Brain Sciences

29 pages, 1960 KiB

Open AccessReview

Lactoferrin as a Candidate Multifunctional Therapeutic in Synucleinopathies

by Caroline A. Barros and Tuane C. R. G. Vieira

Brain Sci. 2025, 15(4), 380; https://doi.org/10.3390/brainsci15040380 (registering DOI) - 6 Apr 2025

Lactoferrin (Lf) is a multifunctional glycoprotein with well-established antimicrobial, anti-inflammatory, and iron-binding properties. Emerging evidence suggests that Lf also plays a neuroprotective role, particularly in neurodegenerative disorders characterized by protein aggregation, such as Parkinson’s disease (PD). Alpha-synuclein (aSyn) aggregation is a pathological hallmark [...] Read more.

Lactoferrin (Lf) is a multifunctional glycoprotein with well-established antimicrobial, anti-inflammatory, and iron-binding properties. Emerging evidence suggests that Lf also plays a neuroprotective role, particularly in neurodegenerative disorders characterized by protein aggregation, such as Parkinson’s disease (PD). Alpha-synuclein (aSyn) aggregation is a pathological hallmark of PD and other synucleinopathies, contributing to neuronal dysfunction and disease progression. Recent studies indicate that Lf may interfere with aSyn aggregation, iron chelation, and modulation of oxidative stress and neuroinflammation. Additionally, Lf’s ability to cross the blood-brain barrier and its potential impact on the gut-brain axis highlight its promise as a therapeutic agent. This review explores Lf’s mechanisms of action in synucleinopathies, its potential as a disease-modifying therapy, and innovative delivery strategies that could enhance its clinical applicability. By addressing the pathological and therapeutic dimensions of aSyn aggregation, we propose Lf as a compelling candidate for future research and clinical development in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Alpha-Synuclein in Neurodegenerative Disorders: From Pathogenesis to Potential Therapies)

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12 pages, 804 KiB

Open AccessReview

TREM 2 in Parkinson’s Disease: A Promising Candidate Gene for Disease Susceptibility and Progression

by Paolo Alonge, Carmela Rita Balistreri, Angelo Torrente, Daniele Magro, Elisa Rubino and Roberto Monastero

Brain Sci. 2025, 15(4), 379; https://doi.org/10.3390/brainsci15040379 (registering DOI) - 5 Apr 2025

Abstract

Background/Objectives: The activation of microglia and the activity of innate immunity have recently been recognized as part of Parkinson’s Disease (PD) pathophysiology. Triggering receptor expressed on myeloid cells 2 (TREM2) is a gene with neuroprotective roles. Its variations are associated with microglial-associated [...] Read more.

Background/Objectives: The activation of microglia and the activity of innate immunity have recently been recognized as part of Parkinson’s Disease (PD) pathophysiology. Triggering receptor expressed on myeloid cells 2 (TREM2) is a gene with neuroprotective roles. Its variations are associated with microglial-associated neurodegeneration. The objective of the present review is to investigate the current evidence on the role of TREM2 in PD pathophysiology. Methods: A comprehensive search was performed using PubMed, Medline, and Web of Science, looking for English papers investigating the role of TREM2 in PD, or more in general, the genetic profile of microglia. Results: Thirty-one papers were considered relevant. Preclinical studies with PD models showed some contradictory results, even if a loss of function of TREM2 is generally associated with a microglial activation in α-synuclein-induced inflammatory processes. The role for TREM2 genetic variations in PD patients should be taken with even more caution. The increase in the soluble extracellular segment of TREM2 (sTREM2) in cerebrospinal fluid of PD patients seems to be associated with increased risk of cognitive decline. Conclusions: There is increasing evidence that TREM2 may have an important role in PD pathophysiology as demonstrated by preclinical and clinical studies. Further investigations are needed to confirm this role and may lead the way for future targeted therapies for different neurodegenerative disorders. Full article

(This article belongs to the Special Issue New Advances in Neuroimmunology and Neuroinflammation)

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13 pages, 817 KiB

Open AccessArticle

Creative Cognitive Reappraisal Promotes Estimation Strategy Execution in Individuals with Trait Anxiety

by Huan Song, Chenghui Tan, Chuanlin Zhu, Dianzhi Liu and Wenbo Peng

Brain Sci. 2025, 15(4), 378; https://doi.org/10.3390/brainsci15040378 - 4 Apr 2025

Abstract

Objectives: This study aimed to investigate the impact of the creative cognitive reappraisal on the estimation strategies execution in college students with trait anxiety. Methods: Using the Trait Anxiety Scale, 47 participants with high (HTA) and low trait anxiety (LTA) were selected from [...] Read more.

