Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and death. Although significant progress has been made in understanding ALS, its molecular mechanisms remain complex and multifactorial. This review explores the potential convergent mechanisms underlying ALS pathogenesis, focusing on the roles of key proteins including NEK1, C21ORF2, Cyclin F, VCP, and TDP-43. Recent studies suggest that mutations in C21ORF2, lead to the stabilization of NEK1, while Cyclin F mutations activate VCP, resulting in TDP-43 aggregation. TDP-43 aggregation, a hallmark of ALS, impairs RNA processing and protein transport, both of which are essential for neuronal function. Furthermore, TDP-43 has emerged as a key player in DNA damage repair, translocating to DNA damage sites and recruiting repair proteins. Given that NEK1, VCP, and Cyclin F are also involved in DNA repair, this review examines how these proteins may intersect to disrupt DNA damage repair mechanisms, contributing to ALS progression. Impaired DNA repair and protein homeostasis are suggested to be central downstream mechanisms in ALS pathogenesis. Ultimately, understanding the interplay between these pathways could offer novel insights into ALS and provide potential therapeutic targets. This review aims to highlight the emerging connections between protein aggregation, DNA damage repair, and cellular dysfunction in ALS, fostering a deeper understanding of its molecular basis and potential avenues for intervention.

Abstract: Glioblastoma (GBM) poses a formidable challenge to patients for several reasons. Given its grim prognosis, understanding the various mechanisms GBM tumors utilize to resist therapy is essential to improve patient outcomes. Using PubMed, this focused review identifies and characterizes five critical elements of GBM tumors that contribute to their resistance to treatment: DNA repair enzymes, temozolomide (TMZ) and radiation mechanisms, anti-apoptosis mechanisms, GBM tumor heterogeneity and its effects on the cell cycle. This review explores various challenges associated with GBM tumors, such as their resistance against standard treatments such as TMZ and radiation therapy (RT). We explore the importance of epigenetic reprogramming, genetic mutations critical for cell proliferation and tumor suppression, and the role of mismatch repair (MMR) processes that influence RT and immune response interplay as contributors to GBM resistance. In addition, this review highlights vital DNA repair enzymes such as O6-methylguanine-DNA methyltransferase (MGMT) and Alkylpurine-DNA N-Glycosylase (APNG), which repair DNA damage introduced by alkylating agents such as TMZ. The involvement of the NuRD complex, particularly CHD4, in regulating access to DNA repair enzymes. Recent advancements in understanding the transcriptional regulation of MGMT through NF-κB activity are examined. Further, we explore novel approaches, including using anticancer neural stem cells and targeting hexokinase 2 (HK2) with antifungal drugs. Examining critical elements of the GBM cell cycle, such as the role of CDK's, cyclin(s) and proliferation markers such as ki67, can also give us a foundation for identifying possible target proteins and kinases for cancer drugs. While targeting DNA repair enzymes, proteins, and regulatory elements shows promise in enhancing GBM treatment efficacy, we acknowledge the challenges, including potential side effects and the risk of secondary cancers. Future research should focus on leveraging personalized medicine approaches and emerging biotechnologies, such as CRISPR gene editing, to develop targeted therapies that can overcome resistance mechanisms of GBM and improve patient outcomes.

Abstract: Freezing of Gait (FoG) is a debilitating motor symptom of Parkinson’s Disease (PD), characterized by sudden episodes where patients struggle to initiate or sustain movement, often describing a sensation of their feet being “glued to the ground.” This study investigates the potential of machine learning (ML) models to predict FoG severity in PD patients, focusing on the influence of dopaminergic medication by comparing gait parameters in ON and OFF medication states. Specifically, we employ spatiotemporal gait features to develop a predictive model for FoG episodes, leveraging a Random Forest Regressor to identify the most influential gait parameters associated with FoG severity in each medication state. The results indicate that the model achieved higher predictive performance in the OFF-medication condition (R² = 0.82, MAE = 2.25, MSE = 15.23) compared to the ON-medication condition (R² = 0.52, MAE = 4.16, MSE = 42.00). These findings suggest that dopaminergic treatment alters gait dynamics, potentially reducing the reliability of FoG predictions when patients are medicated. Feature importance analysis further highlights distinct gait characteristics that contribute to FoG prediction depending on medication status. In the OFF condition, step length asymmetry and stride variability emerged as dominant predictors, while in the ON condition, changes in gait rhythm and stepping frequency became more prominent, reflecting medication-induced compensatory adjustments. These findings underscore the need for predictive models that account for medication-induced gait variability, ensuring more reliable FoG detection. By integrating spatiotemporal gait analysis and ML-based prediction, this study contributes to the development of personalized intervention strategies for PD patients experiencing freezing episodes.

