Human cerebellum and corticocerebellar connections involved in emotional memory enhancement.

Emotional information is better remembered than neutral information. Extensive evidence indicates that the amygdala and its interactions with other cerebral regions play an important role in the memory-enhancing effect of emotional arousal. While the cerebellum has been found to be involved in fear conditioning, its role in emotional enhancement of episodic memory is less clear. To address this issue, we used a whole-brain functional MRI approach in 1,418 healthy participants. First, we identified clusters significantly activated during enhanced memory encoding of negative and positive emotional pictures. In addition to the well-known emotional memory-related cerebral regions, we identified a cluster in the cerebellum. We then used dynamic causal modeling and identified several cerebellar connections with increased connection strength corresponding to enhanced emotional memory, including one to a cluster covering the amygdala and hippocampus, and bidirectional connections with a cluster covering the anterior cingulate cortex. The present findings indicate that the cerebellum is an integral part of a network involved in emotional enhancement of episodic memory.

Sex-dependent differences in connectivity patterns are related to episodic memory recall.

Previous studies have shown that females typically outperform males on episodic memory tasks. In this study, we investigated if (1) there are differences between males and females in their connectome characteristics, (2) if these connectivity patterns are associated with memory performance, and (3) if these brain connectome characteristics contribute to the differences in episodic memory performance between sexes. In a sample of 655 healthy young subjects (n = 391 females; n = 264 males), we derived brain network characteristics from diffusion-weighted imaging (DWI) data using models of crossing fibers within each voxel of the brain and probabilistic tractography (graph strength, shortest path length, global efficiency, and weighted transitivity). Group differences were analysed with linear models and mediation analyses were used to explore how connectivity patterns might relate to sex-dependent differences in memory performance. Our results show significant sex-dependent differences in weighted transitivity (d = 0.42), with males showing higher values. Further, we observed a negative association between weighted transitivity and memory performance (r = -0.12). Finally, these distinct connectome characteristics partially mediated the observed differences in memory performance (effect size of the indirect effect r = 0.02). Our findings indicate a higher interconnectedness in females compared to males. Additionally, we demonstrate that the sex-dependent differences in episodic memory performance can be partially explained by the differences in this connectome measure. These results further underscore the importance of sex-dependent differences in brain connectivity and their impact on cognitive function.

NTRK2 methylation is related to reduced PTSD risk in two African cohorts of trauma survivors.

Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of posttraumatic stress disorder (PTSD). In the present study we investigated the epigenetic pattern of 12 genes involved in the regulation of GR signaling in two African populations of heavily traumatized individuals: Survivors of the rebel war in northern Uganda (n = 463) and survivors of the Rwandan genocide (n = 350). The strongest link between regional methylation and PTSD risk and symptoms was observed for NTRK2, which encodes the transmembrane receptor tropomyosin-related kinase B, binds the brain-derived neurotrophic factor, and has been shown to play an important role in memory formation. NTRK2 methylation was not related to trauma load, suggesting that methylation differences preexisted the trauma. Because NTRK2 methylation differences were predominantly associated with memory-related PTSD symptoms, and because they seem to precede traumatic events, we next investigated the relationship between NTRK2 methylation and memory in a sample of nontraumatized individuals (n = 568). We found that NTRK2 methylation was negatively associated with recognition memory performance. Furthermore, fMRI analyses revealed NTRK2 methylation-dependent differences in brain network activity related to recognition memory. The present study demonstrates that NTRK2 is epigenetically linked to memory functions in nontraumatized subjects and to PTSD risk and symptoms in traumatized populations.

Genetic control of variability in subcortical and intracranial volumes.

Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8-89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.

Reducing Amygdala Activity and Phobic Fear through Cognitive Top-Down Regulation.

