Search Results (196)

Background/Objectives: Substance use behaviors share a complex, overlapping polygenic architecture, yet translating genome-wide association study (GWAS) findings into actionable biological mechanisms remains challenging. This study aimed to characterize the genetic architecture of five substance use traits (alcohol consumption, alcohol dependence, nicotine use, illicit drug use, and behavioral disinhibition) and identify shared and distinct gene expression signatures within the neural circuits governing addiction. Methods: We reanalyzed 7188 individuals from the Minnesota Center for Twin and Family Research (MCTFR) cohort utilizing longitudinal composite phenotypes spanning five substance-use domains and general behavioral disinhibition. Post-QC, 6874 individuals were retained for downstream analysis. Following genomic imputation and linear mixed model GWAS (GEMMA), we utilized the SNipar framework to partition polygenic risk scores (PRS) into direct and indirect genetic effects, investigating intergenerational shifts in genetic penetrance and effects of assortative mating. Finally, we integrated our summary statistics with brain tissue reference panels to perform a transcriptome-wide association study (TWAS) modeling genetically regulated gene expression within neural circuits relevant to addiction. Results: Partitioning of polygenic risk revealed that while surface-level parental DNA correlations were modest (r = 0.08), underlying latent genetic correlations approached unity (R_δ ≈ 0.99), indicating that addiction risk clustering in families is driven by intense assortive mating and concentrated biological inheritance. Multi-phenotype TWAS identified several significant gene–phenotype associations—notably ADAM32 and SLC9A3, which demonstrated pleiotropic effects across multiple substance use categories. Crucially, these significant TWAS signals were enriched in striatal structures (caudate, putamen, substantia nigra) and frontal cortical regions. Conclusions: Our findings support a model of shared genetic liability across diverse substance use behaviors, mediated by specific gene expression patterns in the mesolimbic dopamine system and frontal cortex. By integrating multi-phenotype GWAS and TWAS, this study highlights pleiotropic candidate genes and provides critical insights into the tissue-specific neurobiological pathways underlying addiction vulnerability. Full article

Background: Multiple sclerosis (MS) is a neurodegenerative and chronic inflammatory disease, often associated with psychiatric comorbidities, particularly depression and anxiety, which play a major role in disability, cognitive dysfunction, and quality of life. Growing evidence suggests that affective symptoms in MS are not only related to psychosocial burden but also to structural and functional abnormalities in the brain that can be identified using magnetic resonance imaging (MRI). Methods: A systematic database search was performed to identify studies for a structured narrative review. Original articles that examined MRI correlates of depression and anxiety in adult MS patients were included. Structural MRI, diffusion imaging, and functional MRI studies evaluating lesion distribution, cortical and subcortical atrophy, white matter microstructure, and network connectivity were analyzed alongside psychometric instruments used to assess affective symptoms. Results: Depression in MS was consistently associated with fronto-limbic and subcortical abnormalities including cortical thinning, hippocampal and thalamic atrophy, white matter disconnection and altered connectivity within the default mode, salience and executive control networks. Diffusion MRI studies have shown microstructural damage in associative white matter tracts, and functional MRI studies have supported a model of network-level dysfunction. In contrast, anxiety had less robust and reproducible associations with conventional MRI findings, indicating a more complex interaction between inflammatory, neurobiological and psychosocial mechanisms. Conclusions: Multimodal MRI approaches may increase our knowledge of the neurobiological substrates of depression and anxiety in MS and may contribute to more personalized diagnostic and therapeutic strategies. Full article