Abstract: Hypnosis is a state of intense focus and heightened suggestibility, where individuals become absorbed in internal experiences like thoughts, emotions, and mental imagery. Research on neural oscillations has shown distinct brain activity patterns during hypnosis, including increased theta power in the left parietal and occipital regions, elevated beta power in the frontal and left temporal areas, and enhanced slow-gamma power in the frontal and left parietal regions. Most studies focus on the physiological and neural responses of the subjects under hypnosis, but the dynamic between the hypnotist and the subject, particularly how the hypnotist influences the subject’s brain activity, remains underexplored.In this study, EEG data was analyzed using a deep learning model (U-Net). After preprocessing, the cleaned EEG data were transformed into images with a resolution of 128×128×3. They were randomized and classified into train and test groups (0.8 train, 0.2 test) after normalization.Features extracted from the model’s bottleneck layer were examined with principal component analysis (PCA) to compare the EEG data of a hypnotist and a hypnotized individual. The results showed highly similar EEG representations at the bottleneck layer, confirmed by PCA, with only minor differences.These findings suggest that hypnosis may involve shared neural mechanisms, possibly supporting theories of neural synchronization or cognitive mirroring. While much is known about the brain activity of hypnotized individuals, research on the hypnotist’s neural dynamics is limited. Future research should involve simultaneous neuroimaging or EEG recordings of both the hypnotist and the hypnotized individual to explore whether hypnotists modulate brain activity intentionally and how these patterns interact, including functional connectivity measures like coherence or phase-locking.

Abstract:

This study explores the neuropharmacological potential of various molecular and amino acid components derived from Syzygium aromaticum (clove), an aromatic spice with a long history of culinary and medicinal use. Key bioactive compounds such as eugenol, α-humulene, β-caryophyllene, gallic acid, quercetin, and luteolin demonstrate antioxidant, anti-inflammatory, and neuroprotective properties by scavenging free radicals, modulating calcium channels, and reducing neuroinflammation and oxidative stress. Moreover, gallic acid and asiatic acid exhibit protective effects, including apoptosis inhibition, while other useful properties of clove phytocompounds include NF-κB pathway inhibition, membrane stabilization, and suppression of pro-inflammatory pathways, further contributing to neuroprotection and cognitive enhancement. Amino acid analysis revealed essential and non-essential amino acids such as aspartic acid, serine, glutamic acid, glycine, histidine, and arginine in various clove parts (buds, fruits, branches, and leaves). These amino acids play crucial roles in neurotransmitter synthesis, immune modulation, antioxidant defense, and metabolic regulation. Collectively, these bioactive molecules and amino acids contribute to clove’s antioxidant, anti-inflammatory, neurotrophic, and neurotransmitter-modulating effects, highlighting its potential as a preventive and therapeutic candidate for neurodegenerative disorders. While preliminary preclinical studies support these neuroprotective properties, further research, including clinical trials, is needed to validate the efficacy and safety of clove-based interventions in neuroprotection.

Abstract: Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, yet effective agents for its prevention and therapy remain highly limited. Epicoccin A, a significant secondary metabolite from Exserohilum sp., demonstrates various biological activities, however, its neuroprotective effects have not been elucidated. Here, we investigated the therapeutic potential of epicoccin A for PD by evaluating its impact on neural phenotype, reactive oxygen species (ROS) generation, and locomotor activity in PD-like zebrafish. Transcriptomic analysis and molecular docking were conducted, with key gene expressions further verified using real-time qPCR. As a result, epicoccin A notably mitigated dopaminergic neuron loss, neural vasculature deficiency, nervous system injury, ROS accumulation, locomotor impairments, and abnormal expressions of hallmark genes associated with PD and oxidative stress. Underlying mechanism investigation indicated epicoccin A may alleviate PD-like symptoms by activating PINK1/Parkin-dependent mitophagy, as evidenced by the reversal of aberrant gene expressions related to PINK1/Parkin pathway and its upstream mTOR/FoxO pathway following epicoccin A co-treatments. This finding was further confirmed by the robust interactions between epicoccin A and these mitophagy regulators. Our results suggest that epicoccin A relieves PD symptoms by activating PINK1/Parkin-dependent mitophagy and inhibiting excessive oxidative stress, highlighting its potential as a therapeutic approach for PD.