The amygdala is critically involved in emotional processing, including fear responses, and shows hyperactivity in anxiety disorders. Previous research in healthy participants has indicated that amygdala activity is down-regulated by cognitively demanding tasks that engage the PFC. It is unknown, however, if such an acute down-regulation of amygdala activity might correlate with reduced fear in anxious participants. In an fMRI study of 43 participants (11 men) with fear of snakes, we found reduced amygdala activity when visual stimuli were processed under high cognitive load, irrespective of whether the stimuli were of neutral or phobic content. Furthermore, dynamic causal modeling revealed that this general reduction in amygdala activity was partially mediated by a load-dependent increase in dorsolateral PFC activity. Importantly, high cognitive load also resulted in an acute decrease in perceived phobic fear while viewing the fearful stimuli. In conclusion, our data indicate that a cognitively demanding task results in a top-down regulation of amygdala activity and an acute reduction of fear in phobic participants. These findings may inspire the development of novel psychological intervention approaches aimed at reducing fear in anxiety disorders.

Predicting emotional arousal and emotional memory performance from an identical brain network.

Encoding and retrieval of emotionally arousing stimuli depend on the activation of multiple interconnected brain regions, with people showing differences in their individual strength of emotional perception and recollection. Understanding the association between these brain regions and the behavioral outcome might therefore have important clinical implications as dysfunctional emotional memory processes are characteristic of many psychiatric disorders. Based on behavioral and fMRI data collected from healthy young adults (N = 1'385), we investigated brain activation patterns, arousal ratings and memory performance during encoding and retrieval of negative and neutral pictures. We performed multi-voxel pattern analysis (MVPA) and voxel-wise association analyses. Subjects' individual strength of perceived arousal at encoding and subjects' memory performance at recognition could be predicted from the fMRI data of the respective tasks by using a topographically identical network of brain regions. This network was mainly left lateralized including dense clusters of voxels in the occipital and parietal lobe and including the amygdala. Voxel-wise association analyses confirmed the close link between the brain activation of both tasks and their relation to the respective behavioral outcome. These results point to the importance of the here identified brain network for emotional memory processes in health and, possibly, disease.

Resting-state functional connectivity remains unaffected by preceding exposure to aversive visual stimuli.

While much is known about immediate brain activity changes induced by the confrontation with emotional stimuli, the subsequent temporal unfolding of emotions has yet to be explored. To investigate whether exposure to emotionally aversive pictures affects subsequent resting-state networks differently from exposure to neutral pictures, a resting-state fMRI study implementing a two-group repeated-measures design in healthy young adults (N = 34) was conducted. We focused on investigating (i) patterns of amygdala whole-brain and hippocampus connectivity in both a seed-to-voxel and seed-to-seed approach, (ii) whole-brain resting-state networks with an independent component analysis coupled with dual regression, and (iii) the amygdala's fractional amplitude of low frequency fluctuations, all while EEG recording potential fluctuations in vigilance. In spite of the successful emotion induction, as demonstrated by stimuli rating and a memory-facilitating effect of negative emotionality, none of the resting-state measures was differentially affected by picture valence. In conclusion, resting-state networks connectivity as well as the amygdala's low frequency oscillations appear to be unaffected by preceding exposure to widely used emotionally aversive visual stimuli in healthy young adults.

Computational dissection of human episodic memory reveals mental process-specific genetic profiles.

Episodic memory performance is the result of distinct mental processes, such as learning, memory maintenance, and emotional modulation of memory strength. Such processes can be effectively dissociated using computational models. Here we performed gene set enrichment analyses of model parameters estimated from the episodic memory performance of 1,765 healthy young adults. We report robust and replicated associations of the amine compound SLC (solute-carrier) transporters gene set with the learning rate, of the collagen formation and transmembrane receptor protein tyrosine kinase activity gene sets with the modulation of memory strength by negative emotional arousal, and of the L1 cell adhesion molecule (L1CAM) interactions gene set with the repetition-based memory improvement. Furthermore, in a large functional MRI sample of 795 subjects we found that the association between L1CAM interactions and memory maintenance revealed large clusters of differences in brain activity in frontal cortical areas. Our findings provide converging evidence that distinct genetic profiles underlie specific mental processes of human episodic memory. They also provide empirical support to previous theoretical and neurobiological studies linking specific neuromodulators to the learning rate and linking neural cell adhesion molecules to memory maintenance. Furthermore, our study suggests additional memory-related genetic pathways, which may contribute to a better understanding of the neurobiology of human memory.