Background/Objectives: Serum brain-derived neurotrophic factor (BDNF) is linked to post-stroke neuroplasticity, but its temporal dynamics and clinical relevance during early rehabilitation remain unclear. We investigated changes in serum mature BDNF, proBDNF, and matrix metalloproteinase-9 (MMP-9) during the early subacute phase of stroke and their associations with functional improvement under standardized inpatient rehabilitation. Methods: In this prospective observational study at a tertiary inpatient rehabilitation unit, 100 stroke patients were enrolled and 84 were analyzed. Serum biomarkers and clinical assessments—including the National Institutes of Health Stroke Scale (NIHSS), Korean Mini-Mental State Examination, Fugl-Meyer Assessment, and Berg Balance Scale—were obtained at baseline (T0) and after two weeks of rehabilitation (T1). Correlation and multivariable regression analyses examined relationships between biomarker changes and functional outcomes, adjusting for age, sex, time from onset, and BDNF genotype. Results: An increase in serum mature BDNF from T0 to T1 was significantly associated with NIHSS improvement (r = −0.273, p = 0.014), which persisted after multivariable adjustment (β = −0.737, p = 0.009). Changes in proBDNF and MMP-9 showed no significant associations. Conclusions: Greater individual increases in serum mature BDNF during early subacute rehabilitation were independently associated with greater reductions in stroke severity, whereas the group-level mean did not increase over time. Serum mature BDNF may serve as a time-sensitive, objective biomarker of neurobiological recovery, potentially supporting individualized rehabilitation strategies. Full article

Background/Objectives: Antipsychotic dosing for behavioral and psychological symptoms of dementia (BPSD) in Alzheimer’s disease remains empirical and variable. This study develops a deep learning model to predict individualized antipsychotic doses from structural MRI. Methods: A transfer learning approach with a cascaded ResNet (Cas-ResNet) was used. The model was first pre-trained on a large healthy aging dataset (CBMFM, n = 646) for brain age prediction, then fine-tuned on a BPSD dataset (SMHC, n = 86) to predict the defined daily dose (DDD) of antipsychotics. Model interpretability was performed using Grad CAM to identify predictive brain regions. Results: The proposed model achieved a mean absolute error of 0.19 and a Pearson correlation of 0.66 between predicted and actual doses, outperforming baseline 3DCNN, VGG, and DenseNet. Key contributing regions included the left inferior temporal gyrus, right parahippocampal gyrus, right putamen, left middle temporal gyrus, and left caudate. Conclusions: This proof-of-concept study demonstrates that deep learning can predict personalized antipsychotic doses from structural MRI, offering an objective tool to standardize BPSD pharmacotherapy and reduce empirical prescribing. The identified brain regions provide neurobiological insights into treatment response. Full article

Cancer-related cognitive impairment (CRCI), also known as chemobrain or chemofog, is characterized by subjective and/or objective changes in attention, executive functions, memory, and processing speed in patients with non-CNS cancers, particularly women with breast cancer. This structured narrative review synthesizes current evidence on mechanisms, neuropsychological assessment, neuroimaging correlates, clinical and demographic risk factors, emerging artificial intelligence and machine learning applications, and non-pharmacological approaches to CRCI in breast cancer. A structured literature search was conducted using PubMed/MEDLINE, PsycInfo, and Clinical Key up to May 2026, with emphasis on studies published between 2023 and 2026. Peer-reviewed English-language studies involving adult breast cancer populations and addressing predefined thematic domains of CRCI were considered. Given the heterogeneity of study designs, assessment tools, interventions, and outcomes, the findings were synthesized narratively. Current evidence supports a multifactorial model of CRCI involving neurobiological, treatment-related, psychological, and behavioral mechanisms. Neuroinflammation, endocrine disruption, oxidative stress, glial alterations, and structural or functional brain changes may contribute to cognitive symptoms; however, the strength of evidence varies, and many findings remain correlational or preclinical. Non-pharmacological interventions, including cognitive training, physical activity, mindfulness-based and psychological approaches, and multimodal digital programs, appear promising as supportive strategies. However, evidence remains heterogeneous, with benefits more consistently reported for patient-reported outcomes, fatigue, emotional distress, and quality of life than for objective neuropsychological performance. CRCI in breast cancer should be approached as a heterogeneous condition requiring early recognition, standardized assessment, and multidisciplinary supportive care. Future research should prioritize longitudinal designs, harmonized endpoints, and a clearer distinction between subjective and objective outcomes. Full article