Abstract: Reward processing is a vital function for health and survival and is impaired in various psychiatric and neurological disorders. Using a monetary gambling task, the current study aims to elucidate neural substrates in the reward network underlying evaluation of win versus loss outcomes, and their association with behavioral characteristics, such as impulsivity and task performance, and neuropsychological functioning. Functional MRI was recorded in thirty healthy, male community volunteers (mean age = 27.4 years) while they performed a monetary gambling task in which they bet with either 10 or 50 tokens and received feedback of whether they won or lost the bet amount. Results showed that a set of key brain structures in the reward network, including putamen, caudate nucleus, superior and inferior parietal lobule, angular gyrus, and Rolandic operculum, had greater blood oxygenation level dependent (BOLD) signal during win relative to loss trials, and the BOLD signals in most of these regions were highly correlated with one another. Further, exploratory bivariate analyses between these reward related regions and behavioral and neuropsychological domains showed significant correlations with moderate effect sizes, including: (i) negative correlations between non-planning impulsivity and activations in putamen and caudate regions, (ii) positive correlations between risky bets and right putamen activation, (iii) negative correlations between safer bets and right putamen activation, (iv) a negative correlation between short-term memory capacity and right putamen activity, and (v) a negative correlation between poor planning skills and left inferior occipital cortex activation. These findings contribute to our understanding of the neural underpinnings of monetary reward processing and their relationships to aspects of behavior and cognitive function. Future studies may confirm these findings with larger samples of healthy controls and extend these findings by investigating various clinical groups with impaired reward processing.

Abstract: We investigated the cellular and neurophysiological mechanisms underlying the pro-cognitive effects of 5-HT4R activation in hippocampal-prefrontal pathways. Our findings show that, in addition to pyramidal neurons, 30–60% of parvalbumin+ interneurons in the CA1, CA3, and dentate gyrus (DG) of the hippocampus and the anterior cingulate (ACC), prelimbic (PL), and infralimbic (IL) regions of the prefrontal cortex co-express 5-HT4Rs. Additionally, 15% of somatostatin+ interneurons in CA1 and CA3 express 5-HT4Rs. The partial 5-HT4R agonist RS-67333 (1 mg/kg, i.p.) exerted anxiolytic effects and ameliorated short-term (3-minute) and long-term (24-hour) memory deficits in a mouse model of schizophrenia-like cognitive impairment induced by sub-chronic phencyclidine (sPCP) but did not enhance memory in healthy mice. At the neurophysiological level, RS-67333 normalized sPCP-induced disruptions in hippocampal-prefrontal neural dynamics while having no effect in healthy animals. Specifically, sPCP increased delta oscillations in CA1 and PL, leading to aberrant delta–high-frequency coupling in CA1 and delta–high-gamma coupling in PL. RS-67333 administration attenuated this abnormal delta synchronization without altering phase coherence or signal directionality within the circuit. Collectively, these results highlight the therapeutic potential of 5-HT4R activation in pyramidal, parvalbumin+, and somatostatin+ neurons of hippocampal-prefrontal pathways for mitigating cognitive and negative symptoms associated with schizophrenia.

Abstract:

Isolation of neurons and glial cells from the enteric nervous system (ENS) enables ex-vivo studies, including analysis of genomic and transcriptomic profiles. While we previously reported a fluorescence activated cell sorting (FACS)-based isolation protocol for human ENS cells, no equivalent exists for mice. As directly applying the human protocol to mouse tissue, resulted in low recovery of live ENS cells, we compared different protocols to optimize tissue dissociation of mouse colons. A 30-minute Liberase-based digestion showed optimal recovery of viable ENS cells, with CD56 and CD24 emerging as the most reliable markers to select and subdivide these cells. ENS identity was further validated by FACS using neuronal (TUBB3) and glial (SOX10) markers, and reverse transcriptase quantitative PCR (RT-qPCR) on sorted fractions. Overall, the mouse ENS expression profile significantly overlapped with the human one, confirming that current dissociation protocols yield a mixed staining pattern of enteric neurons and glia. Nonetheless, using the imaging flow cytometer BD S8 FACS Discover, and ELAVL4 as a neuronal soma-associated marker, we observed enrichment of neurons, at the TIP of the CD56/CD24 population. In conclusion, we present here a protocol for high purity FACS-based isolation of viable enteric neurons and glial cells, suitable for downstream applications.

