Long-Term Follow-Up of HRQoL up to Six Years after Outpatient Phase-II Cardiac Rehabilitation.

Background: Low health-related quality of life (HRQoL) is associated with adverse cardiovascular outcomes in coronary heart disease (CHD) patients. Cardiac rehabilitation (CR) improves HRQoL; however, evidence on long-term HRQoL changes after CR, and their predictors, is missing. Methods: A total of 153 patients with complete HRQoL data in the short-form (SF)-36 Health Survey at CR entry, discharge and follow-up were included. Using linear mixed-effects regression models for repeated time measurements, we examined predictors of follow-up HRQoL, including age and clinical characteristics. Results: Both physical (t = -5.66, p < 0.001) and mental (t = -2.06, p = 0.040) HRQoL improved significantly from CR entry to discharge, with improvements remaining stable over a mean follow-up of four years (range 2.4-6.1). Better functional capacity (6MWT) at CR entry predicted better physical HRQoL (t = 5.50, p < 0.001) and, with a trend, better mental HRQoL (t = 1.92, p = 0.056) at follow-up. A psychiatric diagnosis at CR entry predicted better mental HRQoL at follow-up (t = 3.85, p < 0.001). Conclusions: Improvements in HRQoL during CR remain stable during long-term follow-up. Levels of functional capacity appear to be relevant to both physical and mental HRQoL at follow-up.

Differential associations of sex and age with changes in HRQoL during outpatient cardiac rehabilitation.

INTRODUCTION: Cardiovascular diseases (CVD) represent the world's leading cause of death. Health-related quality of life (HRQoL) is a widely applied concept of patients' perceived health and is directly linked to CVD morbidity, mortality, and re-hospitalization rates. Cardiac rehabilitation (CR) improves both cardiovascular outcomes and HRQoL. Regrettably, CR is still underutilized, especially in subgroups like women and elderly patients. The aim of our study was to investigate the predictive potential of sex and age on change of HRQoL throughout outpatient CR. METHODS: 497 patients of outpatient CR were retrospectively assessed from August 2015 to September 2019 at the University Hospital Zurich. A final sample of 153 individuals with full HRQoL data both at CR entry and discharge was analyzed. HRQoL was measured using the 36-Item Short Form Survey (SF-36) with its physical (PCS) and mental (MCS) component scale. In two-factorial analyses of variance, we analyzed sex- and age-specific changes in HRQoL scores throughout CR, adjusting for psychosocial and clinical characteristics. Age was grouped into participants over and under the age of 65. RESULTS: In both sexes, mean scores of physical HRQoL improved significantly during CR (p <.001), while mean scores of mental HRQoL improved significantly in men only (p =.003). Women under the age of 65 had significantly greater physical HRQoL improvements throughout CR, compared with men under 65 (p =.043) and women over 65 years of age (p =.014). Sex and age did not predict changes in mental HRQoL throughout CR. CONCLUSIONS: Younger women in particular benefit from CR with regard to their physical HRQoL. Among older participants, women report equal improvements of physical HRQoL than men. Our results indicate that sex- and age-related aspects of HRQoL outcomes should be considered in CR.

Underutilization of effective coping styles in male physicians with burnout.

Ineffective coping is a risk factor for burnout among physicians, in whom the prevalence of burnout is high and has also increased in recent years. We examined in a cross-sectional study whether physicians with burnout show different coping styles compared with healthy controls. Male physicians (n = 60) were recruited into two groups (burnout vs. healthy). The Coping Inventory for Stressful Situations (CISS) and the Maslach Burnout Inventory (MBI) were applied. Wilcoxon rank-sum test showed group differences in two of the three coping styles, task-oriented and emotion-oriented, and also in one of the two subscales of the avoidance-oriented coping: social-diversion-oriented coping. Multiple binomial logistic regression, controlling for age, showed that lower task-oriented coping (OR = 0.38 (0.13 - 0.93), p = 0.048, d = 0.534) and lower social-diversion-oriented coping (OR = 0.33 (0.11 - 0.80), p = 0.024, d = 0.611) significantly predicted the burnout group. The findings suggest that male physicians with burnout differ from healthy controls in terms of less frequent utilization of effective coping styles. These findings could be explored for their utility in preventing burnout in future studies.