Objectives: This study aimed to investigate the impact of the creative cognitive reappraisal on the estimation strategies execution in college students with trait anxiety. Methods: Using the Trait Anxiety Scale, 47 participants with high (HTA) and low trait anxiety (LTA) were selected from a total of 803 college students. These participants then completed a two-digit multiplication estimation task after using cognitive reappraisal to regulate negative emotions. Results: The results showed that for individuals with low trait anxiety, both standard cognitive reappraisal and creative cognitive reappraisal effectively improved their negative emotional experiences, with creative cognitive reappraisal demonstrating a superior regulatory effect. For individuals with high trait anxiety, creative cognitive reappraisal was effective in regulating negative emotions, whereas the effect of standard cognitive reappraisal on emotion regulation was not significant. Conclusions: Both standard cognitive reappraisal and creative cognitive reappraisal can enhance the speed of estimation strategy execution in college students with trait anxiety after regulating negative emotions, with creative cognitive reappraisal showing a more pronounced facilitative effect. Full article

(This article belongs to the Section Cognitive, Social and Affective Neuroscience)

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15 pages, 3256 KiB

Open AccessArticle

The Neural Correlates of Consciousness: A Spectral Exponent Approach to Diagnosing Disorders of Consciousness

by Ying Zhao, Anqi Wang, Weiqiao Zhao, Nantu Hu, Steven Laureys and Haibo Di

Brain Sci. 2025, 15(4), 377; https://doi.org/10.3390/brainsci15040377 - 4 Apr 2025

Abstract

Background/Objectives: Disorder of consciousness (DoC) poses diagnostic challenges due to behavioral assessment limitations. This study evaluates the spectral exponent (SE)—a neurophysiological biomarker quantifying the decay slope of electroencephalography (EEG) aperiodic activity—as an objective tool for consciousness stratification and clinical behavior scores correlation. Methods: [...] Read more.

Background/Objectives: Disorder of consciousness (DoC) poses diagnostic challenges due to behavioral assessment limitations. This study evaluates the spectral exponent (SE)—a neurophysiological biomarker quantifying the decay slope of electroencephalography (EEG) aperiodic activity—as an objective tool for consciousness stratification and clinical behavior scores correlation. Methods: The study involved 15 DoC patients, nine conscious brain-injured controls (BI), and 23 healthy controls (HC). Resting-state 32-channel EEG data were analyzed to compute SE across broadband (1–40 Hz) and narrowband (1–20 Hz, 20–40 Hz). Statistical frameworks included Bonferroni-corrected Kruskal–Wallis H tests, Bayesian ANOVA, and correlation analyses with CRS-R behavioral scores. Results: Narrowband SE (1–20 Hz) showed superior diagnostic sensitivity, differentiating DoC from controls (HC vs. DoC: p < 0.0001; BI vs. DoC: p = 0.0006) and MCS from VS/UWS (p = 0.0014). SE correlated positively with CRS-R index (1–20 Hz: r = 0.590, p = 0.021) and visual subscale (1–20 Hz: r = 0.684, p = 0.005). High-frequency (20–40 Hz) SE exhibited inconsistent results. Longitudinal tracking in an individual revealed a reduction in SE negativity, a flattening of the 1/f slope, and behavioral recovery occurring in parallel. Conclusions: Narrowband SE (1–20 Hz) is a robust biomarker for consciousness quantification, overcoming behavioral assessment subjectivity. Its correlation with visual function highlights potential clinical utility. Future studies should validate SE in larger cohorts and integrate multimodal neuroimaging. Full article

(This article belongs to the Section Neurorehabilitation)

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8 pages, 186 KiB

Open AccessOpinion

Evidence for Cognitive Spatial Models from Ancient Roman Land-Measurement

by Andrew M. Riggsby

Brain Sci. 2025, 15(4), 376; https://doi.org/10.3390/brainsci15040376 - 4 Apr 2025

Abstract

Influential studies in the history of cartography have argued that map-like representations of space were (virtually) unknown in the Classical Mediterranean world and that the cause of this was an absence of underlying cognitive maps. That is, persons in that time/place purportedly had [...] Read more.

Influential studies in the history of cartography have argued that map-like representations of space were (virtually) unknown in the Classical Mediterranean world and that the cause of this was an absence of underlying cognitive maps. That is, persons in that time/place purportedly had only route/egocentric-type mental representations, not survey/allocentric ones. The present study challenges that cognitive claim by examining the verbal descriptions of plots of land produced by ancient Roman land-measurers. Despite the prescription of a route-based form, actual representations persistently show a variety of features which suggest the existence of underlying survey-type mental models and the integration of those with the route-type ones. This fits better with current views on interaction between types of spatial representation and of cultural difference in this area. The evidence also suggests a linkage between the two kinds of representations. Full article

(This article belongs to the Special Issue Latest Research Progress of Human Navigation in Physical and Mental Space)

22 pages, 1558 KiB

Open AccessReview

Stroke in Young Adults: An Overview and Non-Pharmacological Preventive Strategies

by Aleksandar Sič, Nikola Andrejić, Jovana Ivanović, Vidna Karadžić Ristanović, Selena Gajić, Danka Bjelić, Marko Baralić and Nikola Stojanovic

Brain Sci. 2025, 15(4), 375; https://doi.org/10.3390/brainsci15040375 - 3 Apr 2025

Abstract

Stroke is one of the most common causes of death and disability worldwide, with significant impact on both physical and cognitive health. Although strokes are less common in young adults, they still occur in this population, particularly in those with certain comorbidities, such [...] Read more.

