortisol reached the highest levels in the ISS phenotype. CONCLUSION: The ISS and SSD phenotypes are associated with increased cortisol levels in elderly with MCI. Improving sleep quality and duration and decreasing cortisol levels may delay further cognitive decline.

Converging evidence of impaired brain function in systemic lupus erythematosus: changes in perfusion dynamics and intrinsic functional connectivity.

PURPOSE: Τhe study examined changes in hemodynamics and functional connectivity in patients with systemic lupus erythematosus (SLE) with or without neuropsychiatric manifestations. METHODS: Participants were 44 patients with neuropsychiatric SLE (NPSLE), 20 SLE patients without such manifestations (non-NPSLE), and 35 healthy controls. Resting-state functional MRI (rs-fMRI) was used to obtain whole-brain maps of (a) perfusion dynamics derived through time shift analysis (TSA), (b) regional functional connectivity (intrinsic connectivity contrast (ICC) coefficients), and (c) hemodynamic-connectivity coupling. Group differences were assessed through independent samples t-tests, and correlations of rs-fMRI indices with clinical variables and neuropsychological test scores were, also, computed. RESULTS: Compared to HC, NPSLE patients demonstrated intrinsic hypoconnectivity of anterior Default Mode Network (DMN) and hyperconnectivity of posterior DMN components. These changes were paralleled by elevated hemodynamic lag. In NPSLE, cognitive performance was positively related to higher intrinsic connectivity in these regions, and to higher connectivity-hemodynamic coupling in posterior DMN components. Uncoupling between hemodynamics and connectivity in the posterior DMN was associated with worse task performance. Non-NPSLE patients displayed hyperconnectivity in posterior DMN and sensorimotor regions paralleled by relatively increased hemodynamic lag. CONCLUSION: Adaptation of regional brain function to hemodynamic changes in NPSLE may involve locally decreased or locally increased intrinsic connectivity (which can be beneficial for cognitive function). This process may also involve elevated coupling of hemodynamics with functional connectivity (beneficial for cognitive performance) or uncoupling, which may be detrimental for the cognitive skills of NPSLE patients.

The association of basal cortisol levels with episodic memory in older adults is mediated by executive function.

Elevated basal cortisol levels in elderly may indicate dysregulation of the internal stress-related system, as well as dysfunction and structural alterations in brain structures necessary for cognition, such as hippocampus and prefrontal cortex. Because of the close relation of executive functions and episodic memory processing, in this study we explored whether the association of elevated cortisol levels on episodic memory could be partly attributed to cortisol effects on executive functions. In this cross-sectional study we analyzed data from a sample of 236 community-dwelling older adults from the Cretan Aging Cohort aged 75.56 ± 7.21 years [53 with dementia due to probable Alzheimer's disease, 99 with Mild Cognitive Impairment (MCI) and 84 cognitively non-impaired participants (NI)]. Morning serum cortisol levels were higher in the probable AD as compared to the NI group (p = .031). Mediated regression models in the total sample supported the hypothesis that the negative association of basal cortisol levels with delayed memory was fully mediated by the relation of basal cortisol levels with executive functions and immediate memory (adjusted for age and self-reported depression symptoms). Moderated mediation regression models revealed that the direct effect of cortisol on executive function and the effect of executive function on delayed memory performance were statistically significant among participants diagnosed with MCI, while the immediate memory effect on delayed memory was more pronounced in AD patients, as compared to the NI group. The current findings corroborate neuroimaging research highlighting cortisol effects on executive functions and immediate memory and further suggest that dysregulation of systems involved in these functions may account for the purported detrimental long-term effects of high cortisol levels on delayed memory.

Improving the Sensitivity of Task-Related Functional Magnetic Resonance Imaging Data Using Generalized Canonical Correlation Analysis.

General Linear Modeling (GLM) is the most commonly used method for signal detection in Functional Magnetic Resonance Imaging (fMRI) experiments, despite its main limitation of not taking into consideration common spatial dependencies between voxels. Multivariate analysis methods, such as Generalized Canonical Correlation Analysis (gCCA), have been increasingly employed in fMRI data analysis, due to their ability to overcome this limitation. This study, evaluates the improvement of sensitivity of the GLM, by applying gCCA to fMRI data after standard preprocessing steps. Data from a block-design fMRI experiment was used, where 25 healthy volunteers completed two action observation tasks at 1.5T. Whole brain analysis results indicated that the application of gCCA resulted in significantly higher intensity of activation in several regions in both tasks and helped reveal activation in the primary somatosensory and ventral premotor area, theoretically known to become engaged during action observation. In subject-level ROI analyses, gCCA improved the signal to noise ratio in the averaged timeseries in each preselected ROI, and resulted in increased extent of activation, although peak intensity was considerably higher in just two of them. In conclusion, gCCA is a promising method for improving the sensitivity of conventional statistical modeling in task related fMRI experiments.