Abstract: Neurocognitive disorders (NCD) are neurodegenerative diseases characterized by decline or loss of cognitive function. Two main risk factors for this condition have been identified: age and the APOE genotype. One of the proposed mechanisms of aging is telomere length (TL), as an association between shorter TL and NCD has been suggested. This study investigated the relationship between TL and the APOE genotype in individuals with neurocognitive impairment (CI). 170 participants aged > 60 years were included. Cognitive function was assessed using MMSE and MoCA tests. Relative telomere quantification and APOE genotyping were performed using RT-PCR. A shorter TL was significantly associated with an increased risk of CI (p < 0.001). The APOE ε4 genotype showed a less significant association, with individuals not carrying the ε4 allele displaying a higher risk of CI (p < 0.05). However, a trend toward shorter TL were observed in individuals carrying the ε4 allele with CI compared to those Non-Cognitive Impairment with subjective memory Complaint. Additionally, the number of years of education was negatively correlated with CI (p < 0.0001). Individuals with shorter TL and fewer years of education demonstrated a higher risk of CI. APOE genotype would be a risk factor for shorter telomeres.

Abstract: Transformative neuropathology is redefining human brain research by integrating foundational descriptive pathology with advanced methodologies to drive discoveries that inform diagnostics, therapeutics, and disease prevention. These approaches, spanning multi-omics studies and machine learning applications, enable the identification of biomarkers, therapeutic targets, and complex disease patterns through comprehensive analyses of postmortem human brain tissue. Yet critical challenges, including sustainability of brain banks, expanding donor participation, strengthening training pipelines, enabling rapid autopsies, and supporting collaborative platforms. Innovations in digital pathology, tissue quality enhancement, harmonized data standards, and machine learning integration offer groundbreaking opportunities to accelerate research in aging and neurodegeneration. Lessons from neuroimaging, regarding progress in establishing common data frameworks and multi-site collaborations, offer a valuable roadmap for streamlining innovations. In this Perspective, we outline actionable solutions to leverage existing resources, envision future opportunities, and advance collaboration to drive translational discoveries and safeguard the sustainability of brain banks underpinning transformative neuropathology.

Abstract: Ever since the monocarboxylate, lactate, was shown to be more than a useless end-product of anaerobic glycolysis, the members of the brain energy metabolism research community are divided by two issues: First, could lactate replace glucose as the oxidative mitochondrial energy substrate? Second, should glycolysis continue to be divided into aerobic and anaerobic pathways? This review examines both the history and the reasons for this division and offers a unifying solution.

Abstract:

C-terminal binding proteins (CtBPs) dimerize and function predominantly as transcriptional corepressors by targeting various chromatin-modifying factors to promoter-bound repressors. Hypotonia, Ataxia, Developmental-Delay, and Tooth-Enamel Defects Syndrome (HADDTS) is a recently discovered neurodevelopmental disorder resulting from a heterozygous missense mutation in CTBP1. It is often associated with the early onset of profound cerebellar atrophy in patients. To understand CtBP1's role in brain function and the etiology of HADDTS, Allen Institute’s Allen Brain Cell (ABC) human brain atlas was used. Based on the ABC atlas, CTBP1 is highly expressed in the upper rhombic lip supercluster which gives rise to the majority of the cerebellar granule cells. The results correlate with the cerebellum related manifestations observed in HADDTS patients.

Abstract: In this study, machine learning techniques for identification of brain tumor were compared with the BraTS 2024 dataset. A variety of models included traditional machine learning algorithms such as Random Forest or more advanced deep learning architectures including Simple CNN, VGG16, VGG19, ResNet50, Inception-ResNetV2, and Efficient Net are investigated within the research. Preprocessing techniques were adopted to optimize the model performance on the dataset. The Random Forest algorithm gave the best result, with an accuracy of 87%, which was much better than the deep learning models, which had an accuracy between 47% and 70%. These findings have important applications for automated brain tumor diagnosis. They emphasize the criticality of the correct selection and tuning of the algorithm to improve the classification of tumor subtypes. First, this research shows that deep learning models are typically considered to be state of the art deep learning models for image analysis tasks, but in some cases traditional machine learning methods such as random forest might still achieve better results than the most complex of neural networks. This delineates the importance of a fine-grained approach to model selection, with regard for details of the dataset as well as computational constraints and particular diagnostic requirements. The aim of the study is to improve patient outcome for more accurate and efficient brain tumor identification by refinement and optimization of these automated diagnosis systems.