Stroke is one of the most common causes of death and disability worldwide, with significant impact on both physical and cognitive health. Although strokes are less common in young adults, they still occur in this population, particularly in those with certain comorbidities, such as Autosomal Dominant Polycystic Kidney Disease (ADPKD). Despite the lack of specific guidelines for stroke prevention in young adults, certain preventive measures can be implemented. Smoking cigarettes is the most significant stroke risk factor in this group. Additionally, psychosocial stress, often exacerbated by academic, career, and financial pressures, is emerging as a modifiable risk factor for stroke in young adults. Key preventive measures include dietary changes, management of underlying health conditions, incorporating regular physical activity into daily routines, smoking cessation, and effective stress management techniques such as mindfulness-based stress reduction (MBSR) and cognitive–behavioral therapy (CBT). Promoting mental health awareness, directing public health campaigns toward young adults, educating them on recognizing stroke symptoms and administering first aid, and improving the quality of healthcare for this population all play a vital role in preventing stroke in young adults. Full article

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14 pages, 246 KiB

Open AccessArticle

Psychological and Clinical Parameters as Predictors of Relapse in Alcohol-Dependent Patients During and After Extensive Inpatient Rehabilitation Treatment

by Josef Rabl, Dieter Geyer, Katharina Steiner, Fabrizio Schifano and Norbert Scherbaum

Brain Sci. 2025, 15(4), 374; https://doi.org/10.3390/brainsci15040374 - 3 Apr 2025

Abstract

Background: Psychological parameters related to alcohol dependence (AD) affect patients’ behavioral and cognitive control, decision making, impulsivity and inhibitory control. People with AD often have a chronic course with a relapse to dependent substance use even after extensive treatment. This study investigated whether [...] Read more.

Background: Psychological parameters related to alcohol dependence (AD) affect patients’ behavioral and cognitive control, decision making, impulsivity and inhibitory control. People with AD often have a chronic course with a relapse to dependent substance use even after extensive treatment. This study investigated whether the psychological parameters of patients with AD predict (a) premature termination of treatment, and/or (b) relapse into consumption of alcohol from admission until 6 weeks after discharge from an inpatient rehabilitation treatment. Methods: Participants: Alcohol-dependent patients consecutively admitted for a duration of about three months to inpatient rehabilitation treatment in a hospital specialized in substance use disorders. Craving (OCDS-G) and impulsivity (BIS-11; UPPS) were assessed with computerized questionnaires. Attentional bias and inhibitory control were measured with two computer-based experiments (dot-probe task; stop-signal task (SST)). Investigations were conducted at entry (T1); after 6 weeks (T2); and during the last two weeks of the inpatient treatment (T3). Some N = 128 patients finished the first, N = 102 the second and N = 83 the third assessments. Outcome variables were discontinuation of treatment and abstinence or relapse until follow-up 6 weeks after discharge; participants were contacted via telephone. Results: None of the variables are associated with discontinuation of treatment. Poor inhibitory control (SST) and high craving (OCDS-5) levels, measured at T1, are significantly associated with relapse. Higher impulsivity (UPPS) measured at T2 and T3 is significantly associated with relapse. Exploratory analyses showed that older age, longer inpatient treatment duration and time spent in abstinence before rehabilitation treatment were significantly associated with a reduced risk of relapse. Conclusions: Psychological parameters, craving and impulsivity levels did not predict relapse to a high degree. It is assumed that discontinuation of treatment and relapse may be associated with different issues, such as social context, and individual motivation levels. In contrast, the length of both abstinence before admission and of inpatient treatment were significantly associated with abstinence; it is here suggested that recovery time duration may be an underestimated influencing factor regarding relapse in AD patients. Full article

(This article belongs to the Section Neuropharmacology and Neuropathology)

4 pages, 175 KiB

Open AccessEditorial

Integrating Body Schema and Body Image in Neurorehabilitation: Where Do We Stand and What’s Next?

by Rocco Salvatore Calabrò

Brain Sci. 2025, 15(4), 373; https://doi.org/10.3390/brainsci15040373 - 3 Apr 2025

Abstract

Given the widespread debate surrounding the definitions and functional roles of “Body Schema” and “Body Image”, these constructs have become central to understanding motor control and rehabilitation, particularly for individuals with neurological impairments [...] Full article

(This article belongs to the Section Neurorehabilitation)

14 pages, 278 KiB

Open AccessArticle

Emotional Eating, Impulsivity, and Affective Temperaments in a Sample of Obese Candidates for Bariatric Surgery: Which Linkage?

by Davide Gravina, Miriam Violi, Andrea Bordacchini, Elisa Diadema, Sara Fantasia, Marly Simoncini and Claudia Carmassi

Brain Sci. 2025, 15(4), 372; https://doi.org/10.3390/brainsci15040372 - 3 Apr 2025

Abstract

Background/Objectives: Obesity is a major public health challenge of the 21st century, with prevalence rates steadily rising globally. Disordered eating behaviors, particularly emotional eating (EE), complicate the clinical management of obesity and hinder long-term outcomes, such as maintaining weight loss after bariatric [...] Read more.

