Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease.

Shifts in the magnitude and nature of gut microbial metabolites have been implicated in Alzheimer's disease (AD), but the host receptors that sense and respond to these metabolites are largely unknown. Here, we develop a systems biology framework that integrates machine learning and multi-omics to identify molecular relationships of gut microbial metabolites with non-olfactory G-protein-coupled receptors (termed the "GPCRome"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs and 335 gut microbial metabolites. Using genetics-derived Mendelian randomization and integrative analyses of human brain transcriptomic and proteomic profiles, we identify orphan GPCRs (i.e., GPR84) as potential drug targets in AD and that triacanthine experimentally activates GPR84. We demonstrate that phenethylamine and agmatine significantly reduce tau hyperphosphorylation (p-tau181 and p-tau205) in AD patient induced pluripotent stem cell-derived neurons. This study demonstrates a systems biology framework to uncover the GPCR targets of human gut microbiota in AD and other complex diseases if broadly applied.

Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart.

Nicotine is the primary addictive component in tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. To assess underlying mechanisms, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days prior to performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the 1st - 3rd thoracic vertebrae, and ß-adrenergic responsiveness was additionally evaluated following norepinephrine (NE) perfusion. Baseline ex vivo HR and SNS stimulation threshold were higher in NIC vs. CT (P = 0.004 and P = 0.003, respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC vs. CT at baseline (P = 0.002) and during SNS (P = 0.0003), with similar results obtained for Ca2+ transient alternans. SNS shortened the PCL at which alternans emerged in CT but not NIC hearts. NIC exposed hearts tended to have slower and reduced HR responses to NE perfusion, but ventricular responses to NE were comparable between groups. While fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P = 0.03) but no difference in NE content vs. CT. These results suggest both sympathetic hypo-innervation of the myocardium and regional differences in ß-adrenergic responsiveness with NIC. This autonomic remodeling may contribute to the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with long-term use.

Submicron- and nanoplastic detection at low micro- to nanogram concentrations using gold nanostar-based surface-enhanced Raman scattering (SERS) substrates.

The presence of submicron- (1 µm-100 nm) and nanoplastic (<100 nm) particles within various sample matrices, ranging from marine environments to foods and beverages, has become a topic of increasing interest in recent years. Despite this interest, very few analytical techniques are known that allow for the detection of these small plastic particles in the low concentration ranges that they are anticipated to be present at. Research focused on optimizing surface-enhanced Raman scattering (SERS) to enhance signal obtained in Raman spectroscopy has been shown to have great potential for the detection of plastic particles below conventional resolution limits. In this study, we produce SERS substrates composed of gold nanostars and assess their potential for submicron- and nanoplastic detection. The results show 33 nm polystyrene could be detected down to 1.25 µg mL-1 while 36 nm poly(ethylene terephthalate) was detected down to 5 µg mL-1. These results confirm the promising potential of the gold nanostar-based SERS substrates for nanoplastic detection. Furthermore, combined with findings for 121 nm polypropylene and 126 nm polyethylene particles, they highlight potential differences in analytical performance that depend on the properties of the plastics being studied.

ADSS: A Composite Score to Detect Disease Progression in Alzheimer's Disease.

Background: Composite scores have been increasingly used in trials for Alzheimer's disease (AD) to detect disease progression, such as the AD Composite Score (ADCOMS) in the lecanemab trial. Objective: To develop a new composite score to improve the prediction of outcome change. Methods: We proposed to develop a new composite score based on the statistical model in the ADCOMS, by removing duplicated sub-scales and adding the model selection in the partial least squares (PLS) regression. Results: The new AD composite Score with variable Selection (ADSS) includes 7 cognitive sub-scales. ADSS can increase the sensitivity to detect disease progression as compared to the existing total scores, which leads to smaller sample sizes using the ADSS in trial designs. Conclusions: ADSS can be utilized in AD trials to improve the success rate of drug development with a high sensitivity to detect disease progression in early stages.

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.

INTRODUCTION: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood. METHODS: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort. RESULTS: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism. DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. HIGHLIGHTS: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.

Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart.

Nicotine is the primary addictive component in tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. However, the underlying mechanisms are unclear. To address this, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days prior to performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca 2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the 1 st - 3 rd thoracic vertebrae, and ß-adrenergic responsiveness was additionally evaluated as changes in heart rate (HR) following norepinephrine (NE) perfusion. Baseline ex vivo HR and SNS stimulation threshold were increased in NIC vs. CT ( P = 0.004 and P = 0.003 respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC vs. CT at baseline ( P = 0.002) and during SNS ( P = 0.0003), with similar results obtained for Ca 2+ transient alternans. SNS reduced the PCL at which alternans emerged in CT but not NIC hearts. NIC exposed hearts also tended to have slower and reduced HR responses to NE perfusion. While fibrosis was unaltered, NIC hearts had lower sympathetic nerve density ( P = 0.03) but no difference in NE content vs. CT. These results suggest both sympathetic hypo-innervation of the myocardium and diminished ß-adrenergic responsiveness with NIC. This autonomic remodeling may underlie the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with continued long-term usage. NEW & NOTEWORTHY: Here we show that chronic nicotine exposure was associated with increased heart rate, lower threshold for alternans and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to the sympathetic hypo-innervation of the myocardium and diminished ß- adrenergic responsiveness observed following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this pro-arrhythmic remodeling.

Microglial Imaging in Alzheimer's Disease and Its Relationship to Brain Amyloid: A Human 18F-GE180 PET Study.

BACKGROUND: Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer's disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans. OBJECTIVE: The goal of this study was to study human GE180 from the perspective of the previous animal observations. METHODS: With data from twenty-four participants having 18F-GE180 and 18F-AV45 PET scans, we evaluated the group differences of 18F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18F-GE180 and 18F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model. RESULTS: Elevated 18F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18F-GE180 uptake. Consistent with mouse model, a two-stage association between 18F-GE180 and 18F-AV45 was observed. CONCLUSIONS: 18F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18F-GE180 and amyloid PET in human and mouse suggested that 18F-GE180 uptake in human might be considerably influenced by microglial activation.

Topological reorganization of functional hubs in patients with Parkinson's disease with freezing of gait.

BACKGROUND AND PURPOSE: Resting-state functional MRI (rs-fMRI) studies in Parkinson's disease (PD) patients with freezing of gait (FOG) have implicated dysfunctional connectivity over multiple resting-state networks (RSNs). While these findings provided network-specific insights and information related to the aberrant or altered regional functional connectivity (FC), whether these alterations have any effect on topological reorganization in PD-FOG patients is incompletely understood. Understanding the higher order functional organization, which could be derived from the "hub" and the "rich-club" organization of the functional networks, could be crucial to identifying the distinct and unique pattern of the network connectivity associated with PD-FOG. METHODS: In this study, we use rs-fMRI data and graph theoretical approaches to explore the reorganization of RSN topology in PD-FOG when compared to those without FOG. We also compared the higher order functional organization derived using the hub and rich-club measures in the FC networks of these PD-FOG patients to understand whether there is a topological reorganization of these hubs in PD-FOG. RESULTS: We found that the PD-FOG patients showed a noticeable reorganization of hub regions. Regions that are part of the prefrontal cortex, primary somatosensory, motor, and visuomotor coordination areas were some of the regions exhibiting altered hub measures in PD-FOG patients. We also found a significantly altered feeder and local connectivity in PD-FOG. CONCLUSIONS: Overall, our findings demonstrate a widespread topological reorganization and disrupted higher order functional network topology in PD-FOG that may further assist in improving our understanding of functional network disturbances associated with PD-FOG.

Correlative Light, Electron Microscopy and Raman Spectroscopy Workflow To Detect and Observe Microplastic Interactions with Whole Jellyfish.