Obsessive–compulsive disorder (OCD) is a chronic and disabling psychiatric condition whose neurobiological underpinnings remain incompletely characterized. A growing body of evidence suggests that vitamin D, through its modulatory actions on neuroinflammation, serotonin synthesis, and cortico-striato-thalamo-cortical circuitry, may be implicated in its clinical expression. The present cross-sectional study examined the association between serum 25-hydroxyvitamin D levels and OCD severity in 306 adult outpatients with a diagnosis of OCD, of whom 173 had vitamin D measurements available. Symptom severity was assessed through the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS), and associations were examined using non-parametric tests, partial correlations and multivariable linear regression adjusted for age, gender, age at onset, and bipolar comorbidity. Mean vitamin D was 20.0 ± 13.1 ng/mL, with 60.1% of patients meeting criteria for deficiency. Lower vitamin D levels correlated inversely with Y-BOCS total score (ρ = −0.26, p = 0.001) and with both subscales, and deficient patients showed a mean Y-BOCS total approximately 5.5 points higher than non-deficient ones. In multivariable models, lower vitamin D (β = −0.253, p = 0.001) and earlier age at onset (β = −0.278, p = 0.001) independently predicted greater severity (R² = 0.133), while a history of suicide attempts neither predicted severity nor moderated the vitamin D association. These findings support vitamin D status as a biological correlate of OCD severity and warrant longitudinal and interventional investigation. Full article

Background/Objectives: Insomnia is one of the most prevalent and persistent symptoms among patients with breast cancer, yet it remains under-recognized and undertreated in routine clinical practice. Beyond its impact on sleep quality, insomnia is increasingly understood as a multidimensional condition involving neurobiological, psychological, and behavioral mechanisms, closely intertwined with cancer-related stress and psychiatric comorbidities. This narrative review aims to provide a comprehensive and integrative overview of insomnia in breast cancer, focusing on its epidemiology, pathophysiological underpinnings, neuropsychiatric correlates, and clinical implications, while highlighting gaps in current research and management. Methods: A narrative review of the literature was conducted, including studies published in major medical databases (PubMed, Scopus, and Web of Science) up to 2025. Relevant articles addressing insomnia, sleep disturbances, psychiatric symptoms, and neurobiological mechanisms in breast cancer populations were selected and synthesized. Results: Insomnia affects a substantial proportion of breast cancer patients across the disease trajectory, from diagnosis to survivorship. Its etiology is multifactorial, involving dysregulation of the hypothalamic–pituitary–adrenal axis, inflammatory processes, and circadian rhythm, as well as treatment-related factors such as chemotherapy, endocrine therapy, and menopausal symptoms. Insomnia frequently co-occurs with depression, anxiety, fatigue, and pain, forming symptom clusters that significantly impair quality of life and may influence clinical outcomes. Emerging evidence supports a bidirectional relationship between insomnia and psychiatric vulnerability, suggesting a shared neurobiological substrate within the brain–body stress axis. Conclusions: Insomnia in breast cancer should be conceptualized as a neuropsychiatric condition embedded within a broader stress-related symptom network rather than as an isolated sleep disturbance. Improved screening, interdisciplinary management, and the integration of evidence-based interventions such as cognitive behavioral therapy for insomnia are essential. Research should focus on personalized and mechanistically informed approaches to better address this highly prevalent yet insufficiently managed condition. Full article