Predictors of gain in exercise capacity through cardiac rehabilitation: Sex and age matter.

BACKGROUND: Cardiac rehabilitation (CR) is a cornerstone of secondary prevention that improves cardiovascular outcomes. However, the determinants of treatment success are poorly understood. OBJECTIVES: We investigated the associations of health-related quality of life (HRQoL), sex, age, employment status and housing situation with improvement in exercise capacity throughout CR. METHODS: We analyzed data from 392 CR outpatients (81% men and 19% women). Exercise capacity at baseline and upon completion of the program was measured with the 6-minute walk distance (6MWD). HRQoL at CR entry was assessed with the Short Form 36 Health Survey (SF-36). RESULTS: A multivariable regression analysis revealed that both men and women showed significant improvement in exercise capacity (p < .001). Female sex (B = 18.118, 95% CI 0.341 - 36.035, p = .046) and younger age (B = -0.887, 95% CI -1.463 - -0.312, p = .003) emerged as predictors of greater improvement, while HRQoL, employment status, and housing situation were not associated with significant change in exercise capacity. The final model explained 25% of the variance in exercise capacity change (adjusted R2 = 0.25, p < .001). CONCLUSIONS: Our results indicate that women and younger participants benefit from CR by improving their exercise capacity. Employment status, housing situation and HRQoL showed no effects on CR outcome.

Association of positive psychological well-being with circulating inflammatory markers: A systematic review and meta-analysis.

Accumulating evidence shows a protective effect of positive psychological well-being (PPWB) on health outcomes. However, the underlying mechanisms remain poorly understood. One pathway relates to enhanced immune functioning (Boehm, 2021). The aim of this project was to conduct a systematic review and meta-analysis of the association between PPWB and circulating inflammatory biomarkers and determine the magnitude of this association. After examining 748 references, 29 studies were included. Results from over 94'700 participants revealed a significant association between PPWB and reduced levels of interleukin (IL)- 6 (r = -0.05; P < .001) and C-reactive protein (CRP) (r = -0.06; P < .001) with a heterogeneity of I2 = 31.5% and I2 = 84.5%, respectively. Only the association of PPWB with CRP was independent of co-variates included in the individual studies (r = -0.04; P = .027). The findings of this systematic review and meta-analysis suggest that PPWB is associated with lower levels of inflammatory biomarkers IL-6 and CRP in the circulation. Such relationships with inflammatory biomarkers may partly explain positive effects of PPWB on health.

Differential associations of emotional and physical domains of the MacNew Heart with changes in 6-min walking test.

AIMS: Cardiac rehabilitation (CR), a key component of secondary prevention in cardiac patients, contributes fundamentally to improved cardiovascular health outcomes. Health-related quality of life (HRQOL) represents a widely employed outcome measure in CR, yet, its predictive properties on exercise capacity change during CR are poorly understood. Aim of this study was to examine the association between baseline HRQOL and its subdomains on improvement of exercise capacity during CR. METHODS: Study participants were 13,717 inpatients of six Swiss CR clinics from 2012 to 2018. We measured HRQOL at admission to CR with the MacNew Heart (MNH) questionnaire and exercise capacity at admission and discharge using the six minutes walking test (6MWT). Following factorial analyses, we performed univariate and multivariate analyses to test the predictive properties of baseline global HRQOL and its domains for improvement in exercise capacity, adjusting for demographic and clinical characteristics. RESULTS: Mean improvement in 6MWT was 114 m (SD = 90), achieved after 17.4 days (SD = 5.5). Lower emotional HRQOL (b = 7.85, p = < .001, 95% CI [- 5.67, 10.03]) and higher physical HRQOL (b = - 5.23, p < .001, 95% CI [- 6.56, - 3.90]) were associated with less improvement in the 6MWT. Global MNH and social HRQOL showed no association with exercise capacity improvement. CONCLUSION: Patients entering CR with low emotional and high physical HRQOL are at risk for a lower gain in exercise capacity during CR. Global MNH alone does not provide a reliable assessment of HRQOL; thus a focus on specific domains of HRQOL is needed.

Sex and age as predictors of health-related quality of life change in Phase II cardiac rehabilitation.