The Significance of Echo Time in fMRI BOLD Contrast: A Clinical Study during Motor and Visual Activation Tasks at 1.5 T.

Blood Oxygen Level Dependent (BOLD) is a commonly-used MR imaging technique in studying brain function. The BOLD signal can be strongly affected by specific sequence parameters, especially in small field strengths. Previous small-scale studies have investigated the effect of TE on BOLD contrast. This study evaluates the dependence of fMRI results on echo time (TE) during concurrent activation of the visual and motor cortex at 1.5 T in a larger sample of 21 healthy volunteers. The experiment was repeated using two different TE values (50 and 70 ms) in counterbalanced order. Furthermore, T2* measurements of the gray matter were performed. Results indicated that both peak beta value and number of voxels were significantly higher using TE = 70 than TE = 50 ms in primary motor, primary somatosensory and supplementary motor cortices (p < 0.007). In addition, the amplitude of activation in visual cortices and the dorsal premotor area was also higher using TE = 70 ms (p < 0.001). Gray matter T2* of the corresponding areas did not vary significantly. In conclusion, the optimal TE value (among the two studied) for visual and motor activity is 70 ms affecting both the amplitude and extent of regional hemodynamic activation.

Suppressing the Morning Cortisol Rise After Memory Reactivation at 4 A.M. enhances Episodic Memory Reconsolidation in Humans.

Evidence from animal and human research shows that established memories can undergo changes after reactivation through a process called reconsolidation. Alterations of the level of the stress hormone cortisol may provide a way to manipulate reconsolidation in humans. Here, in a double-blind, within-subject design, we reactivated a 3-d-old memory at 3:55 A.M. in sixteen men and four women, immediately followed by oral administration of metyrapone versus placebo, to examine whether metyrapone-induced suppression of the morning cortisol rise may influence reconsolidation processes during and after early morning sleep. Crucially, reactivation followed by cortisol suppression versus placebo resulted in enhanced memory for the reactivated episode tested 4 d after reactivation. This enhancement after cortisol suppression was specific for the reactivated episode versus a non-reactivated episode. These findings suggest that when reactivation of memories is immediately followed by suppression of cortisol levels during early morning sleep in humans, reconsolidation processes change in a way that leads to the strengthening of episodic memory traces.SIGNIFICANCE STATEMENT How can we change formed memories? Modulation of established memories has been long debated in cognitive neuroscience and remains a crucial question to address for basic and clinical research. Stress-hormone cortisol and sleep are strong candidates for changing consolidated memories. In this double-blind, placebo-controlled, within-subject pharmacological study, we investigate the role of cortisol on the modulation of reconsolidation of episodic memories in humans. Blocking cortisol synthesis (3 g metyrapone) during early morning sleep boosts memory for a reactivated but not for a non-reactivated story. This finding contributes to our understanding of the modulatory role of cortisol and its circadian variability on reconsolidation, and moreover can critically inform clinical interventions for the case of memory dysfunctions, and trauma and stress-related disorders.

Changing memories by interference: the effect of emotional dimensions in reconsolidation of episodic memories.

Episodes with an emotional component preoccupy memory formation and this advantage facilitates their preservation and mitigates the impact of interfering episodes. The present study examined the relation of the emotional dimensions of original and interfering episodes to the memory outcome, using a reconsolidation paradigm. In a between-subjects design, 102 healthy young adults were presented with an emotional or neutral image and learned either an emotional or neutral story, respectively (day 1). On day 2, experimental groups were presented with an image of the opposite emotionality, reactivated the original story, and learned a story of the opposite emotionality. On day 3, experimental and control groups were tested for their memory on target and filler clues of the original story and rated both stories for arousal and valence. Overall, there was evidence of interference on the long-term retention of target clues only for the neutral story (i.e. when the interfering story was emotional), and of filler clues for both types of stories. Moreover, individual target clue retention rates correlated with the arousal ratings for both the original neutral story and the interfering emotional story, while they were not related to arousal ratings for the original emotional story or the interfering neutral one.

Anxiety and depression severity in neuropsychiatric SLE are associated with perfusion and functional connectivity changes of the frontolimbic neural circuit: a resting-state f(unctional) MRI study.

