Associations between brain imaging-derived phenotypes and cognitive functions.

We aimed to evaluate the potential causal relationship between brain imaging-derived phenotypes and cognitive functions via Mendelian randomization analyses. Genetic instruments for 470 brain imaging-derived phenotypes were selected from a genome-wide association study based on the UK Biobank (n = 33,224). Statistics for cognitive functions were obtained from the genome-wide association study based on the UK Biobank. We used the inverse variance weighted Mendelian randomization method to investigate the associations between brain imaging-derived phenotypes and cognitive functions, and reverse Mendelian randomization analyses were performed for significant brain imaging-derived phenotypes to examine the reverse causation for the identified associations. We identified three brain imaging-derived phenotypes to be associated with verbal-numerical reasoning, including cortical surface area of the left fusiform gyrus (beta, 0.18 [95% confidence interval, 0.11 to 0.25], P = 4.74 × 10-7), cortical surface area of the right superior temporal gyrus (beta, 0.25 [95% confidence interval, 0.15 to 0.35], P = 6.30 × 10-7), and orientation dispersion in the left superior longitudinal fasciculus (beta, 0.14 [95% confidence interval, 0.09 to 0.20], P = 8.37 × 10-7). The reverse Mendelian randomization analysis indicated that verbal-numerical reasoning had no effect on these three brain imaging-derived phenotypes. This Mendelian randomization study identified cortical surface area of the left fusiform gyrus, cortical surface area of the right superior temporal gyrus, and orientation dispersion in the left superior longitudinal fasciculus as predictors of verbal-numerical reasoning.

Dodecyl creatine ester therapy: from promise to reality.

Pathogenic variants in SLC6A8, the gene which encodes creatine transporter SLC6A8, prevent creatine uptake in the brain and result in a variable degree of intellectual disability, behavioral disorders (e.g., autism spectrum disorder), epilepsy, and severe speech and language delay. There are no treatments to improve neurodevelopmental outcomes for creatine transporter deficiency (CTD). In this spotlight, we summarize recent advances in innovative molecules to treat CTD, with a focus on dodecyl creatine ester, the most promising drug candidate.

Anterior thalamic circuits crucial for working memory.

Alterations in the structure and functional connectivity of anterior thalamic nuclei (ATN) have been linked to reduced cognition during aging. However, ATN circuits that contribute to higher cognitive functions remain understudied. We found that the anteroventral (AV) subdivision of ATN is necessary specifically during the maintenance phase of a spatial working memory task. This function engages the AV→parasubiculum (PaS)→entorhinal cortex (EC) circuit. Aged mice showed a deficit in spatial working memory, which was associated with a decrease in the excitability of AV neurons. Activation of AV neurons or the AV→PaS circuit in aged mice was sufficient to rescue their working memory performance. Furthermore, rescued aged mice showed improved behavior-induced neuronal activity in prefrontal cortex (PFC), a critical site for working memory processes. Although the direct activation of PFC neurons in aged mice also rescued their working memory performance, we found that these animals exhibited increased levels of anxiety, which was not the case for AV→PaS circuit manipulations in aged mice. These results suggest that targeting AV thalamus in aging may not only be beneficial for cognitive functions but that this approach may have fewer unintended effects compared to direct PFC manipulations.

Comprehensive investigation of predictive processing: A cross- and within-cognitive domains fMRI meta-analytic approach.

Predictive processing (PP) stands as a predominant theoretical framework in neuroscience. While some efforts have been made to frame PP within a cognitive domain-general network perspective, suggesting the existence of a "prediction network," these studies have primarily focused on specific cognitive domains or functions. The question of whether a domain-general predictive network that encompasses all well-established cognitive domains exists remains unanswered. The present meta-analysis aims to address this gap by testing the hypothesis that PP relies on a large-scale network spanning across cognitive domains, supporting PP as a unified account toward a more integrated approach to neuroscience. The Activation Likelihood Estimation meta-analytic approach was employed, along with Meta-Analytic Connectivity Mapping, conjunction analysis, and behavioral decoding techniques. The analyses focused on prediction incongruency and prediction congruency, two conditions likely reflective of core phenomena of PP. Additionally, the analysis focused on a prediction phenomena-independent dimension, regardless of prediction incongruency and congruency. These analyses were first applied to each cognitive domain considered (cognitive control, attention, motor, language, social cognition). Then, all cognitive domains were collapsed into a single, cross-domain dimension, encompassing a total of 252 experiments. Results pertaining to prediction incongruency rely on a defined network across cognitive domains, while prediction congruency results exhibited less overall activation and slightly more variability across cognitive domains. The converging patterns of activation across prediction phenomena and cognitive domains highlight the role of several brain hubs unfolding within an organized large-scale network (Dynamic Prediction Network), mainly encompassing bilateral insula, frontal gyri, claustrum, parietal lobules, and temporal gyri. Additionally, the crucial role played at a cross-domain, multimodal level by the anterior insula, as evidenced by the conjunction and Meta-Analytic Connectivity Mapping analyses, places it as the major hub of the Dynamic Prediction Network. Results support the hypothesis that PP relies on a domain-general, large-scale network within whose regions PP units are likely to operate, depending on the context and environmental demands. The wide array of regions within the Dynamic Prediction Network seamlessly integrate context- and stimulus-dependent predictive computations, thereby contributing to the adaptive updating of the brain's models of the inner and external world.