AIMS: Cardiac rehabilitation (CR) not only improves cardiovascular outcomes, but also health-related quality of life (HRQOL). Unfortunately, CR is still underutilized, especially among women and older patients. Aim of this study was to highlight age- and sex-specific effects of inpatient CR on HRQOL. METHODS AND RESULTS: From 2012 to 2018, 18 459 patients were prospectively assessed in six Swiss CR clinics. Of these, we retrospectively analysed a final sample of 8286 patients with a mean (standard deviation) age of 67.8 (11.3) in men and 72.2 (11.3) in women. HRQOL was measured at CR entry and discharge. In multivariable analyses, sex- and age-specific changes in HRQOL throughout CR were estimated, adjusting for baseline HRQOL and clinical characteristics. Participants of both sexes improved significantly (P < 0.001) in all domains of HRQOL during CR. Women reported significantly lower social (P < 0.001) and emotional (P < 0.001) HRQOL than men at CR entry. Female sex predicted greater improvement in social (F = 19.63, P < 0.001), emotional (F = 27.814, P < 0.001), and physical HRQOL (F = 20.473, P < 0.001). In a subgroup of n = 2632 elderly patients (>75 years), female sex predicted greater changes in emotional (F = 15.738, P < 0.001) and physical (F = 6.295, P = 0.012), but not in social HRQOL. CONCLUSION: Women report poorer HRQOL at CR entry compared with men, but in turn particularly benefit from CR in this regard. Our results indicate that sex- and age-specific needs of patients should be considered.

The personality traits activity, self-reproach, and negative affect jointly predict clinical recurrence, depressive symptoms, and low quality of life in inflammatory bowel disease patients.

BACKGROUND: The bidirectional "gut-brain axis" has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). While the influence of stress and depressive symptoms on IBD is well-characterized, the role of personality remains insufficiently investigated. METHODS: Personality was assessed in 1154 Swiss IBD cohort study (SIBDCS) patients via the NEO-Five-Factor Inventory (NEO-FFI) as well as in 2600 participants of the population-based CoLaus¦PsyCoLaus cohort study (NEO-FFI-revised). The NEO-FFI subcomponents activity, self-reproach and negative affect were associated with higher IBD disease activity and were combined to a NEO-FFI risk score. This risk score was validated and its effect on clinical IBD course and psychological endpoints was analysed in time-to-event and cumulative incidence analyses. RESULTS: In time-to-event analyses, a high NEO-FFI risk score was predictive for the clinical endpoints of new extraintestinal manifestation [EIM, adjusted hazard ratio (aHR) = 1.64, corrected p value (q) = 0.036] and two established composite flare endpoints (aHR = 1.53-1.63, q = 0.003-0.006) as well as for the psychological endpoints depressive symptoms (aHR = 7.06, q < 0.001) and low quality of life (aHR = 3.06, q < 0.001). Furthermore, cumulative incidence analyses showed that patients at high NEO-FFI risk experienced significantly more episodes of active disease, new EIMs, one of the flare endpoints, depressive episodes and low disease-related quality of life. Personalities of IBD patients showed only minor differences from the general population sample (Pearson's r = 0.03-0.14). CONCLUSIONS: Personality assessed by the NEO-FFI contained considerable predictive power for disease recurrence, depressive symptoms and low quality of life in IBD patients. Nevertheless, the personalities of IBD patients did not substantially differ from the general population.

The use of serotonin reuptake inhibitors increases the risk of bleeding in patients with assist devices.

BACKGROUND: Bleedings are frequent and dreaded complications in heart failure patients with ventricular assist devices (VAD). Serotonin reuptake inhibitor (SRI) antidepressants are widely used to treat depression in these patients, though they are attributed an increased risk of bleeding due to their modification of hemostasis. Evidence on bleeding risk of VAD patients under SRI medication is scarce and limited. We therefore aimed to assess if SRI use is associated with an elevated bleeding risk in this particularly vulnerable population. METHODS: We analyzed the medical records of 92 VAD patients at the University Heart Center Zurich between September 2004 and April 2018 for the occurrence of bleedings and the concomitant use of an SRI. Bleeding was defined as any type of post-implantation bleeding requiring medical treatment. We performed univariate analyses and linear mixed-effects models, adjusting for baseline clinical characteristics as potential predictors to identify differences in bleeding rates in patients with vs. without SRI intake. RESULTS: The cohort comprised 60.9% of patients with a continuous-flow VAD and 39.1% with a pulsatile-flow VAD. A total of 77.2% of patients experienced at least one bleeding incident. Overall, 28.6% of bleedings occurred under SRI therapy. A generalized linear mixed model showed a predictive effect of SRI medication on bleeding rate, independent of VAD type (z = 2.091, p = 0.037). CONCLUSIONS: Bleeding events in heart failure patients occur frequently after VAD implantation. Patients with SRI medication were at increased risk of bleeding. The indication and use of SRI, therefore, should be considered carefully.