Background: Radio Electric Asymmetric Conveyer (REAC) neurobiological modulation is proposed as an approach designed to interact with endogenous bioelectrical processes involved in cortical regulation. However, its electrophysiological correlates in physiologically preserved neural systems remain insufficiently characterized. The present study explored whether a standardized REAC Brain Wave Optimization Gamma (BWO-G_B) protocol is associated with measurable changes in resting-state EEG activity in healthy adults. Methods: Nine neurologically healthy participants completed a standardized REAC BWO-G_B protocol consisting of 18 sessions administered over six consecutive days. Resting-state EEG recordings were obtained before and after the intervention. Spectral power was analyzed across the 1–100 Hz range. Multivariate organization of cortical activity was explored using Principal Component Analysis (PCA) and Canonical Discriminant Analysis (CDA), with CDA used only as a descriptive visualization of within-dataset multivariate organization. Cross-correlation analysis was applied to evaluate changes in inter-regional temporal synchronization. Individual-level non-parametric testing (Wilcoxon signed-rank test) was conducted only to characterize within-subject directional spectral modulation across the recorded montage. Results: Post-intervention EEG recordings showed a consistent redistribution of spectral power across cortical regions, predominantly within frequencies below approximately 20 Hz. This pattern was observed across subjects at the individual level. Multivariate analysis revealed a dissociation between PCA, which showed partial overlap between conditions, and CDA, which descriptively showed within-dataset separability between baseline and post-intervention cortical states. Cross-correlation analysis indicated a spatially differentiated redistribution of temporal synchronization across cortical regions. At the individual level, descriptive Wilcoxon analyses indicated broadband spectral differences in seven of nine participants (p < 0.05), with consistent directional trends across all subjects; these p-values should not be interpreted as confirmatory statistical evidence. Conclusions: The findings indicate the presence of a reproducible electrophysiological pattern observed after completion of the REAC BWO-G_B protocol in healthy adults. The observed combination of spectral redistribution, descriptive multivariate organization, and changes in temporal synchronization is consistent with a structured post-intervention modification of cortical activity organization within the present dataset. However, given the exploratory design, small sample size, absence of a control condition, and absence of objective vigilance monitoring, these results should be interpreted cautiously and should not be considered as evidence of intervention-specific effects. Further controlled studies are required to determine specificity, underlying mechanisms, and potential functional relevance. Full article

Attention deficit hyperactivity disorder (ADHD) is a common and highly heterogeneous neurodevelopmental condition with complex biological underpinnings. Despite substantial progress in identifying genetic and neurobiological correlates, the cellular mechanisms linking genetic variation to functional brain alterations remain poorly understood. Human induced pluripotent stem cell (iPSC) technology provides a powerful platform to investigate these mechanisms by enabling the generation of patient-specific neural cell types and the direct interrogation of molecular, cellular, and network-level phenotypes. In this review, we summarise the current understanding of the neurobiological mechanisms underlying ADHD, including dopaminergic dysregulation, delayed neurodevelopmental maturation, and excitatory/inhibitory imbalance. We then discuss how iPSC-based models, combined with genome engineering and advanced functional assays, can be used to dissect gene-specific effects, study neural circuit development, and establish scalable platforms for therapeutic discovery. Finally, we outline key methodological considerations for designing robust iPSC-based models of ADHD. Together, these approaches provide new opportunities to bridge genetic risk with cellular function and accelerate the development of mechanistically informed therapeutic strategies. Full article

Background/Objectives: Alexithymia is a potential transdiagnostic risk factor for psychiatric and medical disorders involving affect dysregulation. But there is debate over whether a constricted imaginal capacity constitutes a core component of the construct or is a separable correlate. Our aim was to further explore this controversy as any revision to the construct has implications for clinical formulation, neurobiological models of associated default mode network dysfunction, and the coherence of the original psychiatric conceptualization. Methods: To replicate and extend previous factor analytic work, we conducted a two-stage exploratory factor analysis in a community sample that included individuals with a psychiatric history (N = 681). Using most of the subscale indicators employed in two prior factor analytic studies, we used a two-stage procedure: Stage 1 re-employed the general design of those studies. Stage 2 re-specified the analytic space by removing emotional reactivity and fantasizing-for-regulation variables that form their own separable latent dimensions. Results: Stage 1 yielded a conceptual replication of structural separation between alexithymia and imaginal processes. Stage 2 revealed meaningful cross-loadings obscured in the full set, most notably positive constructive daydreaming loading negatively on an externally oriented thinking factor, providing empirical support for the pensée opératoire construct. Additional cross-loadings linked dysphoric daydreaming and poor attentional control with negative emotion appraisal. Conclusions: The structural independence of alexithymia and imaginal processes is partly contingent on indicator set composition. Construct revision should be grounded not on two factor analytic studies using abbreviated self-report measures, but in convergent evidence across methods, including neuroimaging, electroencephalography, structured interview, performance-based assessment, and clinical observation. Full article