OBJECTIVE: To examine the hypothesis that perfusion and functional connectivity disturbances in brain areas implicated in emotional processing are linked to emotion-related symptoms in neuropsychiatric SLE (NPSLE). METHODS: Resting-state fMRI (rs-fMRI) was performed and anxiety and/or depression symptoms were assessed in 32 patients with NPSLE and 18 healthy controls (HC). Whole-brain time-shift analysis (TSA) maps, voxel-wise global connectivity (assessed through intrinsic connectivity contrast (ICC)) and within-network connectivity were estimated and submitted to one-sample t-tests. Subgroup differences (high vs low anxiety and high vs low depression symptoms) were assessed using independent-samples t-tests. In the total group, associations between anxiety (controlling for depression) or depression symptoms (controlling for anxiety) and regional TSA or ICC metrics were also assessed. RESULTS: Elevated anxiety symptoms in patients with NPSLE were distinctly associated with relatively faster haemodynamic response (haemodynamic lead) in the right amygdala, relatively lower intrinsic connectivity of orbital dlPFC, and relatively lower bidirectional connectivity between dlPFC and vmPFC combined with relatively higher bidirectional connectivity between ACC and amygdala. Elevated depression symptoms in patients with NPSLE were distinctly associated with haemodynamic lead in vmPFC regions in both hemispheres (lateral and medial orbitofrontal cortex) combined with relatively lower intrinsic connectivity in the right medial orbitofrontal cortex. These measures failed to account for self-rated, milder depression symptoms in the HC group. CONCLUSION: By using rs-fMRI, altered perfusion dynamics and functional connectivity was found in limbic and prefrontal brain regions in patients with NPSLE with severe anxiety and depression symptoms. Although these changes could not be directly attributed to NPSLE pathology, results offer new insights on the pathophysiological substrate of psychoemotional symptomatology in patients with lupus, which may assist its clinical diagnosis and treatment.

Cortisol suppression after memory reactivation impairs later memory performance.

Experiencing stressful or traumatic events can result in disabling clinical symptoms of maladaptive emotional memory retrieval, which are only partly addressed by the currently proposed treatments. Cortisol modulation has been shown to affect emotional memory retrieval and potentially reconsolidation, offering an opportunity for developing more efficient treatments for disorders with an emotional memory component. Here, we investigated if cortisol suppression after reactivation of emotional memories weakens later memory thereof. Forty healthy young men were tested in a randomized, placebo controlled, double-blind, and between-subject design, assigned either to a cortisol suppression (metyrapone) group or a placebo group. Participants of both groups, were presented with two emotional stories at an encoding session (Day 1). One of the two stories was later reactivated and followed by metyrapone vs. placebo administration (Day 3). Memory for both stories was tested at a recognition memory session (Day 7). In the group undergoing cortisol suppression after memory reactivation memory performance was weaker compared to the placebo group, tested four days after reactivation. This study shows that cortisol suppression can weaken memory for past events, possibly by altering reconsolidation processes and thus exerting long-lasting weakening effects on the original memory.

Suppressing but not intensifying emotion decreases arousal and subjective sense of recollection.

Emotional memories are commonly recalled with an increased subjective sense of recollection but not necessarily with more accurate context recollection, depending on the type of context. Response-focused emotion regulation techniques, such as suppressing and intensifying emotion expression, can alter subjective arousal and later memory and confidence about memory. Here, we investigated if emotion suppression affects later subjective sense of recollection as well as context recollection for different types of details. To disentangle the contribution of arousal modulation versus potential cognitive costs of emotion suppression effects on later subjective sense of recollection, we further explored if intensifying emotion expression similarly affects later subjective sense of recollection and actual context recollection as emotion suppression. We found that emotion suppression decreases the subjective sense of recollection, while intensifying emotion expression has no effect on the subjective sense of recollection. In contrast, suppressing emotion did not affect the recollection of extrinsic and intrinsic contextual details, while intensifying emotion expression decreased recollection of intrinsic item features of emotional scenes. In conclusion, response-focused emotion regulation techniques with distinct effects on subjective arousal differentially affect the subjective sense of recollection and memory for contextual details. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Suppressing cortisol at encoding reduces the emotional enhancement in subjective sense of recollection.

The stress hormone cortisol, released when encountering an emotional event, contributes to form a strong emotional memory. Such emotionally arousing memories are recalled with an enhanced subjective sense of recollection, i.e. experienced in memory as more vivid and richer in details. We examined here whether cortisol plays a role in this emotional enhancement in subjective sense of recollection for a set of learned scenes. Suppressing cortisol at encoding decreased the emotional enhancement in subjective sense of recollection at a test 28 h later, but did not affect familiarity and memory for a contextual detail. Individual cortisol levels were significantly correlated to emotional enhancement in subjective sense of recollection. These findings indicate that cortisol plays a modulatory role for enhanced subjective sense of recollection for emotional events.