Depressive Symptoms Predict Clinical Recurrence of Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) patients are at high risk for depression, and depression has been shown to affect disease course. We examined interrelations between depression, genetic risk factors for depression, and IBD flares. METHOD: In 1973 patients (1137 Crohn's disease, 836 ulcerative colitis) of the Swiss IBD Cohort Study (SIBDCS), depressive status (hospital anxiety and depression subscale for depression, HADS-D ≥11) was assessed on a yearly basis. We investigated the impact of depression on IBD-relevant clinical outcomes in Cox proportional hazards models. We used active disease (CDAI ≥150 or MTWAI ≥10) and 2 published composite flare definitions-FNCE (physician-reported flare, nonresponse to therapy, new complication, or extraintestinal manifestation) and AFFSST (active disease, physician-reported flare, fistula, stenosis, and new systemic therapy)-as clinical end points. Additionally, 62 preselected single nucleotide polymorphisms (SNPs) were screened for cross-sectional associations with depression, and if present, their predictive value for future depression and clinical deterioration was assessed. RESULTS: Depression was a strong risk factor for disease-related end points, including active disease (adjusted hazard ratio [aHR], 3.55; P < 0.001), AFFSST (aHR, 1.62; P < 0.001), and FNCE (aHR, 1.35; P = 0.019). The SNP rs2522833 was significantly associated with depression at enrollment (q = 0.059). The TC allele of rs588765 was negatively associated with the presence of depression at enrollment (q = 0.050) and after enrollment (aHR, 0.67; P = 0.035) and with fewer active disease states (aHR, 0.72; P = 0.045) during follow-up. CONCLUSION: In IBD, depressive symptoms and inflammatory activity are intimately related. Depressive symptoms were a strong predictor of clinical deterioration, and genetic markers may play a role in this relationship.

Type D personality is associated with depressive symptoms and clinical activity in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) can be exacerbated by stress and depression. Type D personality, characterised by high negative affectivity and social inhibition, represents a vulnerability towards stressors and is associated with adverse outcomes in coronary heart disease. AIMS: To assess the prevalence of Type D personality in IBD patients and investigate potential associations with disease course. METHODS: We tested for associations between Type D (Type D Scale-14), depressive symptoms (Hospital Anxiety and Depression Scale's depression subscore ≥11) and recurrent IBD amongst Swiss IBD cohort patients. We built regression models for cross-sectional and Cox proportional hazards models for time-to-event analyses. IBD disease course was assessed by the future occurrence of active disease (Crohn's Disease Activity Index ≥150/Modified Truelove & Witts activity index ≥10) and several IBD-relevant endpoints. RESULTS: Amongst 2275 patients (1005 ulcerative colitis, 1270 Crohn's disease), 672 (29.5%) had Type D. Type D was a significant risk factor for future active disease (adjusted hazard ratio, aHR: 1.60, corrected P value, q = 0.007) and predicted the future presence of depressive symptoms (aHR: 3.30, P < 0.001). The combination of Type D and depressive symptoms further increased the risk for active disease (aHR: 3.98, q < 0.001). However, Type D associated depressive symptoms seemed to be the main contributor to this effect as Type D's predictive power decreased considerably in models corrected for depressive symptoms (aHR: 1.32, CI: 0.97-1.79, q = 0.292). CONCLUSIONS: Type D personality's prevalence amongst IBD patients was comparable with its prevalence in the general population. Type D was strongly associated with depressive symptoms and showed modest independent associations with IBD prognosis.

Are you angry at me? Negative interpretations of neutral facial expressions are linked to child maltreatment but not to posttraumatic stress disorder.

