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Annual Review of Neuroscience Jul 2023Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are... (Review)
Review
Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are strongest in pain, indicating that psychosocial factors directly influence pain. In this review, I focus on the neural and psychological mechanisms by which instructions, learning, and expectations shape subjective pain. I address new experimental designs that help researchers tease apart the impact of these distinct processes and evaluate the evidence regarding the neural mechanisms by which these cognitive factors shape subjective pain. Studies reveal that expectations modulate pain through parallel circuits that include both pain-specific and domain-general circuits such as those involved in affect and learning. I then review how expectations, learning, and verbal instructions impact clinical outcomes, including placebo analgesia and responses to pharmacological treatments, and discuss implications for future work.
Topics: Humans; Motivation; Pain; Analgesia; Learning; Placebo Effect
PubMed: 36917820
DOI: 10.1146/annurev-neuro-101822-122427 -
Scientific Reports Nov 2023Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via...
Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.
Topics: Humans; Aged; Alzheimer Disease; Cohort Studies; Amyloid beta-Peptides; Brain; Tomography, X-Ray Computed; Positron-Emission Tomography; Amyloid; Leukocyte L1 Antigen Complex; Biomarkers; tau Proteins; Cognitive Dysfunction
PubMed: 37963908
DOI: 10.1038/s41598-023-45929-z -
Molecular Psychiatry Jul 2023Stressful experiences, both physical and psychological, that are overwhelming (i.e., inescapable and unpredictable), can measurably affect subsequent neuronal properties... (Review)
Review
Stressful experiences, both physical and psychological, that are overwhelming (i.e., inescapable and unpredictable), can measurably affect subsequent neuronal properties and cognitive functioning of the hippocampus. At the cellular level, stress has been shown to alter hippocampal synaptic plasticity, spike and local field potential activity, dendritic morphology, neurogenesis, and neurodegeneration. At the behavioral level, stress has been found to impair learning and memory for declarative (or explicit) tasks that are based on cognition, such as verbal recall memory in humans and spatial memory in rodents, while facilitating those that are based on emotion, such as differential fear conditioning in humans and contextual fear conditioning in rodents. These vertically related alterations in the hippocampus, procedurally observed after subjects have undergone stress, are generally believed to be mediated by recurrently elevated circulating hypothalamic-pituitary-adrenal (HPA) axis effector hormones, glucocorticoids, directly acting on hippocampal neurons densely populated with corticosteroid receptors. The main purposes of this review are to (i) provide a synopsis of the neurocognitive effects of stress in a historical context that led to the contemporary HPA axis dogma of basic and translational stress research, (ii) critically reappraise the necessity and sufficiency of the glucocorticoid hypothesis of stress, and (iii) suggest an alternative metaparadigm approach to monitor and manipulate the progression of stress effects at the neural coding level. Real-time analyses can reveal neural activity markers of stress in the hippocampus that can be used to extrapolate neurocognitive effects across a range of stress paradigms (i.e., resolve scaling and dichotomous memory effects issues) and understand individual differences, thereby providing a novel neurophysiological scaffold for advancing future stress research.
Topics: Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Glucocorticoids; Fear; Hippocampus; Spatial Memory; Stress, Psychological
PubMed: 36759545
DOI: 10.1038/s41380-023-01986-4 -
GeroScience Oct 2023Limited research exists on the association between resting-state functional network connectivity in the brain and learning and memory processes in advanced age. This... (Randomized Controlled Trial)
Randomized Controlled Trial
Limited research exists on the association between resting-state functional network connectivity in the brain and learning and memory processes in advanced age. This study examined within-network connectivity of cingulo-opercular (CON), frontoparietal control (FPCN), and default mode (DMN) networks, and verbal and visuospatial learning and memory in older adults. Across domains, we hypothesized that greater CON and FPCN connectivity would associate with better learning, and greater DMN connectivity would associate with better memory. A total of 330 healthy older adults (age range = 65-89) underwent resting-state fMRI and completed the Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) in a randomized clinical trial. Total and delayed recall scores were assessed from baseline data, and a learning ratio calculation was applied to participants' scores. Average CON, FPCN, and DMN connectivity values were obtained with CONN Toolbox. Hierarchical regressions controlled for sex, race, ethnicity, years of education, and scanner site, as this was a multi-site study. Greater within-network CON connectivity was associated with better verbal learning (HVLT-R Total Recall, Learning Ratio), visuospatial learning (BVMT-R Total Recall), and visuospatial memory (BVMT-R Delayed Recall). Greater FPCN connectivity was associated with better visuospatial learning (BVMT-R Learning Ratio) but did not survive multiple comparison correction. DMN connectivity was not associated with these measures of learning and memory. CON may make small but unique contributions to learning and memory across domains, making it a valuable target in future longitudinal studies and interventions to attenuate memory decline. Further research is necessary to understand the role of FPCN in learning and memory.