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.

Dynamic modulation of amygdala-hippocampal connectivity by emotional arousal.

Positive and negative emotional events are better remembered than neutral events. Studies in animals suggest that this phenomenon depends on the influence of the amygdala upon the hippocampus. In humans, however, it is largely unknown how these two brain structures functionally interact and whether these interactions are similar between positive and negative information. Using dynamic causal modeling of fMRI data in 586 healthy subjects, we show that the strength of the connection from the amygdala to the hippocampus was rapidly and robustly increased during the encoding of both positive and negative pictures in relation to neutral pictures. We also observed an increase in connection strength from the hippocampus to the amygdala, albeit at a smaller scale. These findings indicate that, during encoding, emotionally arousing information leads to a robust increase in effective connectivity from the amygdala to the hippocampus, regardless of its valence.

Characteristics of the default mode functional connectivity in normal ageing and Alzheimer's disease using resting state fMRI with a combined approach of entropy-based and graph theoretical measurements.

Cognitive decline in normal ageing and Alzheimer's disease (AD) emerges from functional disruption in the coordination of large-scale brain systems sustaining cognition. Integrity of these systems can be examined by correlation methods based on analysis of resting state functional magnetic resonance imaging (fMRI). Here we investigate functional connectivity within the default mode network (DMN) in normal ageing and AD using resting state fMRI. Images from young and elderly controls, and patients with AD were processed using spatial independent component analysis to identify the DMN. Functional connectivity was quantified using integration and indices derived from graph theory. Four DMN sub-systems were identified: Frontal (medial and superior), parietal (precuneus-posterior cingulate, lateral parietal), temporal (medial temporal), and hippocampal (bilateral). There was a decrease in antero-posterior interactions (lower global efficiency), but increased interactions within the frontal and parietal sub-systems (higher local clustering) in elderly compared to young controls. This decreased antero-posterior integration was more pronounced in AD patients compared to elderly controls, particularly in the precuneus-posterior cingulate region. Conjoint knowledge of integration measures and graph indices in the same data helps in the interpretation of functional connectivity results, as comprehension of one measure improves with understanding of the other. The approach allows for complete characterisation of connectivity changes and could be applied to other resting state networks and different pathologies.

Neurofunctional underpinnings of individual differences in visual episodic memory performance.

Episodic memory, the ability to consciously recollect information and its context, varies substantially among individuals. While prior fMRI studies have identified certain brain regions linked to successful memory encoding at a group level, their role in explaining individual memory differences remains largely unexplored. Here, we analyze fMRI data of 1,498 adults participating in a picture encoding task in a single MRI scanner. We find that individual differences in responsivity of the hippocampus, orbitofrontal cortex, and posterior cingulate cortex account for individual variability in episodic memory performance. While these regions also emerge in our group-level analysis, other regions, predominantly within the lateral occipital cortex, are related to successful memory encoding but not to individual memory variation. Furthermore, our network-based approach reveals a link between the responsivity of nine functional connectivity networks and individual memory variability. Our work provides insights into the neurofunctional correlates of individual differences in visual episodic memory performance.

Glucagon-like peptide-1 analogues: a new way to quit smoking? (SKIP)-a structured summary of a study protocol for a randomized controlled study.