Background: Individuals with a high prevalence of child maltreatment, e.g. those with borderline personality disorder, tend to see neutral facial expressions as negative. Objective: Our aim was to assess whether this bias is present in individuals with posttraumatic stress disorder (PTSD) and whether it is linked to child maltreatment. Methods: Thirty-nine PTSD participants, 44 traumatized and 35 non-traumatized healthy controls watched 300 one-second movies showing 30 neutral and 270 emotional facial expressions, and indicated whether they interpreted each as a neutral or as one of nine emotional expressions. Results: PTSD individuals did not perform differently than the two control groups in the recognition and interpretation of neutral facial expressions (p's < .300). Higher levels of childhood sexual and emotional abuse, and physical neglect were linked to more interpretations of neutral facial expressions as contempt (p's < .043), and (for sexual abuse and physical neglect) to more interpretations of neutral facial expressions as anger (p's < .014). Comparisons of statistical model fits suggested that childhood sexual abuse was the most relevant predictor of recognition accuracy in our sample. Alexithymia, state dissociation, interpersonal trauma, and number of experienced trauma types were not associated with deficits in the interpretation of neutral expressions. Conclusions: Child maltreatment, especially sexual abuse, may shape the interpretation of neutral facial expressions. Future research should explore whether the observed biases extend to real-life situations. If so, therapists might improve the therapeutic relationship with patients with a history of child maltreatment by paying more attention to their own non-verbal communication and their patients' responses to it. Furthermore, similarly to individuals with high depressive and high social anxiety symptoms, facial expression recognition training might counteract negativity bias in individuals with a history of childhood (sexual and emotional) abuse, and (physical) neglect.

Antecedentes: las personas con una alta prevalencia de maltrato infantil, por ejemplo, aquellos con trastorno límite de la personalidad, tienden a ver las expresiones faciales neutras como negativas.Objetivo: Nuestro objetivo fue evaluar si este sesgo está presente en personas con trastorno de estrés postraumático (TEPT) y si está relacionado con el maltrato infantil.Métodos: Treinta y nueve participantes con TEPT, 44 controles sanos traumatizados y 35 no traumatizados vieron 300 películas de un segundo que mostraban 30 expresiones faciales neutras y 270 emocionales, e indicaron si interpretaron cada una de ellas como una de las nueve expresiones emocionales.Resultados: los individuos con TEPT no tuvieron un desempeño diferente al de los dos grupos de control en el reconocimiento e interpretación de expresiones faciales neutras (p 's <.300). Los niveles más altos de abuso sexual y emocional infantil y negligencia física se vincularon a interpretar más las expresiones faciales neutras como desprecio (p's <.043) y (por abuso sexual y negligencia física) a interpretar más las expresiones faciales neutras como ira (p's <.014). Las comparaciones de los ajustes estadísticos del modelo sugirieron que el abuso sexual infantil fue el predictor más relevante de precisión de reconocimiento en nuestra muestra. La alexitimia, la disociación del estado, el trauma interpersonal y el número de tipos de trauma experimentados no se asociaron con déficits en la interpretación de las expresiones neutrales.Conclusiones: El maltrato infantil, especialmente el abuso sexual, puede dar forma a la interpretación de las expresiones faciales neutras. La investigación futura debería explorar si los sesgos observados se extienden a situaciones de la vida real. De ser así, los terapeutas podrían mejorar la relación terapéutica con pacientes con antecedentes de maltrato infantil prestando más atención a su propia comunicación no verbal y a las respuestas de sus pacientes. Además, de manera similar a las personas con síntomas depresivos y de ansiedad social, el entrenamiento de reconocimiento de la expresión facial podría contrarrestar el sesgo de negatividad en personas con antecedentes de abuso infantil (sexual y emocional) y negligencia (física).

Identification of Two Distinct Working Memory-Related Brain Networks in Healthy Young Adults.

Working memory (WM) is an important cognitive domain for everyday life functioning and is often disturbed in neuropsychiatric disorders. Functional magnetic resonance imaging (fMRI) studies in humans show that distributed brain areas typically described as fronto-parietal regions are implicated in WM tasks. Based on data from a large sample of healthy young adults (N = 1369), we applied independent component analysis (ICA) to the WM-fMRI signal and identified two distinct networks that were relevant for differences in individual WM task performance. A parietally-centered network was particularly relevant for individual differences in task measures related to WM performance ("WM dependent") and a frontally-centered network was relevant for differences in attention-dependent task performance. Importantly, frontal areas that are typically considered as key regions for WM were either involved in both WM-dependent and attention-dependent performance, or in attention-dependent performance only. The networks identified here are provided as publicly available datasets. These networks can be applied in future studies to derive a low-dimensional representation of the overall WM brain activation.