Topics: Humans; Aged; Aged, 80 and over; Magnetic Resonance Imaging; Brain; Memory; Learning; Mental Recall
PubMed: 37814198
DOI: 10.1007/s11357-023-00967-3 -
Current Psychiatry Reports Oct 2023To review recent research regarding cognitive problems during perimenopause, including which menopause-related symptoms, demographic variables, stress exposures, and... (Review)
Review
PURPOSE OF REVIEW
To review recent research regarding cognitive problems during perimenopause, including which menopause-related symptoms, demographic variables, stress exposures, and neural biomarkers are associated with cognitive problems and which interventions demonstrate efficacy at improving cognitive performance.
RECENT FINDINGS
Cognitive problems are common during perimenopause and have a significant impact on a substantial proportion of women. Evidence continues to indicate that verbal learning and verbal memory are the cognitive functions that are most negatively affected during perimenopause, and new research suggests that perimenopause may also be associated with deficits in processing speed, attention, and working memory. Recent research suggests that the cognitive profiles of women transitioning through perimenopause are heterogenous - with some showing strengths and others demonstrating weaknesses in particular cognitive domains. Depression, sleep problems, and vasomotor symptoms in perimenopause may be associated with cognitive difficulties. Recent neuroimaging studies are identifying changes in activity patterns within brain regions that correlate with cognitive performance in perimenopause, but future causal studies are needed to understand the neural mechanisms of cognitive problems during this time. Although clinical treatment studies for cognitive concerns have historically focused on postmenopause, some small trials in perimenopausal samples have been conducted recently but are frequently underpowered. Current guidelines from the North American Menopause Society do not support the use of hormone therapy at any age for cognitive problems. Animal research demonstrates that estradiol and levonorgestrel combined may alleviate working memory problems. Much progress has been made in understanding how perimenopause impacts cognition, and more research is needed to better identify who is at highest risk and how to meaningfully prevent and alleviate cognitive problems during this reproductive stage. Larger-scale randomized intervention trials specifically during perimenopause are urgently needed to address cognitive concerns in this population of women. More consistent reproductive staging, inclusion of covariates, and analyses examining perimenopause specifically would improve study quality and the ability to draw clear conclusions from this research.
Topics: Female; Humans; Perimenopause; Menopause; Postmenopause; Estradiol; Cognition
PubMed: 37755656
DOI: 10.1007/s11920-023-01447-3 -
JAMA Psychiatry Jul 2023Understanding the mechanisms of delusion formation in Alzheimer disease (AD) could inform the development of therapeutic interventions. It has been suggested that...
IMPORTANCE
Understanding the mechanisms of delusion formation in Alzheimer disease (AD) could inform the development of therapeutic interventions. It has been suggested that delusions arise as a consequence of false memories.
OBJECTIVE
To investigate whether delusions in AD are associated with false recognition, and whether higher rates of false recognition and the presence of delusions are associated with lower regional brain volumes in the same brain regions.
DESIGN, SETTING, AND PARTICIPANTS
Since the Alzheimer's Disease Neuroimaging Initiative (ADNI) launched in 2004, it has amassed an archive of longitudinal behavioral and biomarker data. This cross-sectional study used data downloaded in 2020 from ADNI participants with an AD diagnosis at baseline or follow-up. Data analysis was performed between June 24, 2020, and September 21, 2021.
EXPOSURE
Enrollment in the ADNI.
MAIN OUTCOMES AND MEASURES
The main outcomes included false recognition, measured with the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) and the Rey Auditory Verbal Learning Test (RAVLT) and volume of brain regions corrected for total intracranial volume. Behavioral data were compared for individuals with delusions in AD and those without using independent-samples t tests or Mann-Whitney nonparametric tests. Significant findings were further explored using binary logistic regression modeling. For neuroimaging data region of interest analyses using t tests, Poisson regression modeling or binary logistic regression modeling and further exploratory, whole-brain voxel-based morphometry analyses were carried out to explore the association between regional brain volume and false recognition or presence of delusions.
RESULTS
Of the 2248 individuals in the ADNI database, 728 met the inclusion criteria and were included in this study. There were 317 (43.5%) women and 411 (56.5%) men. Their mean (SD) age was 74.8 (7.4) years. The 42 participants with delusions at baseline had higher rates of false recognition on the ADAS-Cog 13 (median score, 3; IQR, 1 to 6) compared with the 549 control participants (median score, 2; IQR, 0 to 4; U = 9398.5; P = .04). False recognition was not associated with the presence of delusions when confounding variables were included in binary logistic regression models. An ADAS-Cog 13 false recognition score was inversely associated with left hippocampal volume (odds ratio [OR], 0.91 [95% CI, 0.88-0.94], P < .001), right hippocampal volume (0.94 [0.92-0.97], P < .001), left entorhinal cortex volume (0.94 [0.91-0.97], P < .001), left parahippocampal gyrus volume (0.93 [0.91-0.96], P < .001), and left fusiform gyrus volume (0.97 [0.96-0.99], P < .001). There was no overlap between locations associated with false recognition and those associated with delusions.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study, false memories were not associated with the presence of delusions after accounting for confounding variables, and no indication for overlap of neural networks for false memories and delusions was observed on volumetric neuroimaging. These findings suggest that delusions in AD do not arise as a direct consequence of misremembering, lending weight to ongoing attempts to delineate specific therapeutic targets for treatment of psychosis.