Background/Objectives: Obesity is a major public health challenge of the 21st century, with prevalence rates steadily rising globally. Disordered eating behaviors, particularly emotional eating (EE), complicate the clinical management of obesity and hinder long-term outcomes, such as maintaining weight loss after bariatric surgery. Studies reveal that EE affects 65–75% of overweight or obese adults, and such behavior may stem from a disrupted brain reward system linked to emotional dysregulation and impulsivity. Impulsivity in obesity involves deficient cognitive inhibitory control, creating an imbalance between impulsive and reflective systems. While problematic eating behaviors and obesity are well studied, the role of affective temperaments—innate traits influencing mood, energy, and responses to stimuli—remains underexplored. This study aims to examine the interplay between emotional eating, impulsivity, and affective temperaments in obese patients preparing for bariatric surgery. Methods: A total sample of 304 obese outpatients was consecutively enrolled at the Psychiatry Clinic of the Department of Clinical and Experimental Medicine of the University of Pisa during the presurgical mental health evaluation routinely performed before the bariatric intervention. Sociodemographic and clinical data were collected by psychiatrists during a single consultation. Assessments also included the following psychometric tests: the Structured Clinical Interview (SCID-5), the Emotional Eating Scale (EES), the Barratt Impulsivity Scale-Version 11 (BIS-11), and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto-questionnaire (TEMPS-A). Results: A significant correlation was observed between the EES total score and the BIS total score (p = 0.003), as well as with the sub-dimensions of attentional impulsivity (p < 0.001) and motor impulsivity (p = 0.024). In addition, a significant correlation has been found between the total score of EES and the cyclothymic (p < 0.001), depressive (p < 0.001), irritable (p = 0.013), and anxious (0.020) temperaments. When comparing obese patients with EE and without EE (No-EE), higher rates of both current (p = 0.007) and lifetime (p = 0.024) psychiatric comorbidities were observed in the EE group, namely for anxiety disorders (p = 0.008) and eating disorders (p = 0.014). Conclusions: Our study highlights a significant association between EE in obese patients with the cyclothymic, irritable, anxious, and depressive temperaments, and impulsivity dimension. Thus, problematic eating behaviors and temperamental traits may have a bidirectional psychopathological influence in obese patients and need to be carefully evaluated in subjects seeking bariatric surgery. Full article

(This article belongs to the Special Issue Personalized Approach to the Diagnosis and Treatment of Bipolar Disorder)

14 pages, 1939 KiB

Open AccessArticle

Marital Status-Specific Associations Between Multidomain Leisure Activities and Cognitive Reserve in Clinically Unimpaired Older Adults: Based on a National Chinese Cohort

by Cheng Cai, Junyi Wang, Dan Liu, Jing Liu, Juan Zhou, Xiaochang Liu, Dan Song, Shiyue Li, Yuyang Cui, Qianqian Nie, Feifei Hu, Xinyan Xie, Guirong Cheng and Yan Zeng

Brain Sci. 2025, 15(4), 371; https://doi.org/10.3390/brainsci15040371 - 3 Apr 2025

Abstract

Background: It is unclear how marital status moderates the association between multidomain leisure activities and the progression of cognitive decline in community-dwelling older adults. Methods: Data from the Chinese Longitudinal Healthy Longevity Survey with up to 10 years of follow-up were used. The [...] Read more.

Background: It is unclear how marital status moderates the association between multidomain leisure activities and the progression of cognitive decline in community-dwelling older adults. Methods: Data from the Chinese Longitudinal Healthy Longevity Survey with up to 10 years of follow-up were used. The study included participants aged ≥65 years without cognitive impairment at baseline. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Linear mixed-effect models were used to evaluate the modifying effect of marriage on leisure activities (multiple types, frequency, and single type) and cognitive decline. Results: A total of 5286 participants (aged 79.01 ± 9.54 years, 50.0% women, and 61.4% rural residents) were enrolled. The results indicated that marital status moderates the relationship between leisure activities and cognitive decline. In the unmarried group, multi-type and high-frequency leisure activities were more strongly associated with slower cognitive decline. Specific activities such as gardening, reading, performing household chores, and playing cards were found to significantly contribute to cognitive protection exclusively within the unmarried group, with no such effect observed in the married group. Conclusions: Marital status affects the relationship between participation in multiple leisure activities and cognitive decline in cognitively intact elderly people. For unmarried older adults, regular participation in leisure activities may be an effective intervention. Full article

(This article belongs to the Section Cognitive, Social and Affective Neuroscience)

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23 pages, 13995 KiB

Open AccessArticle

The Effect of Dopaminergic Therapy in Parkinson’s Disease: A Graph Theory Analysis

by Karthik Siva, Palanisamy Ponnusamy, Vishal Chavda and Nicola Montemurro

Brain Sci. 2025, 15(4), 370; https://doi.org/10.3390/brainsci15040370 - 2 Apr 2025

Abstract

Background: Dopaminergic therapy (DT) is the gold standard pharmacological treatment for Parkinson’s disease (PD). Currently, understanding the neuromodulation effect in the brain of PD after DT is important for doctors to optimize doses and identify the adverse effects of medication. The objective [...] Read more.