Many researchers have turned their attention to understanding microplastic interaction with marine fauna. Efforts are being made to monitor exposure pathways and concentrations and to assess the impact such interactions may have. To answer these questions, it is important to select appropriate experimental parameters and analytical protocols. This study focuses on medusae of Cassiopea andromeda jellyfish: a unique benthic jellyfish known to favor (sub-)tropical coastal regions which are potentially exposed to plastic waste from land-based sources. Juvenile medusae were exposed to fluorescent poly(ethylene terephthalate) and polypropylene microplastics (<300 µm), resin embedded, and sectioned before analysis with confocal laser scanning microscopy as well as transmission electron microscopy and Raman spectroscopy. Results show that the fluorescent microplastics were stable enough to be detected with the optimized analytical protocol presented and that their observed interaction with medusae occurs in a manner which is likely driven by the microplastic properties (e.g., density and hydrophobicity).

Olfaction and Anxiety Are Differently Associated in Men and Women in Cognitive Physiological and Pathological Aging.

BACKGROUND: Olfaction impairment in aging is associated with increased anxiety. We explored this association in cognitively healthy controls (HCs), Mild Cognitive Impairment (MCI) and Parkinson's disease (PD) patients. Both olfaction and anxiety have sex differences, therefore we also investigated these variances. OBJECTIVES: Investigate the association of olfaction with anxiety in three distinct clinical categories of aging, exploring the potential role of sex. METHODS: 117 subjects (29 HCs, 43 MCI, and 45 PD patients) were assessed for olfaction and anxiety. We used regression models to determine whether B-SIT predicted anxiety and whether sex impacted that relationship. RESULTS: Lower olfaction was related to greater anxiety traits in all groups (HCs: p = 0.015; MCI: p = 0.001 and PD: p = 0.038), significantly differed by sex. In fact, in HCs, for every unit increase in B-SIT, anxiety traits decreased by 7.63 in men (p = 0.009) and 1.5 in women (p = 0.225). In MCI patients for every unit increase in B-SIT, anxiety traits decreased by 1.19 in men (p = 0.048) and 3.03 in women (p = 0.0036). Finally, in PD patients for every unit increase in B-SIT, anxiety traits decreased by 1.73 in men (p = 0.004) and 0.41 in women (p = 0.3632). DISCUSSION: Olfaction and anxiety are correlated in all three distinct diagnostic categories, but differently in men and women.

The aging brain: risk factors and interventions for long term brain health in women.

PURPOSE OF REVIEW: Poor cognitive aging and dementia pose a significant public health burden, and women face unique risks compared to men. Recent research highlights the role of genetics, menopause, chronic disease, and lifestyle in risk and resilience in women's cognitive aging. This work suggests avenues for clinical action at midlife that may change the course of brain health in aging. RECENT FINDINGS: Studies indicate women's risk for poor cognitive aging relates in part to hormone changes at menopause, a time when memory, brain structure and function, and Alzheimer's pathology may be observed in women and not men. Medical and lifestyle risks including diabetes, hypertension, and low physical activity also contribute to women's unique risks. At the same time, literature on resilience suggests women may benefit from lifestyle and chronic disease intervention, possibly more than men. Current studies emphasize the importance of interacting genetic and lifestyle risks, and effects of social determinants of health. SUMMARY: Women have greater risk than men for poor cognitive aging; however, by treating the whole person, including genetics, lifestyle, and social environment, clinicians have an opportunity to support healthy cognitive aging in women and reduce the future public health burden of dementia.

Whole-heart multiparametric optical imaging reveals sex-dependent heterogeneity in cAMP signaling and repolarization kinetics.

Cyclic adenosine 3',5'-monophosphate (cAMP) is a key second messenger in cardiomyocytes responsible for transducing autonomic signals into downstream electrophysiological responses. Previous studies have shown intracellular heterogeneity and compartmentalization of cAMP signaling. However, whether cAMP signaling occurs heterogeneously throughout the intact heart and how this drives sex-dependent functional responses are unknown. Here, we developed and validated a novel cardiac-specific fluorescence resonance energy transfer-based cAMP reporter mouse and a combined voltage-cAMP whole-heart imaging system. We showed that in male hearts, cAMP was uniformly activated in response to pharmacological ß-adrenergic stimulation. In contrast, female hearts showed that cAMP levels decayed faster in apical versus basal regions, which was associated with nonuniform action potential changes and notable changes in the direction of repolarization. Apical phosphodiesterase (PDE) activity was higher in female versus male hearts, and PDE inhibition prevented repolarization changes in female hearts. Thus, our imaging approach revealed sex-dependent regional breakdown of cAMP and associated electrophysiological differences.