Fibromyalgia, a syndrome characterized by hyperalgesia and ‘negative emotionality’, and major depressive disorder (MDD) demonstrate substantial overlaps in clinical, neurobiological, and therapeutic domains. Currently, treatment options for fibromyalgia remain limited; however, the epidemiology of this syndrome continues to grow worldwide. The use of animal models is indispensable for developing new treatment strategies for fibromyalgia. Meanwhile, the choice of animal paradigms is limited. Here, we used the ultrasound exposure of emotional stress on CBA, BALB/c, and C57BL/6 mouse strains to model this condition and to identify new molecular targets of fibromyalgia treatment. We exposed young male mice of three common strains to a three-week ultrasound stress (US) comprising emotionally negative and neutral frequencies of 20–25 kHz and 25–45 kHz, resulting in the development of altered pain sensitivity and signs of ‘negative emotionality’. Specifically, mice were studied for timid-like/aggressive behaviors and the tail flick response. Serum levels of corticosterone, cortisol, β-Endorphin, and brain-derived neurotrophic factor (BDNF), as well as brain gene expression of interleukin-33 (Il-33), Bdnf, and its receptor Trkb were investigated. Among the stressed mouse strains, C57BL/6 mice displayed augmented pain sensitivity, allodynia, and suppressed dominant behavior, whereas CBA and BALB/c mice demonstrated opposing changes. Glucocorticoid levels were increased in all stressed groups. Stressed C57BL/6 mice showed downregulated gene and protein expression of functionally inter-related BDNF and IL-33 molecules in the hippocampus, amygdala, and striatum, significantly correlating with behavioral outcomes, as well as lowered blood levels of β-Endorphin and elevated cortisol concentrations. Altogether, our study identified the BDNF/IL-33 regulatory pathway as a molecular correlate of fibromyalgia, and the use of US-exposed young C57BL/6 mice as a potential model that recapitulates this syndrome. Full article

The human genome produces a large repertoire of non-coding RNAs (ncRNAs) with important regulatory roles in development, physiology, and most of diseases. Among these, long non-coding RNAs (lncRNAs) have emerged as key modulators of gene expression, chromatin organization, and cellular homeostasis, despite displaying remarkably low primary-sequence conservation across species. This apparent evolutionary paradox questions the limitations of predicting biological function based on conservation, particularly across different biological domains. Here, we examine current evidence on lncRNA evolution, with a focus on their roles in metabolic regulation compared with neurobiological processes. We hypothesize that lncRNAs involved in ancient and conserved pathways such as metabolism may be under stronger evolutionary constraint than those associated with higher-order, species-specific traits, although available data support a more nuanced interpretation. Functional importance often correlates poorly with linear sequence conservation and instead appears to depend on higher-level features, including RNA secondary or tertiary structure, genomic context, regulatory architecture, and interactions with conserved molecular partners. We propose a systematic comparative framework to empirically assess conservation among metabolism- and neuro-associated lncRNAs using phylogenetic, syntenic, structural, and expression-based metrics. Finally, we discuss the therapeutic implications of lncRNA biology, highlighting how a deeper understanding of their evolutionary and mechanistic properties may inform the development of more precise and effective RNA-targeting strategies. Together, these insights underscore the non-coding transcriptome as a critical frontier for both fundamental biology and precision medicine. Full article