Background: Dopaminergic therapy (DT) is the gold standard pharmacological treatment for Parkinson’s disease (PD). Currently, understanding the neuromodulation effect in the brain of PD after DT is important for doctors to optimize doses and identify the adverse effects of medication. The objective of this study is to investigate the brain connectivity alteration with and without DT in PD using resting-state EEG. Methods: Graph theory (GT) is an efficient technique for analyzing brain connectivity alteration in healthy and patient groups. We applied GT analyses on three groups, namely healthy control (HC), Parkinson with medication OFF (PD-OFF), and Parkinson with medication ON (PD-ON). Results: Using the clustering coefficient (CC), participation coefficient (PC), and small-worldness (SW) properties of GT, we showed that PD-ON patients’ brain connectivity normalized towards healthy group brain connectivity due to DT. This normalization effect appeared in the brain connectivity of all EEG frequency bands, such as theta, alpha, beta-1, beta-2, and gamma except the delta band. We also analyzed region-wise brain connectivity between 10 regions of interest (ROIs) (right and left frontal, right and left temporal, right and left parietal, right and left occipital, upper and lower midline regions) at the scalp level and compared across conditions. During PD-ON, we observed a significant decrease in alpha band connectivity between right frontal and left parietal (p-value 0.0432) and right frontal and left occipital (p-value 0.008) as well as right frontal and right temporal (p-value 0.041). Conclusion: These findings offer new insights into how dopaminergic therapy modulates brain connectivity across frequency bands and highlight the continuous elevation of both the segregation and small-worldness of the delta band even after medication as a potential biomarker for adverse effects due to medication. Additionally, reduced frontal alpha band connectivity is associated with cognitive impairment and levodopa-induced dyskinesia, highlighting its potential role in Parkinson’s disease progression. This study underscores the need for personalized treatments that address both motor and non-motor symptoms in PD patients. Full article

(This article belongs to the Special Issue Brain Network Connectivity Analysis in Neuroscience)

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16 pages, 2662 KiB

Open AccessArticle

Vitamin C Modulates the PI3K/AKT Pathway via Glutamate and Nitric Oxide in Developing Avian Retina Cells in Culture

by Aline T. Duarte-Silva, Ivan Domith, Isabele Gonçalves-da-Silva and Roberto Paes-de-Carvalho

Brain Sci. 2025, 15(4), 369; https://doi.org/10.3390/brainsci15040369 - 2 Apr 2025

Abstract

Background: In addition to its known antioxidant function, the reduced form of vitamin C, ascorbate, also acts as a neuromodulator in the nervous system. Previous work showed a reciprocal interaction of ascorbate with glutamate in chicken embryo retinal cultures. Ascorbate modulates extracellular glutamate [...] Read more.

Background: In addition to its known antioxidant function, the reduced form of vitamin C, ascorbate, also acts as a neuromodulator in the nervous system. Previous work showed a reciprocal interaction of ascorbate with glutamate in chicken embryo retinal cultures. Ascorbate modulates extracellular glutamate levels by inhibiting excitatory amino acid transporter 3 and promoting the activation of NMDA receptors and the consequent activation of intracellular signaling pathways involved in transcription and survival. Objective: In the present work, we investigated the regulation of AKT phosphorylation by ascorbate in chicken embryo retina cultures. Methodology: Cultures of chicken embryo retina cells were tested using Western blot, immunocytochemistry, fluorescent probe transfection, and cellular imaging techniques. Results: Our results show that ascorbate induces a concentration and time-dependent increase in AKT phosphorylation via the accumulation of extracellular glutamate, the activation of glutamate receptors, and the activation of the PI3K pathway. Ascorbate produces an increase in intracellular calcium accumulation and, accordingly, AKT phosphorylation by ascorbate is blocked by the calcium chelator BAPTA-AM. Moreover, AKT phosphorylation is also blocked by the nitric oxide synthase inhibitor 7-nitroindazole, indicating that it is mediated by calcium and nitric oxide-dependent mechanisms. Conclusions: We demonstrate that ascorbate modulates the PI3K/AKT pathway in retinal cultures through the activation of glutamate receptors and NO production in a calcium-dependent manner. Given that previous research has shown that glutamate induces ascorbate release in retinal cultures, our findings emphasize the significance of the reciprocal interactions between ascorbate and glutamate in retinal development. These findings provide further evidence supporting the role of ascorbate as a neuromodulator in retinal development. Full article

(This article belongs to the Special Issue Retinal Neurochemistry and Development)

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Graphical abstract

19 pages, 11005 KiB

Open AccessArticle

The Bulb, the Brain and the Being: New Insights into Olfactory System Anatomy, Organization and Connectivity

by Anton Stenwall, Aino-Linnea Uggla, David Weibust, Markus Fahlström, Mats Ryttlefors and Francesco Latini

Brain Sci. 2025, 15(4), 368; https://doi.org/10.3390/brainsci15040368 - 31 Mar 2025

Abstract

Background/Objectives: Olfaction is in many ways the least understood sensory modality. Its organization and connectivity are still under debate. The aim of this study was to investigate the anatomy of the olfactory system by using a cadaver fiber dissection technique and in vivo [...] Read more.