Brain functional topology differs by sex in cognitively normal older adults.

Introduction: Late onset Alzheimer's disease (AD) is the most common form of dementia, in which almost 70% of patients are women. Hypothesis: We hypothesized that women show worse global FC metrics compared to men, and further hypothesized a sex-specific positive correlation between FC metrics and cognitive scores in women. Methods: We studied cognitively healthy individuals from the Alzheimer's Disease Neuroimaging Initiative cohort, with resting-state functional Magnetic Resonance Imaging. Metrics derived from graph theoretical analysis and functional connectomics were used to assess the global/regional sex differences in terms of functional integration and segregation, considering the amyloid status and the contributions of APOE E4. Linear mixed effect models with covariates (education, handedness, presence of apolipoprotein [APOE] E4 and intra-subject effect) were utilized to evaluate sex differences. The associations of verbal learning and memory abilities with topological network properties were assessed. Result: Women had a significantly lower magnitude of the global and regional functional network metrics compared to men. Exploratory association analysis showed that higher global clustering coefficient was associated with lower percent forgetting in women and worse cognitive scores in men. Conclusion: Women overall show lower magnitude on measures of resting state functional network topology and connectivity. This factor can play a role in their different vulnerability to AD. Significance statement: Two thirds of AD patients are women but the reasons for these sex difference are not well understood. When this late onset form dementia arises is too late to understand the potential causes of this sex disparities. Studies on cognitively healthy elderly population are a fundamental approach to explore in depth this different vulnerability to the most common form of dementia, currently affecting 6.2 million Americans aged 65 and older are, which means that >1 in 9 people (11.3%) 65 and older are affected by AD. Approaches such as resting-state functional network topology and connectivity may play a key role in understanding and elucidate sex-dependent differences relevant to late-onset dementia syndromes.

Sex Modulates the Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment.

Purpose: To assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process. Materials and Methods: Two hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI. Results: The MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10-7, right: P = 3.37 × 10-8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI. Conclusion: Sex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.

Relationship of sex differences in cortical thickness and memory among cognitively healthy subjects and individuals with mild cognitive impairment and Alzheimer disease.

BACKGROUND: An aging society has increased rates of late onset Alzheimer disease dementia (ADD), the most common form of age-related dementia. This neurodegenerative disease disproportionately affects women. METHODS: We use data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine sex differences in cortical thickness (CT) and memory performance. Analyses of covariance (ANCOVA) models were used to examine effects of sex and diagnosis (DX) on CT and verbal memory. For regions demonstrating significant interaction effects of sex and DX, we tested whether sex moderated cognition-thickness relationships. We used machine learning as a complementary method to explore multivariate CT differences between women and men. RESULTS: Women demonstrated greater CT in many brain regions. More specifically, men showed relatively consistent CT declines in all stages, from normal control (NC) to ADD in the bilateral cingulate cortex, bilateral temporal regions, and left precuneus; women had more stable CT in these regions between NC and mild cognitive impairment (MCI) stages, but sharper declines from MCI to ADD. Similarly, for the Rey Auditory Verbal Learning Test (RAVLT), ANCOVA analyses showed that women had significantly better immediate and delayed recall scores than men, at NC and MCI stages, but greater differences, cross-sectionally, from MCI to ADD than men. We found significant sex moderation effects between RAVLT-immediate scores and CT of right isthmus-cingulate for all subjects across DX. Partial correlation analyses revealed that increased CT of right isthmus-cingulate was associated with better verbal learning in women, driven by positron emission tomography defined amyloid positive (Aß+) subjects. Significant sex-moderation effects in cognition-thickness relationships were further found in the right middle-temporal, left precuneus, and left superior temporal regions in Aß+ subjects. Using a machine learning approach, we investigated multivariate CT differences between women and men, showing an accuracy in classification of 75% for Aß+ cognitively NC participants. CONCLUSIONS: Sex differences in memory and CT can play a key role in the different vulnerability and progression of ADD in women compared to men. Machine learning indicates sex differences in CT are most relevant early in the ADD neurodegeneration.