Among Early Appearing Non-Motor Signs of Parkinson's Disease, Alteration of Olfaction but Not Electroencephalographic Spectrum Correlates with Motor Function.

Olfactory decline is a frequent and early non-motor symptom in Parkinson's disease (PD), which is increasingly used for diagnostic purposes. Another early appearing sign of PD consists in electroencephalographic (EEG) alterations. The combination of olfactory and EEG assessment may improve the identification of patients with early stages of PD. We hypothesized that olfactory capacity would be correlated with EEG alterations and motor and cognitive impairment in PD patients. To the best of our knowledge, the mutual influence of both markers of PD-olfactory decrease and EEG changes-was not studied before. We assessed the function of odor identification using olfactory "Screening 12 Test" ("Sniffin' Sticks®"), between two samples: patients with PD and healthy controls (HC). We analyzed correlations between the olfactory function and demographical parameters, Unified Parkinson's Disease Rating Scale (UPDRS-III), cognitive task performance, and spectral alpha/theta ratio (α/θ). In addition, we used receiver operating characteristic-curve analysis to check the classification capacity (PD vs HC) of olfactory function, α/θ, and a combined marker (olfaction and α/θ). Olfactory capacity was significantly decreased in PD patients, and correlated with age, disease duration, UPDRS-III, and with items of UPDRS-III related to gait and axial rigidity. In HC, olfaction correlated with age only. No correlation with α/θ was identified in both samples. Combined marker showed the largest area under the curve. In addition to EEG, the assessment of olfactory function may be a useful tool in the early characterization and follow-up of PD.

The NCAM1 gene set is linked to depressive symptoms and their brain structural correlates in healthy individuals.

Depressive symptoms exist on a continuum, the far end of which is found in depressive disorders. Utilizing the continuous spectrum of depressive symptoms may therefore contribute to the understanding of the biological underpinnings of depression. Gene set enrichment analysis (GSEA) is an important tool for the identification of gene groups linked to complex traits, and was applied in the present study on genome-wide association study (GWAS) data of depression scores and their brain-level structural correlates in healthy young individuals. On symptom level (i.e. depression scores), robust enrichment was identified for two gene sets: NCAM1 Interactions and Collagen Formation. Depression scores were also associated with decreased fractional anisotropy (FA) - a brain white matter property - within the forceps minor and the left superior temporal longitudinal fasciculus. Within each of these tracts, mean FA value of depression score-associated voxels was used as a phenotype in a subsequent GSEA. The NCAM1 Interactions gene set was significantly enriched in these tracts. By linking the NCAM1 Interactions gene set to depression scores and their structural brain correlates in healthy participants, the current study contributes to the understanding of the molecular underpinnings of depressive symptomatology.

Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease.

IMPORTANCE: Human episodic memory performance is linked to the function of specific brain regions, including the hippocampus; declines as a result of increasing age; and is markedly disturbed in Alzheimer disease (AD), an age-associated neurodegenerative disorder that primarily affects the hippocampus. Exploring the molecular underpinnings of human episodic memory is key to the understanding of hippocampus-dependent cognitive physiology and pathophysiology. OBJECTIVE: To determine whether biologically defined groups of genes are enriched in episodic memory performance across age, memory encoding-related brain activity, and AD. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter collaborative study, which began in August 2008 and is ongoing, gene set enrichment analysis was done by using primary and meta-analysis data from 57 968 participants. The Swiss cohorts consisted of 3043 healthy young adults assessed for episodic memory performance. In a subgroup (n = 1119) of one of these cohorts, functional magnetic resonance imaging was used to identify gene set-dependent differences in brain activity related to episodic memory. The German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort consisted of 763 elderly participants without dementia who were assessed for episodic memory performance. The International Genomics of Alzheimer's Project case-control sample consisted of 54 162 participants (17 008 patients with sporadic AD and 37 154 control participants). Analyses were conducted between January 2014 and June 2015. Gene set enrichment analysis in all samples was done using genome-wide single-nucleotide polymorphism data. MAIN OUTCOMES AND MEASURES: Episodic memory performance in the Swiss cohort and German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort was quantified by picture and verbal delayed free recall tasks. In the functional magnetic resonance imaging experiment, activation of the hippocampus during encoding of pictures served as the phenotype of interest. In the International Genomics of Alzheimer's Project sample, diagnosis of sporadic AD served as the phenotype of interest. RESULTS: In the discovery sample, we detected significant enrichment for genes constituting the calcium signaling pathway, especially those related to the elevation of cytosolic calcium (P = 2 × 10-4). This enrichment was replicated in 2 additional samples of healthy young individuals (P = .02 and .04, respectively) and a sample of healthy elderly participants (P = .004). Hippocampal activation (P = 4 × 10-4) and the risk for sporadic AD (P = .01) were also significantly enriched for genes related to the elevation of cytosolic calcium. CONCLUSIONS AND RELEVANCE: By detecting consistent significant enrichment in independent cohorts of young and elderly participants, this study identified that calcium signaling plays a central role in hippocampus-dependent human memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.