Brain-Derived Neurotrophic Factor (BDNF), a key member of the neurotrophin family, is critically involved in neuronal survival, synaptic plasticity, learning, and memory. While its roles in mammals have been extensively documented, the molecular regulatory mechanisms governing BDNF expression and its causal contributions to complex cognitive behaviors remain poorly understood in non-mammalian vertebrates—particularly for the domestic pigeon (Columba livia domestica), a species distinguished by its remarkable spatial navigation and homing capabilities. This review synthesizes the current evidence on BDNF in the pigeon central nervous system across five thematic domains: molecular structure and isoform diversity, transcriptional and epigenetic regulatory networks, involvement in neural development, associations with cognitive and navigational behaviors, and potential translational applications. A particular emphasis is placed on the region-specific and activity-dependent expression patterns of BDNF in brain structures such as the hippocampal formation (HF), optic tectum, and striatum, and their functional relevance to visual processing, homing behavior, and stress adaptation. To date, most findings remain correlational; therefore, establishing a mechanistic understanding necessitates the integration of advanced methodologies—including single-cell omics, CRISPR-based gene editing, and high-resolution behavioral phenotyping—to causally link BDNF dynamics, neural circuit modulation, and spatial cognition. This synthesis aims to bridge gaps in comparative neurobiology, inform molecular approaches to avian cognitive enhancement, and support evidence-based strategies for racing pigeon breeding and welfare assessment. Full article

Insomnia is the most prevalent sleep disorder worldwide, affecting up to 30% of the population, and is frequently accompanied by cognitive complaints and measurable cognitive impairments. Chronic insomnia is characterized by persistent hyperarousal across physiological, cognitive, and neurobiological domains, which may compromise multiple cognitive systems. This review synthesizes current evidence on the impact of insomnia on major cognitive domains, including attention, language, memory and learning, executive functions, perceptual–motor skills, and social cognition. We critically evaluate methodological factors contributing to heterogeneous findings across studies, such as variability in diagnostic criteria, insomnia phenotypes, cognitive assessments, and sample characteristics. Additionally, we summarize emerging evidence on neuroanatomical and molecular correlates of insomnia-related cognitive impairment, including alterations in hippocampal and prefrontal brain structures, amyloid-β accumulation, dysregulation of brain-derived neurotrophic factor, neurotransmitter imbalance, neuroinflammation, and disrupted signaling pathways. Insights from preclinical studies show mechanistic links between sleep loss, synaptic dysfunction, oxidative stress, and memory decline. Despite substantial advances, the precise pathophysiological mechanisms underlying cognitive dysfunction in insomnia remain incompletely understood, suggesting that cognitive impairment arises from the convergence of multiple biological processes rather than a single causal pathway. A deeper mechanistic understanding is essential for developing targeted interventions for preventing cognitive decline in individuals with insomnia. Full article

Physical exercise can influence cognitive performance and neurobiological processes, but evidence spans diverse modalities, intensities, and adult populations. Acute exercise represents a state of transient skeletal muscle activation that induces systemic signaling through metabolic, endocrine, and myokine-mediated pathways, which may contribute to neurocognitive modulation. To map the breadth of acute exercise–cognition research, characterize cognitive and biological outcomes, and identify consistent patterns and gaps. Studies of adults (≥18 years) involving a single exercise session or short microcycle (≤7 days) with pre–post assessment of cognition and/or neurobiological markers across any exercise modality (aerobic, resistance, high-intensity interval training/HIIT, combined, vibration, mind–body) were included. PubMed and CENTRAL were systematically searched, yielding 101 studies. Data were extracted using a structured framework capturing exercise modality, dose, cognitive domains, biomarkers, neuroimaging outcomes, population characteristics, and study design features. Most studies examined young adults (53%) or older adults (32%). Aerobic exercise predominated (62%), followed by resistance (18%) and combined modalities (12%). Moderate-to-vigorous aerobic exercise consistently improved executive function, processing speed, and working memory. Resistance exercise also enhanced executive function in several trials (31 studies). Neurobiological correlates included increases in Brain-Derived Neurotrophic Factor (BDNF), lactate, catecholamines, and prefrontal activation, though variability in sampling limited mechanistic conclusions. Acute exercise is consistently associated with improvements in executive function and processing speed across modalities. Standardized exercise protocols, biomarker timing, and cognitive assessments are needed to strengthen mechanistic synthesis. Full article