The micro-, submicron-, and nanoplastic hunt: A review of detection methods for plastic particles.

Plastic particle pollution has been shown to be almost completely ubiquitous within our surrounding environment. This ubiquity in combination with a variety of unique properties (e.g. density, hydrophobicity, surface functionalization, particle shape and size, transition temperatures, and mechanical properties) and the ever-increasing levels of plastic production and use has begun to garner heightened levels of interest within the scientific community. However, as a result of these properties, plastic particles are often reported to be challenging to study in complex (i.e. real) environments. Therefore, this review aims to summarize research generated on multiple facets of the micro- and nanoplastics field; ranging from size and shape definitions to detection and characterization techniques to generating reference particles; in order to provide a more complete understanding of the current strategies for the analysis of plastic particles. This information is then used to provide generalized recommendations for researchers to consider as they attempt to study plastics in analytically complex environments; including method validation using reference particles obtained via the presented creation methods, encouraging efforts towards method standardization through the reporting of all technical details utilized in a study, and providing analytical pathway recommendations depending upon the exact knowledge desired and samples being studied.

Deciphering cellular signals in adult mouse sinoatrial node cells.

Sinoatrial node (SAN) cells are the pacemakers of the heart. This study describes a method for culturing and infection of adult mouse SAN cells with FRET-based biosensors that can be exploited to examine signaling events. SAN cells cultured in media with blebbistatin or (S)-nitro-blebbistatin retain their morphology, protein distribution, action potential (AP) waveform, and cAMP dynamics for at least 40 h. SAN cells expressing targeted cAMP sensors show distinct ß-adrenergic-mediated cAMP pools. Cyclic GMP, protein kinase A, Ca2+/CaM kinase II, and protein kinase D in SAN cells also show unique dynamics to different stimuli. Heart failure SAN cells show a decrease in cAMP and cGMP levels. In summary, a reliable method for maintaining adult mouse SAN cells in culture is presented, which facilitates studies of signaling networks and regulatory mechanisms during physiological and pathological conditions.

Neural correlates of psychodynamic and non-psychodynamic therapies in different clinical populations through fMRI: A meta-analysis and systematic review.