Background/Objectives: Olfaction is in many ways the least understood sensory modality. Its organization and connectivity are still under debate. The aim of this study was to investigate the anatomy of the olfactory system by using a cadaver fiber dissection technique and in vivo tractography to attain a deeper understanding of the subcortical connectivity and organization. Methods: Ten cerebral hemispheres were used in this study for white matter dissection according to Klingler’s technique. Measurements of different cortical structures and interhemispheric symmetry were compared. Diffusion tensor imaging sequences from twenty-five healthy individuals from the Human Connectome Project dataset were used to explore the connectivity of the olfactory system using DSI Studio. White matter connectivity between the following were reconstructed in vivo: (1) Olfactory bulb to primary olfactory cortices; (2) Olfactory bulb to secondary olfactory cortices; (3) Primary to secondary olfactory cortices. The DTI metrics of the identified major associative, projection and commissural pathways were subsequently correlated with olfactory function and cognition in seventy-five healthy individuals with Spearman’s rank correlation and the Benjamini–Hochberg method for false discoveries (CI 95%, p < 0.05) using R. Results: 1. The dissection showed that the lateral stria was significantly longer on the left side and projected towards the amygdala, the entorhinal and piriform cortex. 2. The medial stria was not evident as a consistent white matter structure. 3. Both dissection and tractography showed that major associative white matter pathways such as the uncinate fasciculus, the inferior fronto-occipital fasciculus and cingulum supported the connectivity between olfactory areas together with the anterior commissure. 4. No significant correlation was found between DTI metrics and sensory or cognition test results. Conclusions: We present the first combined fiber dissection analysis and tractography of the olfactory system. We propose a novel definition where the primary olfactory network is defined by the olfactory tract/bulb and primary olfactory cortices through the lateral stria only. The uncinate fasciculus, inferior fronto-occipital fasciculus and cingulum are the associative pathways supporting the connectivity between primary and secondary olfactory areas together with the anterior commissure. We suggest considering these structures as a secondary olfactory network. Further work is needed to attain a deeper understanding of the pathological and physiological implications of the olfactory system. Full article

(This article belongs to the Special Issue Plasticity and Regeneration in the Olfactory System)

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19 pages, 473 KiB

Open AccessReview

Effectiveness of Lee Silverman Voice Treatment (LSVT)-BIG for Neurological Diseases Other than Parkinson’s Disease: Mini Review

by Changyeon Won, Woohyuk Jang and Sunwook Park

Brain Sci. 2025, 15(4), 367; https://doi.org/10.3390/brainsci15040367 - 31 Mar 2025

Abstract

Background: Lee Silverman Voice Treatment-BIG (LB) was developed for Parkinson’s disease patients to improve patients’ movement amplitude and accuracy through large movements and enhance movements through self-awareness and recalibration. This study aimed to review studies on LB for neurological diseases other than Parkinson’s [...] Read more.

Background: Lee Silverman Voice Treatment-BIG (LB) was developed for Parkinson’s disease patients to improve patients’ movement amplitude and accuracy through large movements and enhance movements through self-awareness and recalibration. This study aimed to review studies on LB for neurological diseases other than Parkinson’s disease and examine its potential as an intervention tool. Method: The main search databases included Google Scholar, PubMed, and ScienceDirect. ‘Neurological disease’, ‘LSVT-BIG’, ‘Treatment or Rehabilitation’, ‘Intervention’, and ‘Therapy’ were used as search keywords until December 2024, and eight articles were finally selected. Results: As a result of analyzing eight studies, there were four studies on stroke (all conducted by occupational therapists) and four studies on other diseases, including two studies on progressive supranuclear palsy, one study on idiopathic normal pressure hydrocephalus, and one study on Huntington’s disease (all conducted by physical therapists). Conclusions: LB had a positive effect on improving physical function and overall motor control in patients with neurological diseases other than Parkinson’s disease, indicating its potential as an intervention tool. In the future, studies that have high-level evidence-based study designs and complement small sample sizes are needed to demonstrate the effectiveness of LB. Full article

(This article belongs to the Section Neurorehabilitation)

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18 pages, 3318 KiB

Open AccessSystematic Review

Utilization of Medicinal Plants in Mental Disorders: Neuroplasticity and Neuroprotection in Biomodels

by Jose Luis Estela-Zape, Valeria Sanclemente-Cardoza, Lizeth Dayana Noreña-Buitrón and Leidy Tatiana Ordoñez-Mora

Brain Sci. 2025, 15(4), 366; https://doi.org/10.3390/brainsci15040366 - 31 Mar 2025

Abstract

Background/Objectives: Mental disorders such as anxiety, schizophrenia, and depression are linked to alterations in neuroplasticity and neuroprotection within the central nervous system. While conventional drugs are widely used, medicinal plants are emerging as a promising alternative due to their potential therapeutic effects on [...] Read more.

Background/Objectives: Mental disorders such as anxiety, schizophrenia, and depression are linked to alterations in neuroplasticity and neuroprotection within the central nervous system. While conventional drugs are widely used, medicinal plants are emerging as a promising alternative due to their potential therapeutic effects on neuronal function. This study aimed to explore and analyze the impact of medicinal plants on neuroplasticity and neuroprotection in relation to mental disorders using biomodels. Methods: Data were collected from Scopus, Dimensions, and PubMed by using the search terms “Medicinal plants”, “Neuronal Plasticity”, and “Mental Disorder” in accordance with the guidelines of the PRISMA checklist. Results: A total of twenty-three relevant studies were selected to investigate the association between medicinal plants and mental disorders, focusing on factors such as administered doses and the modulation of neurotransmitters in the context of neuroplasticity and neuroprotection. This review highlights the complexity of study designs, target populations, and methodologies. Of the studies, 86% investigated depression, while 13% focused on anxiety. Regarding neurotransmitter modulation, 47% found that medicinal plants influenced serotonin levels, followed by 27% which found that they affected dopamine; according to the remaining studies, medicinal plants impacted norepinephrine, GABA, and acetylcholine. These findings emphasize the importance of precise dosing and neurotransmitter modulation, suggesting that targeted interactions with neural systems may help clarify the specific effects of these plants on mental health. Conclusions: Research on the effects of medicinal plants on psychiatric disorders in animal models suggests their potential to support neuroplasticity and neuroprotection. Positive impacts on mental health are indicated through the modulation of cytokines, neurotransmitters, and specific signaling pathways. Full article