Topics: Male; Humans; Female; Aged; Alzheimer Disease; Delusions; Cross-Sectional Studies; Magnetic Resonance Imaging; Neuroimaging; Cognitive Dysfunction
PubMed: 37223934
DOI: 10.1001/jamapsychiatry.2023.1012 -
PloS One 2024Prior cross-cultural studies have demonstrated differences among Eastern and Western cultures in memory and cognition along with variation in neuroanatomy and functional...
Prior cross-cultural studies have demonstrated differences among Eastern and Western cultures in memory and cognition along with variation in neuroanatomy and functional engagement. We further probed cultural neuroanatomical variability in terms of its relationship with memory performance. Specifically, we investigated how memory performance related to gray matter volume in several prefrontal lobe structures, including across cultures. For 58 American and 57 Taiwanese young adults, memory performance was measured with the California Verbal Learning Test (CVLT) using performance on learning trial 1, on which Americans had higher scores than the Taiwanese, and the long delayed free recall task, on which groups performed similarly. MRI data were reconstructed using FreeSurfer. Across both cultures, we observed that larger volumes of the bilateral rostral anterior cingulate were associated with lower scores on both CVLT tasks. In terms of effects of culture, the relationship between learning trial 1 scores and gray matter volumes in the right superior frontal gyrus had a trend for a positive relationship in Taiwanese but not in Americans. In addition to the a priori analysis of select frontal volumes, an exploratory whole-brain analysis compared volumes-without considering CVLT performance-across the two cultural groups in order to assess convergence with prior research. Several cultural differences were found, such that Americans had larger volumes in the bilateral superior frontal and lateral occipital cortex, whereas Taiwanese had larger volumes in the bilateral rostral middle frontal and inferior temporal cortex, and the right precuneus.
Topics: Humans; Young Adult; Brain; Cognition; Gray Matter; Magnetic Resonance Imaging; Prefrontal Cortex; Temporal Lobe; Taiwan; North American People; United States
PubMed: 38551909
DOI: 10.1371/journal.pone.0298235 -
Communicative & Integrative Biology 2024In this hypothesis, I discuss how laughter from physical play could have evolved to being induced via visual or even verbal stimuli, and serves as a signal to highlight...
In this hypothesis, I discuss how laughter from physical play could have evolved to being induced via visual or even verbal stimuli, and serves as a signal to highlight incongruity that could potentially pose a threat to survival. I suggest how laughter's induction could have negated the need for physical contact in play, evolving from its use in tickling, to tickle-misses, and to taunting, and I discuss how the application of deep learning neural networks trained on images of spectra of a variety of laughter types from a variety of individuals or even species, could be used to determine such evolutionary pathways via the use of latent space exploration.
PubMed: 38601922
DOI: 10.1080/19420889.2024.2338073 -
Journal of Lipid Research Jul 2023Type 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway...
Type 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been reported in T2DM, obesity and cognitive impairment. We examine linoleic acid (LA)-derived CYP450-sEH oxylipins and cognition in T2DM and explore potential differences between obese and nonobese individuals. The study included 51 obese and 57 nonobese participants (mean age 63.0 ± 9.9, 49% women) with T2DM. Executive function was assessed using the Stroop Color-Word Interference Test, FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B. Verbal memory was assessed using the California Verbal Learning Test, second Edition. Four LA-derived oxylipins were analyzed by ultra-high-pressure-LC/MS, and the 12,13-dihydroxyoctadecamonoenoic acid (12,13-DiHOME) considered the main species of interest. Models controlled for age, sex, BMI, glycosylated hemoglobin A1c, diabetes duration, depression, hypertension, and education. The sEH-derived 12,13-DiHOME was associated with poorer executive function scores (F = 7.513, P = 0.007). The CYP450-derived 12(13)-epoxyoctadecamonoenoic acid (12(13)-EpOME) was associated with poorer executive function and verbal memory scores (F = 7.222, P = 0.008 and F = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F = 4.126, P = 0.045), predicting executive function such that relationships were stronger in obese individuals. These findings suggest that the CYP450-sEH pathway as a potential therapeutic target for cognitive decline in T2DM. For some markers, relationships may be obesity dependent.
Topics: Humans; Female; Middle Aged; Aged; Male; Linoleic Acid; Diabetes Mellitus, Type 2; Oxylipins; Epoxide Hydrolases; Cognition; Cytochrome P-450 Enzyme System; Obesity
PubMed: 37245563
DOI: 10.1016/j.jlr.2023.100395 -
Journal of the American Heart... Nov 2023Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2... (Randomized Controlled Trial)
Randomized Controlled Trial
Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.
Topics: Male; Adult; Humans; Female; Diabetes Mellitus, Type 2; Prediabetic State; Calcium; Coronary Vessels; Cross-Sectional Studies; Metformin; Cognitive Dysfunction; Calcinosis; Calcium, Dietary; Coronary Artery Disease; Vascular Calcification; Risk Factors
PubMed: 37929764
DOI: 10.1161/JAHA.123.029671