Neuropsychological Changes in Isolated REM Sleep Behavior Disorder: A Systematic Review and Meta-analysis of Cross-sectional and Longitudinal Studies.

The aim of this meta-analysis is twofold: (a) to assess cognitive impairments in isolated rapid eye movement (REM) sleep behavior disorder (iRBD) patients compared to healthy controls (HC); (b) to quantitatively estimate the risk of developing a neurodegenerative disease in iRBD patients according to baseline cognitive assessment. To address the first aim, cross-sectional studies including polysomnography-confirmed iRBD patients, HC, and reporting neuropsychological testing were included. To address the second aim, longitudinal studies including polysomnography-confirmed iRBD patients, reporting baseline neuropsychological testing for converted and still isolated patients separately were included. The literature search was conducted based on PRISMA guidelines and the protocol was registered at PROSPERO (CRD42021253427). Cross-sectional and longitudinal studies were searched from PubMed, Web of Science, Scopus, and Embase databases. Publication bias and statistical heterogeneity were assessed respectively by funnel plot asymmetry and using I2. Finally, a random-effect model was performed to pool the included studies. 75 cross-sectional (2,398 HC and 2,460 iRBD patients) and 11 longitudinal (495 iRBD patients) studies were selected. Cross-sectional studies showed that iRBD patients performed significantly worse in cognitive screening scores (random-effects (RE) model = -0.69), memory (RE model = -0.64), and executive function (RE model = -0.50) domains compared to HC. The survival analyses conducted for longitudinal studies revealed that lower executive function and language performance, as well as the presence of mild cognitive impairment (MCI), at baseline were associated with an increased risk of conversion at follow-up. Our study underlines the importance of a comprehensive neuropsychological assessment in the context of iRBD.

Cerebellar Roles in Motor and Social Functions and Implications for ASD.

The cerebellum, traditionally linked to voluntary motor coordination, is now recognized for its role in nonmotor functions, including cognitive and social behaviors. This expanded understanding is vital for identifying neurodevelopmental disorders such as autism spectrum disorder (ASD), where cerebellar abnormalities are common. Recent research has identified specific cerebellar circuits contributing to these diverse functions, revealing interconnected pathways that regulate both motor and social behaviors. The cerebellum communicates extensively with the cerebral cortex, thalamus, and limbic structures through converging and diverging pathways, integrating sensory and motor information to fine-tune outputs and influence higher-order functions. Mouse models have been instrumental in dissecting cerebellar functions, with studies using genetic and neuroanatomical techniques to manipulate specific circuits and observe behavioral outcomes. Disruptions in cerebellar pathways can lead to motor deficits and social impairments, mirroring human neurodevelopmental disorders. This review explores the anatomical and functional organization of cerebellar pathways in mice, their role in behavior, and the implications of cerebellar dysfunction in disorders such as ASD. Understanding these pathways enhances knowledge of cerebellar contributions to behavior and informs therapeutic strategies for cerebellar and neurodevelopmental disorders, emphasizing the integral role of the cerebellum in motor and social functions.

Morus Alba Fruit Extract and its Fractions Ameliorate Streptozotocin Induced Cognitive Deficit in Mice via Modulating Oxidative and Cholinergic Systems.

Increased oxidative stress and acetylcholinesterase (AChE) activity are key pathological characters contributing to the memory disorders. Thus, drugs targeting both oxidative stress and AChE are being explored for the management of cognitive dysfunction. Morus alba fruits (commonly consumed for its high nutritious value) are known to have antioxidant and AChE inhibitory effects. However, the role of Morus alba fruits in the management of memory disorders has not reported yet. This investigation was conducted to assess the antioxidant and AChE inhibitory potential of Morus alba fruit extracts in-vitro and to identify the components responsible for such effects. Further, the obtained bioactive component was studied for possible memory improvement effects against streptozotocin (STZ) induced dementia. To isolate the bioactive component in-vitro DPPH and AChE assays guided fractionation was performed. Memory functions in mice were determined using Morris Water Maze test while brain biochemical parameters were measured to understand the mechanism of action. In-vitro assays revealed strong AChE and DPPH inhibitory potential of methanol extract (ME), therefore, it was further fractionated. Among various fractions obtained, ethyl-acetate fraction (EAF) was found to possess marked AChE and DPPH inhibitory activities. On subsequent fractionation of EAF, bioactivity of obtained sub-fractions was found to be inferior to EAF. Further, both ME and EAF improved STZ (intracerebroventricular) induced cognitive dysfunction in animals by restoring endogenous antioxidant status (superoxide dismutase and reduced glutathione) and reducing thiobarbituric acid reactive species and nitric oxide levels along with brain AChE and myeloperoxidase activity. TLC densitometric studies showed appreciable levels of phenolic acids and quercetin in both EAF and ME. It can be concluded that Morus alba fruit extract has the ability to modulate cholinergic and oxidative system due to presence of phenolic and flavonoid compounds and hence, could aid in the management of memory disorders.