(This article belongs to the Section Neuropsychiatry)

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9 pages, 313 KiB

Open AccessArticle

Genetic Screening for Hereditary Transthyretin Amyloidosis in the Population of Cammarata and San Giovanni Gemini Through Red Flags and Registry Archives

by Vincenzo Di Stefano, Christian Messina, Antonia Pignolo, Fiore Pecoraro, Ivana Cutrò, Paolo Alonge, Nicasio Rini, Umberto Quartetti, Vito Lo Bue, Eugenia Borgione and Filippo Brighina

Brain Sci. 2025, 15(4), 365; https://doi.org/10.3390/brainsci15040365 - 31 Mar 2025

Abstract

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a severe, multisystemic, autosomal dominant disease with variable penetrance caused by mutations in the TTR gene generating protein misfolding and accumulation of amyloid fibrils. The diagnosis is usually challenging because ATTRv may initially manifest with nonspecific [...] Read more.

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a severe, multisystemic, autosomal dominant disease with variable penetrance caused by mutations in the TTR gene generating protein misfolding and accumulation of amyloid fibrils. The diagnosis is usually challenging because ATTRv may initially manifest with nonspecific multisystemic symptoms. Conversely, an early diagnosis is needed to start timely appropriate therapy. Hence, screening models have been proposed to improve ATTRv diagnosis. In this study, we propose a genetic screening model based on predefined “red flags” followed by “cascading screening” on first-degree relatives of patients who tested positive. Materials and methods: After obtaining written informed consent, genetic testing on salivary swabs was performed in individuals who met at least two major red flags for ATTRv (age > 65 years old, progressive sensory or sensorimotor neuropathy not responsive to steroids or immunomodulant therapies, recent and unexplained weight loss associated with gastrointestinal signs and symptoms, diagnosis of cardiac amyloidosis, bilateral or relapsing carpal tunnel syndrome, unexplained autonomic dysfunction) or one major flag and two minor flags (family history of neuropathy, ambulation disorders or cardiopathy, sudden cardiac death, a bedridden, wheelchaired patient without specific diagnosis excluding upper motor neuron diseases, infections, juvenile cardiac disease, ocular disorders, lumbar spine stenosis, biceps tendon rupture). Results: In the first screening phase, 29 suspected cases (individuals meeting at least two major red flags or one major red flag and two minor red flags) underwent genetic testing. One patient (3.5%) was diagnosed with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), carrying the Phe64Leu mutation. Then, cascade screening allowed for early recognition of two additional individuals (two pre-symptomatic carriers) among two first-degree relatives (100%). The identified patient was a 72-year-old man who had a family history of both cardiopathy, neuropathy, and a diagnosis of juvenile cardiac disease and progressive sensorimotor neuropathy unresponsive to steroids or immunomodulant therapies. Conclusions: ATTRv is a progressive and often fatal disease that should be promptly diagnosed and treated to stop progression and reduce mortality. Systematic screening for ATTRv yielded increased recognition of the disease in our neurological clinic. A focused approach for the screening of ATTRv-PN could lead to an earlier diagnosis and identification of asymptomatic carriers, enabling timely intervention through close clinical monitoring and early treatment initiation at symptom onset. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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16 pages, 3156 KiB

Open AccessArticle

NIC₆-TT Vaccine Reduces Nicotine-Seeking Behavior and Expression of Nicotine-Induced Locomotor Sensitization in Rats

by Susana Barbosa Méndez and Alberto Salazar-Juárez

Brain Sci. 2025, 15(4), 364; https://doi.org/10.3390/brainsci15040364 - 31 Mar 2025

Abstract

Introduction: Various models of nicotine vaccines have been evaluated. In humans, antibody levels are low and variable. In this sense, it is necessary to improve or optimize the nicotine vaccines already evaluated. We reported the efficacy of the M₆-TT vaccine. [...] Read more.

Introduction: Various models of nicotine vaccines have been evaluated. In humans, antibody levels are low and variable. In this sense, it is necessary to improve or optimize the nicotine vaccines already evaluated. We reported the efficacy of the M₆-TT vaccine. Recently, we reported the efficacy of the COC-TT vaccine, which was developed from the M₆-TT vaccine. Both vaccines generate high titers of antibodies and attenuate heroin- or cocaine-induced behavioral effects in rodents. Aims and Methods: The objective of this study was to determine whether the antibodies generated by a tetanus toxoid-conjugated nicotine vaccine (NIC₆-TT) can produce anti-nicotine antibodies and decrease the nicotine-induced reinforcing and psychomotor effects. Male Wistar rats were immunized with the NIC₆-TT. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. The study used nicotine self-administration and nicotine locomotor sensitization testing to evaluate the nicotine-reinforcing and psychomotor effects. Results: The NIC₆-TT vaccine could generate high and sustained levels of anti-nicotine antibodies. The antibodies reduced the nicotine self-administration and expression of nicotine locomotor sensitization. Conclusions: These findings suggest that the NIC₆-TT vaccine generates a robust immunogenic response capable of reducing the reinforcing and psychomotor effects of nicotine, which supports its possible future use in clinical trials for the treatment of smokers. Implications: Smoking is the second most used psychoactive substance in the world, which is associated with millions of preventable deaths. An effective treatment is required. Nicotine vaccines must generate high levels of anti-nicotine antibodies, but above all, the decay curve of the antibodies must be very slow, so that they can provide long-term protection and support long-term smoking abstinence. The NIC₆-TT vaccine meets these properties. Full article