Abstract: The present study was designed to establish the distribution pattern and immunohistochemical characteristics of phoenixin-immunoreactive (PNX-IR) urinary bladder-projecting neurons (UBPNs) of dorsal root ganglia (DRGs) in the female pigs. The investigated sensory cells were visualized with a retrograde tracing method using Fast Blue (FB), while their chemical profile(s) were disclosed with double-labelling immunohistochemistry using antibodies against PNX, calcitonin gene-related peptide (CGRP), calretinin (CRT), galanin (GAL), neuronal nitric oxide synthase (nNOS), pituitary adenylate cyclase-activating polypeptide (PACAP), somatostatin (SOM) and substance P (SP). Nearly half of UBPNs contained PNX (45%), and the majority of such encoded nerve cells were small in size (66%). The most numerous subpopulation of FB/PNX-positive neurons were those containing SP (71%). CGRP, GAL or PACAP were observed in a smaller number of PNX-containing UBPNs (50%, 30% or 25%, respectively), while PNX-positive sensory cells simultaneously immunostained with nNOS, CRT or SOM constituted a small fraction of all retrogradely-traced DRG neurons (15%, 6.5% or 1.6%, respectively). Furthermore, the numerical analysis of neurons expressing individual antigens, performed on 10-μm-thick consecutive sections, allows to state that studied sensory cells can be classified as neurons “coded” either by the simultaneous presence of SP/CGRP/PACAP/GAL, SP/CGRP/PACAP/NOS, SP/CGRP/PACAP/NOS/CRT and/or SP/CGRP/GAL/PACAP, or, as a separate population, those capable of SOM synthesis (SP/CGRP/SOM/PACAP/GAL-positive cells).The present study reveals the extensive expression of PNX in the DRG neurons projecting to the urinary bladder, indicating an important regulatory role of this neuropeptide in the control of physiological function(s) of this organ.

Abstract: Syringomyelia detected in both animals and humans may cause variable degree of dis-comfort and its etiology is commonly unidentified. The aim of the study was to compare the outcome in dogs with syringomyelia of different etiology. Dogs with syringomyelia were subdivided into two groups: A: Syringomyelia associated with Chiari-like malfor-mation (S-CLM) (15 dogs) and B: syringomyelia of other etiology (SOA) (15 dogs). Age on-set of S-CLM clinical signs was earlier compared to SOA (mean S-CLM and SOA values: 50.53 and 97.6 months, respectively, p=0.021). Two neurological dysfunction scoring sys-tems alongside with nociception values were lower in SOA compared to S-CLM (mean values for neurological dysfunction scoring system SOA and S-CLM: 5.87 and 4.2, respec-tively, p=0.032) (mean values for nociception SOA and S-CLM: 20.97 and 10.03, respec-tively, p=0.03). Symptomatic therapy included combinations of corticosteroids, gabapen-tin (10/15, 66.6%) in S-CLM and NSAID +/- gabapentin (8/15, 53.3% and 9/15, 60%, respec-tively) in SOA dogs. Eight S-CLM dogs (53.4%) improved with symptomatic therapy and 11 were still alive however most SOA dogs (9/15, 73.4%) died/were euthanized by the end of the study. SOA dogs demonstrated more severe neurological signs compared to S-CLM, although outcome between the two groups was not associated (p=0.211).

Abstract: Cerebrocardiovascular disease(s) (CCVD) including coronary artery disease, ischemic heart disease, and stroke are the number one cause of mortality. Structural and functional properties of the vascular arterial wall play an important role in creating extracranial vascular arterial stiffness (VAS). VAS has emerged as a marker of risk for aging, dementia, vascular contributions to impaired cognition and dementia (VCID), stroke (ischemic and hemorrhagic), misfolded proteins (amyloid beta and tau) deposition, neurodegeneration, brain atrophy, and late-onset Alzheimer’s disease. VAS is associated with increased oxidative redox stress, inflammation, vascular remodeling and calcification, increased pulse pressure, increased pulse wave velocity, and systolic hypertension, which serves as part of the multiple injurious stimuli to vulnerable neurovascular unit capillaries with high flow and low resistance. Notably, advanceing age, hypertension, atherosclerosis, and vascular calcification are the most common causes of VAS. VAS contributes to cerebral small vessel disease and chronic cerebral hypoperfusion that is capable of instigating neurodegeneration, brain atrophy, and late onset Alzheimer’s disease. This narrative review discusses the evidence that links VAS and microvessel cerebral small vessel disease (SVD) to brain structural and functional abnormalities via a heart, vascular, brain (HVB) axis, which leads to SVD, neurodegeneration, brain atrophy, impaired cognition, and late-onset Alzheimer’s disease.