Background: The COVID-19 pandemic has exacerbated the ongoing crisis in psychiatric and psychological care, contributing to what we have identified as a new psychological and psychiatric pandemic. Psychotherapy is an effective method for easing the psychological suffering experienced also by the various impacts of COVID-19. This treatment can be examined from a neurological perspective, through the application of brain imaging techniques. Specifically, the meta-analysis of imaging studies can aid in expanding researchers' understanding of the many beneficial applications of psychotherapy. Objectives: We examined the functional brain changes accompanying different mental disorders with functional Magnetic Resonance Imaging (fMRI), through a meta-analysis, and systematic review in order to better understand the general neural mechanism involved in psychotherapy and the potential neural difference between psychodynamic and non-psychodynamic approaches. Data sources: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were employed for our systematic review and meta-analysis. We conducted a computer-based literature search, following the Population, Intervention, Comparison and Outcomes (PICO) approach, to retrieve all published articles in English regarding the above-described topics from PubMed (MEDLINE), Scopus, and Web of Science. Study eligibility criteria participants and interventions: We combined terms related to psychotherapy and fMRI: ("psychotherapy" [All Fields] OR "psychotherapy" [MeSH Terms] OR "psychotherapy" [All Fields] OR "psychotherapies" [All Fields] OR "psychotherapy s" [All Fields]) AND ("magnetic resonance imaging" [MeSH Terms]) OR ("magnetic"[All Fields] AND "resonance"[All Fields] AND "imaging"[All Fields]) OR ("magnetic resonance imaging"[All Fields] OR "fmri"[All Fields]). We considered (1) whole brain fMRI studies; (2) studies in which participants have been involved in a clinical trial with psychotherapy sessions, with pre/post fMRI; (3) fMRI results presented in coordinate-based (x, y, and z) in MNI or Talairach space; (4) presence of neuropsychiatric patients. The exclusion criteria were: (1) systematic review or meta-analysis; (2) behavioral study; (3) single-case MRI or fMRI study; and (4) other imaging techniques (i.e., PET, SPECT) or EEG. Results: After duplicates removal and assessment of the content of each published study, we included 38 sources. The map including all studies that assessed longitudinal differences in brain activity showed two homogeneous clusters in the left inferior frontal gyrus, and caudally involving the anterior insular cortex (p < 0.0001, corr.). Similarly, studies that assessed psychotherapy-related longitudinal changes using emotional or cognitive tasks (TASK map) showed a left-sided homogeneity in the anterior insula (p < 0.000) extending to Broca's area of the inferior frontal gyrus (p < 0.0001) and the superior frontal gyrus (p < 0.0001). Studies that applied psychodynamic psychotherapy showed Family-Wise Error (FWE) cluster-corrected (p < 0.05) homogeneity values in the right superior and inferior frontal gyri, with a small cluster in the putamen. No FWE-corrected homogeneity foci were observed for Mindful- based and cognitive behavioral therapy psychotherapy. In both pre- and post-therapy results, studies showed two bilateral clusters in the dorsal anterior insulae (p = 0.00001 and p = 0.00003, respectively) and involvement of the medial superior frontal gyrus (p = 0.0002). Limitations: Subjective experiences, such as an individual's response to therapy, are intrinsically challenging to quantify as objective, factual realities. Brain changes observed both pre- and post-therapy could be related to other factors, not necessary to the specific treatment received. Therapeutic modalities and study designs are generally heterogeneous. Differences exist in sample characteristics, such as the specificity of the disorder and number and duration of sessions. Moreover, the sample size is relatively small, particularly due to the paucity of studies in this field and the little contribution of PDT. Conclusions and implications of key findings: All psychological interventions seem to influence the brain from a functional point of view, showing their efficacy from a neurological perspective. Frontal, prefrontal regions, insular cortex, superior and inferior frontal gyrus, and putamen seem involved in these neural changes, with the psychodynamic more linked to the latter three regions.

Story Memory Impairment Rates and Association with Hippocampal Volumes in a Memory Clinic Population.

OBJECTIVE: Story memory tasks are among the most commonly used memory tests; however, research suggests they may be less sensitive to memory decline and have a weaker association with hippocampal volumes than list learning tasks. To examine its utility, we compared story memory to other memory tests on impairment rates and association with hippocampal volumes. METHOD: Archival records from 1617 older adults (Mage = 74.41, range = 65-93) who completed the Wechsler Memory Scale - 4th edition (WMS-IV) Logical Memory (LM), Hopkins Verbal Learning Test - Revised (HVLT-R), and Brief Visuospatial Memory Test - Revised (BVMT-R) as part of a clinical neuropsychological evaluation were reviewed. Scores >1.5 SD below age-adjusted means were considered impaired, and frequency distributions were used to examine impairment rates. A subset of participants (n = 179) had magnetic resonance imaging (MRI) data that underwent image quality assessment. Partial correlations and linear regression analyses, accounting for age, education, and total intracranial volume (TIV), examined associations between memory raw scores and hippocampal volumes. RESULTS: For delayed recall, nearly half of the sample was impaired on HVLT-R (48.8%) and BVMT-R (46.1%), whereas a little more than a third was impaired on LM (35.7%). Better performance on all three measures was related to larger hippocampal volumes (r's =. 26-.43, p's < .001). Individually adding memory scores to regression models predicting hippocampal volumes improved the model fit for all measures. CONCLUSIONS: Despite findings suggesting that story memory is less sensitive to memory dysfunction, it was not differentially associated with hippocampal volumes compared to other memory measures. Results support assessing memory using different formats and modalities in older adults.