(This article belongs to the Special Issue Neural–Immune Interactions: Understanding the Bidirectional Relationship between the Brain and Immune Cells)

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25 pages, 1231 KiB

Open AccessReview

Neurobiological and Microbiota Alterations After Bariatric Surgery: Implications for Hunger, Appetite, Taste, and Long-Term Metabolic Health

by Sebastián Chapela, Ludwig Alvarez-Córdova, Andres Martinuzzi, Rosario Suarez, Victoria Gonzalez, Ezequiel Manrique, Janeth Castaño, Gianluca Rossetti, Luigi Cobellis, Vincenzo Pilone, Evelyn Frias-Toral and Luigi Schiavo

Brain Sci. 2025, 15(4), 363; https://doi.org/10.3390/brainsci15040363 - 31 Mar 2025

Abstract

Bariatric surgery (BS) is an effective intervention for obesity, inducing significant neurobiological and gut microbiota changes that influence hunger, appetite, taste perception, and long-term metabolic health. This narrative review examines these alterations by analyzing recent findings from clinical and preclinical studies, including neuroimaging, [...] Read more.

Bariatric surgery (BS) is an effective intervention for obesity, inducing significant neurobiological and gut microbiota changes that influence hunger, appetite, taste perception, and long-term metabolic health. This narrative review examines these alterations by analyzing recent findings from clinical and preclinical studies, including neuroimaging, microbiome sequencing, and hormonal assessments. BS modulates appetite-regulating hormones, reducing ghrelin while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY), leading to enhanced satiety and decreased caloric intake. Neuroimaging studies reveal structural and functional changes in brain regions involved in reward processing and cognitive control, contributing to reduced cravings and altered food choices. Additionally, BS reshapes the gut microbiota, increasing beneficial species such as Akkermansia muciniphila, which influence metabolic pathways through short-chain fatty acid production and bile acid metabolism. These findings highlight the complex interplay between the gut and the brain in post-surgical metabolic regulation. Understanding these mechanisms is essential for optimizing post-operative care, including nutritional strategies and behavioral interventions. Future research should explore how these changes impact long-term outcomes, guiding the development of targeted therapies to enhance the recovery and quality of life for BS patients. Full article

(This article belongs to the Special Issue Chronic Non-Infectious Diseases with a High Impact on the Central Nervous System)

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20 pages, 1075 KiB

Open AccessFeature PaperReview

Eye Tracking in Parkinson’s Disease: A Review of Oculomotor Markers and Clinical Applications

by Pierluigi Diotaiuti, Giulio Marotta, Francesco Di Siena, Salvatore Vitiello, Francesco Di Prinzio, Angelo Rodio, Tommaso Di Libero, Lavinia Falese and Stefania Mancone

Brain Sci. 2025, 15(4), 362; https://doi.org/10.3390/brainsci15040362 - 31 Mar 2025

Abstract

(1) Background. Eye movement abnormalities are increasingly recognized as early biomarkers of Parkinson’s disease (PD), reflecting both motor and cognitive dysfunction. Advances in eye-tracking technology provide objective, quantifiable measures of saccadic impairments, fixation instability, smooth pursuit deficits, and pupillary changes. These advances offer [...] Read more.

(1) Background. Eye movement abnormalities are increasingly recognized as early biomarkers of Parkinson’s disease (PD), reflecting both motor and cognitive dysfunction. Advances in eye-tracking technology provide objective, quantifiable measures of saccadic impairments, fixation instability, smooth pursuit deficits, and pupillary changes. These advances offer new opportunities for early diagnosis, disease monitoring, and neurorehabilitation. (2) Objective. This narrative review explores the relationship between oculomotor dysfunction and PD pathophysiology, highlighting the potential applications of eye tracking in clinical and research settings. (3) Methods. A comprehensive literature review was conducted, focusing on peer-reviewed studies examining eye movement dysfunction in PD. Relevant publications were identified through PubMed, Scopus, and Web of Science, using key terms, such as “eye movements in Parkinson’s disease”, “saccadic control and neurodegeneration”, “fixation instability in PD”, and “eye-tracking for cognitive assessment”. Studies integrating machine learning (ML) models and VR-based interventions were also included. (4) Results. Patients with PD exhibit distinct saccadic abnormalities, including hypometric saccades, prolonged saccadic latency, and increased anti-saccade errors. These impairments correlate with executive dysfunction and disease progression. Fixation instability and altered pupillary responses further support the role of oculomotor metrics as non-invasive biomarkers. Emerging AI-driven eye-tracking models show promise for automated PD diagnosis and progression tracking. (5) Conclusions. Eye tracking provides a reliable, cost-effective tool for early PD detection, cognitive assessment, and rehabilitation. Future research should focus on standardizing clinical protocols, validating predictive AI models, and integrating eye tracking into multimodal treatment strategies. Full article

(This article belongs to the Section Neurodegenerative Diseases)

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