BACKGROUND: Cigarette smoking is the leading preventable cause of premature death. Despite dedicated programmes, quit rates remain low due to barriers such as nicotine withdrawal syndrome or post-cessation weight gain. Glucagon-like peptide-1 (GLP-1) analogues reduce energy intake and body weight and seem to modulate addictive behaviour. These GLP-1 properties are of major interest in the context of smoking cessation. The aim of this study is to evaluate the GLP-1 analogue dulaglutide as a new therapy for smoking cessation. METHODS: This is a placebo-controlled, double-blind, parallel group, superiority, single-centre randomized study including 255 patients. The intervention consists of a 12-week dulaglutide treatment phase with 1.5 mg once weekly or placebo subcutaneously, in addition to standard of care (behavioural counselling and pharmacotherapy with varenicline). A 40-week non-treatment phase follows. The primary outcome is the point prevalence abstinence rate at week 12. Smoking status is self-reported and biochemically confirmed by end-expiratory exhaled carbon monoxide measurement. Further endpoints include post-cessational weight gain, nicotine craving analysis, glucose homeostasis and long-term nicotine abstinence. Two separate substudies assess behavioural, functional and structural changes by functional magnetic resonance imaging and measures of energy metabolism (i.e. resting energy expenditure, body composition). DISCUSSION: Combining behavioural counselling and medical therapy, e.g. with varenicline, improves abstinence rates and is considered the standard of care. We expect a further increase in quit rates by adding a second component of medical therapy and assume a dual effect of dulaglutide treatment (blunting nicotine withdrawal symptoms and reducing post-cessational weight gain). This project is of high relevance as it explores novel treatment options aimed at preventing the disastrous consequences of nicotine consumption and obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT03204396 . Registered on June 26, 2017.

The Iranian Corona Stress Study: Psychological Impacts of COVID-19 Pandemic in an Iranian Population.

Background: To assess the psychological consequences of changes during the coronavirus 2019 (COVID-19) pandemic in the Iranian population. Methods: We performed an anonymous online survey in the first 3 weeks of March 2020. Individuals older than 14 who could read Persian, and lived in Iran, were eligible for the study. The participants had to rate their stress levels and depressive symptoms (using a nine-item Patient Health Questionnaire PHQ-9) during the last 2 weeks and before the pandemic retrospectively. The changes in the psychological measurements and their association with the sociodemographic factors and burdens due to confinement were assessed. Results: Overall, among the 3,210 subjects who participated in our study, both the stress levels and average depression scores increased. However, about 23% of the subjects reported a decrease in their stress levels. The burden of childcare, restrictions in private life, and thoughts about the future were positively correlated with the changes in the stress levels and depression scores (|r| > 0.15). However, feeling relieved in the pandemic condition, and enjoying more family time were associated with less change in the stress and depression scores. Being religious (odds ratio [OR] [CI]: 1.5 [1.3-1-8]) and older age (OR [CI]: 2.9 [1.8-4.6] for >55 years old) were identified as the resilience factors, whereas being a student (OR [CI]: 2.1 [1.6;2.7]), seeking a job (OR [CI]: 2.6 [1.8;3.9]), and history of a psychiatric disorder (OR [CI]: 3.2 [2.6;4]) were identified as the risk factors for depression. Conclusions: The stress levels and depressive symptoms have increased during the COVID-19 pandemic and this increase is related to different social and personal burdens due to the confinement conditions.

A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia.

BackgroundPrimary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide 1 (GLP-1) reduces appetite and food intake. In experimental models, GLP-1 has also been shown to play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia.MethodsIn this randomized, double-blind, placebo-controlled, 3-week crossover trial, 34 patients with primary polydipsia received weekly dulaglutide (1.5 mg, Trulicity) in one treatment segment and placebo (0.9% sodium chloride) in the other. During the last treatment week, patients attended an 8-hour evaluation visit with free access to water. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and an additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI.RESULTsPatients on dulaglutide reduced their fluid intake by 490 mL (95% CI: -780, -199; P = 0.002), from 2950 mL (95% CI: 2435, 3465) on placebo to 2460 mL (95% CI: 1946, 2475) on dulaglutide (model estimates), corresponding to a relative reduction of 17%. Twenty-four-hour urinary output was reduced by -943 mL (95% CI: -1473, -413; P = 0.001). Thirst perception in response to beverage pictures was higher for patients with primary polydipsia than for controls, and lower for patients on dulaglutide versus placebo, but functional activity was similar among groups and treatments.CONCLUSIONSGLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registrationClinicaltrials.gov NCT02770885.FundingSwiss National Science Foundation (grant 32473B_162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel.