Abstract:

Hypergraph analysis extends traditional graph theory by enabling the study of complex, many-to-many relationships in networks, offering powerful tools for understanding brain connectivity. This case study introduces a novel methodology for constructing both graphs and hypergraphs of functional brain connectivity during figurative attention tasks, where subjects interpret the ambiguous Necker cube illusion. Using a frequency-tagging approach, we simultaneously modulated two cube faces at distinct frequencies while recording electroencephalography (EEG) responses. Brain connectivity networks were constructed using multiple measures - coherence, cross-correlation, and mutual information - providing complementary insights into functional relationships between regions. Our hypergraph analysis revealed distinct connectivity patterns associated with attending to different cube orientations, including previously unobserved higher-order relationships between brain regions. The results demonstrate bilateral cortico-cortical interactions and suggest integrated processing hubs that may coordinate visual attention networks. This methodological framework not only advances our understanding of the neural basis of visual attention but also offers potential applications in attention monitoring and clinical assessment of attention disorders. While based on a single subject, this proof-of-concept study establishes a foundation for larger-scale investigations of brain network dynamics during ambiguous visual processing.

Abstract:

Background/Objectives: Gelsolin (GSN) is an actin-binding protein that helps maintain neuronal structure and shape, regulates neuronal growth, and apoptosis. Our previous work demonstrated that GSN associated with estrogen receptor beta (ERb1) in the brains of female rats, but this association was lost in advanced age. GSN was also required for ERb1-mediated transcriptional repression at activator protein-1 (AP-1) motifs upstream of a minimal gene promoter. However, the consequences of the loss of GSN:ERb1 protein interaction on ERb1 nuclear translocation and transcriptional repression at AP-1 sites located within complex endogenous gene promoters remained unclear. Methods: We used immunofluorescent super resolution microscopy and luciferase reporter assays to test the hypothesis that GSN facilitates ERb1 nuclear translocation and transcriptional repression of two genes relevant for Alzheimer Disease: APP (amyloid-beta precursor protein) and ITPKB (inositol-1,4,5-trisphosphate 3-kinase B). Results: Our results revealed the novel finding that GSN is required for ERb1 ligand–independent nuclear translocation in neuronal cells. Moreover, we show that GSN increased APP and ITPKB promoter activity, which was repressed by ERb1. Conclusions: Together, these data revealed the importance of the cytoskeletal protein, GSN, in regulating intracellular trafficking of nuclear receptors and demonstrate the first evidence of ERb1 directly regulating two genes that are implicated in the progression of AD.

Abstract: Background: Natural nootropic compounds are evidenced to restore brain function in clinical and older populations and are purported to enhance cognitive abilities in healthy cohorts. This study aimed to provide neurocomputational insight into the discrepancies between the remarkable self-reports and growing interest in nootropics among healthy adults and the inconclusive performance-enhancing effects found in the literature. Methods: Towards this end, we devised a randomised, double-blinded, and placebo-controlled study where participants performed a visual categorisation task prior to and following 60 days of supplementation with a plant-based nootropic, while electroencephalographic (EEG) signals were concurrently captured. Results: We found that although no improvements in choice accuracy or reaction times were observed, the application of multivariate information-theoretic measures to the EEG source space showed broadband increases in similar and complementary interdependencies across brain networks of various spatial scales. These changes not only resulted in localised increases in the redundancy among brain network interactions but also more significant and widespread increases in synergy, especially within the delta frequency band. Conclusions: Our findings suggest that natural nootropics can improve overall brain network cohesion and energetic efficiency, computationally demonstrating the beneficial effects of natural nootropics on brain health. However, these effects could not be related to enhanced rapid perceptual decision-making performance in a healthy adult sample. Future research investigating these specific compounds as cognitive enhancers in healthy populations should focus on complex cognition in deliberative tasks (e.g., creativity, learning) and over longer supplementation durations. Clinical trials registration number: NCT06689644.