Continuous theta burst stimulation over the left dorsolateral prefrontal cortex decreases medium load working memory performance in healthy humans.

The dorsolateral prefrontal cortex (DLPFC) plays a key role in working memory. Evidence indicates that transcranial magnetic stimulation (TMS) over the DLPFC can interfere with working memory performance. Here we investigated for how long continuous theta-burst stimulation (cTBS) over the DLPFC decreases working memory performance and whether the effect of cTBS on performance depends on working memory load. Forty healthy young subjects received either cTBS over the left DLPFC or sham stimulation before performing a 2-, and 3-back working memory letter task. An additional 0-back condition served as a non-memory-related control, measuring general attention. cTBS over the left DLPFC significantly impaired 2-back working memory performance for about 15 min, whereas 3-back and 0-back performances were not significantly affected. Our results indicate that the effect of left DLPFC cTBS on working memory performance lasts for roughly 15 min and depends on working memory load.

Sex-dependent dissociation between emotional appraisal and memory: a large-scale behavioral and fMRI study.

Extensive evidence indicates that women outperform men in episodic memory tasks. Furthermore, women are known to evaluate emotional stimuli as more arousing than men. Because emotional arousal typically increases episodic memory formation, the females' memory advantage might be more pronounced for emotionally arousing information than for neutral information. Here, we report behavioral data from 3398 subjects, who performed picture rating and memory tasks, and corresponding fMRI data from up to 696 subjects. We were interested in the interaction between sex and valence category on emotional appraisal, memory performances, and fMRI activity. The behavioral results showed that females evaluate in particular negative (p < 10(-16)) and positive (p = 2 × 10(-4)), but not neutral pictures, as emotionally more arousing (pinteraction < 10(-16)) than males. However, in the free recall females outperformed males not only in positive (p < 10(-16)) and negative (p < 5 × 10(-5)), but also in neutral picture recall (p < 3.4 × 10(-8)), with a particular advantage for positive pictures (pinteraction < 4.4 × 10(-10)). Importantly, females' memory advantage during free recall was absent in a recognition setting. We identified activation differences in fMRI, which corresponded to the females' stronger appraisal of especially negative pictures, but no activation differences that reflected the interaction effect in the free recall memory task. In conclusion, females' valence-category-specific memory advantage is only observed in a free recall, but not a recognition setting and does not depend on females' higher emotional appraisal.

Converging genetic and functional brain imaging evidence links neuronal excitability to working memory, psychiatric disease, and brain activity.

Working memory, the capacity of actively maintaining task-relevant information during a cognitive task, is a heritable trait. Working memory deficits are characteristic for many psychiatric disorders. We performed genome-wide gene set enrichment analyses in multiple independent data sets of young and aged cognitively healthy subjects (n = 2,824) and in a large schizophrenia case-control sample (n = 32,143). The voltage-gated cation channel activity gene set, consisting of genes related to neuronal excitability, was robustly linked to performance in working memory-related tasks across ages and to schizophrenia. Functional brain imaging in 707 healthy participants linked this gene set also to working memory-related activity in the parietal cortex and the cerebellum. Gene set analyses may help to dissect the molecular underpinnings of cognitive dimensions, brain activity, and psychopathology.