Recognition memory performance can be estimated based on brain activation networks.

BACKGROUND: Recognition memory is an essential ability for functioning in everyday life. Establishing robust brain networks linked to recognition memory performance can help to understand the neural basis of recognition memory itself and the interindividual differences in recognition memory performance. METHODS: We analysed behavioural and whole-brain fMRI data from 1'410 healthy young adults during the testing phase of a picture-recognition task. Using independent component analysis (ICA), we decomposed the fMRI contrast for previously seen vs. new (old-new) pictures into networks of brain activity. This was done in two independent samples (training sample: N = 645, replication sample: N = 665). Next, we investigated the relationship between the identified brain networks and interindividual differences in recognition memory performance by conducting a prediction analysis. We estimated the prediction accuracy in a third independent sample (test sample: N = 100). RESULTS: We identified 12 robust and replicable brain networks using two independent samples. Based on the activity of those networks we could successfully estimate interindividual differences in recognition memory performance with high accuracy in a third independent sample (r = 0.5, p = 1.29 × 10-07). CONCLUSION: Given the robustness of the ICA decomposition as well as the high prediction estimate, the identified brain networks may be considered as potential biomarkers of recognition memory performance in healthy young adults and can be further investigated in the context of health and disease.

Dynamics of motor-related functional integration during motor sequence learning.

Motor skill learning is associated with profound changes in brain activation patterns over time. Associative and rostral premotor cortical and subcortical regions are mostly recruited during the early phase of explicit motor learning, while sensorimotor regions may increase their activity during the late learning phases. Distinct brain networks are therefore engaged during the early and late phases of motor skill learning. How these regions interact with one another and how information is transferred from one circuit to the other has been less extensively studied. In this study, we used functional MRI (fMRI) at 3T to follow the changes in functional connectivity in the associative/premotor and the sensorimotor networks, during extended practice (4 weeks) of an explicitly known sequence of finger movements. Evolution of functional connectivity was assessed using integration, a measure that quantifies the total amount of interaction within a network. When comparing the integration associated with a complex finger movement sequence to that associated with a simple sequence, we observed two patterns of decrease during the 4 weeks of practice. One was not specific as it was observed for all sequences, whereas a specific decrease was observed only for the execution of the learned sequence. This second decrease was a consequence of a relative decrease in associative/premotor network integration, together with a relative increase in between-network integration. These findings are in line with the hypothesis that information is transferred from the associative/premotor circuit to the sensorimotor circuit during the course of motor learning.

Visual Exploration at Higher Fixation Frequency Increases Subsequent Memory Recall.

Only a small proportion of what we see can later be recalled. Up to date it is unknown how far differences in visual exploration during encoding affect the strength of episodic memories. Here, we identified individual gaze characteristics by analyzing eye tracking data in a picture encoding task performed by 967 healthy subjects during fMRI. We found a positive correlation between fixation frequency during visual exploration and subsequent free recall performance. Brain imaging results showed a positive correlation of fixation frequency with activations in regions related to vision and memory, including the medial temporal lobe. To investigate if higher fixation frequency is causally linked to better memory, we experimentally manipulated visual exploration patterns in an independent population of 64 subjects. Doubling the number of fixations within a given exploration time increased subsequent free recall performance by 19%. Our findings provide evidence for a causal relationship between fixation frequency and episodic memory for visual information.

The genetic architecture of human brainstem structures and their involvement in common brain disorders.

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.

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.