The role of fatigue in attentional processing in multiple sclerosis: data from event-related potentials.

Fatigue is an extremely common symptom in in people with multiple sclerosis (PwMS) and has a severe impact on quality of life. The purpose of the present study was to verify whether fatigue in PwMS is associated with a selective covert attention impairment, as measured by event-related potentials and to assess whether it is more associated with an impairment of top-down or bottom-up attentional control. Twenty-two PwMS and fatigue-MSF, 17 without fatigue-MSnF and 35 healthy volunteers underwent a three-stimulus P300 novelty task that elicits both the P3a and the P3b components. P3b latency was comparable between groups, but PwMS, independently from the presence of fatigue displayed significantly greater P3b amplitudes. P3a latency was significantly prolonged in MSF alone, while P3a amplitude in MSnF group was greater than controls. MSF were able to categorize the task-relevant target stimulus but the orienting response to a novel salient stimulus was delayed, indicating an impairment in bottom-up attentional control mechanism related to ventral attention network. Fatigue is selectively associated with a covert attentional deficit related to the ability to reallocate attentional resources to salient stimuli, a crucial function of adaptive decision-making behaviour.

Enhanced audiovisual associative pair learning in migraine without aura in adult patients: An unexpected finding.

BACKGROUND: Altered sensory processing in migraine has been demonstrated by several studies in unimodal, and especially visual, tasks. While there is some limited evidence hinting at potential alterations in multisensory processing among migraine sufferers, this aspect remains relatively unexplored. This study investigated the interictal cognitive performance of migraine patients without aura compared to matched controls, focusing on associative learning, recall, and transfer abilities through the Sound-Face Test, an audiovisual test based on the principles of the Rutgers Acquired Equivalence Test. MATERIALS AND METHODS: The performance of 42 volunteering migraine patients was compared to the data of 42 matched controls, selected from a database of healthy volunteers who had taken the test earlier. The study aimed to compare the groups' performance in learning, recall, and the ability to transfer learned associations. RESULTS: Migraine patients demonstrated significantly superior associative learning as compared to controls, requiring fewer trials, and making fewer errors during the acquisition phase. However, no significant differences were observed in retrieval error ratios, generalization error ratios, or reaction times between migraine patients and controls in later stages of the test. CONCLUSION: The results of our study support those of previous investigations, which concluded that multisensory processing exhibits a unique pattern in migraine. The specific finding that associative audiovisual pair learning is more effective in adult migraine patients than in matched controls is unexpected. If the phenomenon is not an artifact, it may be assumed to be a combined result of the hypersensitivity present in migraine and the sensory threshold-lowering effect of multisensory integration.

Protecting the Brain While Healing Hearts: The Protective Role of Cognitive Reserve in Cardiac Surgery.

OBJECTIVE: One of the most significant complications following coronary artery bypass grafting (CABG) is postoperative cognitive decline (POCD). CABG patients frequently experience considerable postoperative cognitive dysfunction (POCD), including decline in attention, orientation, memory, judgment, and social functioning. DESIGN: These negative effects may potentially be resolved by a protective factor, cognitive reserve (CR) that has been considered to function as a buffer against the consequences of neuropathology. SETTING: We explored the frequency of POCD and CR in coronary artery disease patients undergoing CABG. We hypothesized that high levels of CR would protect against POCD after cardiac surgery. PARTICIPANTS: We assessed 101 patients before surgery, and 4 months after cardiopulmonary bypass surgery with the use of extracorporeal circulation. MEASUREMENTS: Measures of cognitive functions, CR, anxiety, and depression were included in the assessment. RESULTS: Each patient was placed in the high (n = 50) or low CR (n = 51) group, based on median split. Chi-square tests effect showed that patients with low CR were more likely to a great extend to demonstrate postsurgical cognitive decline in attention, memory, visuospatial perception and executive functions than patients with high CR upon postsurgery neuropsychological assessment. CONCLUSIONS: Our results suggest that CR can forecast neuropsychological outcomes of cardiac surgery, recognizing the patients with low CR and help them to participate to interventions programs that could slow cognitive aging or reduce the risk of dementia and enhance their overall postsurgical functional outcome.