Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600
Brain Sciences brainsci	2.7	4.8	2011	15.6 Days	CHF 2200
Cells cells	5.1	9.9	2012	17 Days	CHF 2700
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900
Journal of Clinical Medicine jcm	3.0	5.7	2012	16 Days	CHF 2600

21 pages, 2359 KiB

Open AccessReview

Integrative Analysis of Metabolome and Proteome in the Cerebrospinal Fluid of Patients with Multiple System Atrophy

by Nimisha Pradeep George, Minjun Kwon, Yong Eun Jang, Seok Gi Kim, Ji Su Hwang, Sang Seop Lee and Gwang Lee

Cells 2025, 14(4), 265; https://doi.org/10.3390/cells14040265 - 12 Feb 2025

Viewed by 837

Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative synucleinopathy. Differentiating MSA from other synucleinopathies, especially in the early stages, is challenging because of its overlapping symptoms with other forms of Parkinsonism. Thus, there is a pressing need to clarify the underlying biological mechanisms [...] Read more.

Multiple system atrophy (MSA) is a progressive neurodegenerative synucleinopathy. Differentiating MSA from other synucleinopathies, especially in the early stages, is challenging because of its overlapping symptoms with other forms of Parkinsonism. Thus, there is a pressing need to clarify the underlying biological mechanisms and identify specific biomarkers for MSA. The metabolic profile of cerebrospinal fluid (CSF) is known to be altered in MSA. To further investigate the biological mechanisms behind the metabolic changes, we created a network of altered CSF metabolites in patients with MSA and analysed these changes using bioinformatic software. Acknowledging the limitations of metabolomics, we incorporated proteomic data to improve the overall comprehensiveness of the study. Our in silico predictions showed elevated ROS, cytoplasmic inclusions, white matter demyelination, ataxia, and neurodegeneration, with ATP concentration, neurotransmitter release, and oligodendrocyte count predicted to be suppressed in MSA CSF samples. Machine learning and dimension reduction are important multi-omics approaches as they handle large amounts of data, identify patterns, and make predictions while reducing variance without information loss and generating easily visualised plots that help identify clusters, patterns, or outliers. Thus, integrated multiomics and machine learning approaches are essential for elucidating neurodegenerative mechanisms and identifying potential diagnostic biomarkers of MSA. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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26 pages, 637 KiB

Open AccessReview

Analysis of Anxiety Disorders and Post-Traumatic Stress Disorders for Screening Anxiolytic Drugs and Linking Preclinical and Clinical Research

by Anna Kozłowska, Wan-Jiun Ma, Bai-Chuang Shyu and Andrew Chih Wei Huang

Int. J. Mol. Sci. 2025, 26(4), 1414; https://doi.org/10.3390/ijms26041414 - 7 Feb 2025

Viewed by 671

Abstract

How to determine suitable animal models of anxiety disorders and post-traumatic stress disorders (PTSD) for screening anxiolytic drugs and linking preclinical and clinical research is a crucial issue. This review paper provides background knowledge and critical determination to the animal models for discussing [...] Read more.

How to determine suitable animal models of anxiety disorders and post-traumatic stress disorders (PTSD) for screening anxiolytic drugs and linking preclinical and clinical research is a crucial issue. This review paper provides background knowledge and critical determination to the animal models for discussing this issue. Moreover, this article analyzes the characteristics, properties, advantages, and disadvantages of various animal models of anxiety disorders and PTSD. It offers an overview of the pathophysiology, treatments, prevalence, and symptoms of anxiety disorders in the clinics. Furthermore, it comprehensively discusses pharmacological treatments and neural mechanisms, as well as the types and properties of the animal models of anxiety disorders in shaping and testing anxiety behaviors. In light of the previous literature discussion, we can understand the different functions of the animal models of anxiety disorders and PTSD to help us link preclinical and clinical research. Animal models are used in advanced drug discovery programs, specifically in psychiatry and neuroscience research. The challenge for the future will be to keep pace with developing the appropriate animal models of anxiolytic drugs to improve the translation of large datasets obtained to clinics. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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20 pages, 1119 KiB

Open AccessReview

Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers

by Angelo Moscoso Jamerlan, Kyu Hwan Shim, Niti Sharma and Seong Soo A. An

Int. J. Mol. Sci. 2025, 26(3), 1199; https://doi.org/10.3390/ijms26031199 - 30 Jan 2025

Viewed by 1150

Abstract

Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer’s disease (AD); α-synuclein in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), [...] Read more.

Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer’s disease (AD); α-synuclein in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington’s disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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17 pages, 2394 KiB

Open AccessArticle

Neuroprotective Efficacy of Astragalus mongholicus in Ischemic Stroke: Antioxidant and Anti-Inflammatory Mechanisms

by Yongjae Hong, Geon Ko, Yeong-Jae Jeon, Hyeon-Man Baek, Juni Lee, Donghun Lee, Jieun Park, Jaehong Kim and Keun-A Chang

Cells 2025, 14(2), 117; https://doi.org/10.3390/cells14020117 - 14 Jan 2025

Viewed by 1451

Abstract

Stroke affects over 12 million people annually, leading to high mortality, long-term disability, and substantial healthcare costs. Although East Asian herbal medicines are widely used for stroke treatment, the pathways of operation they use remain poorly understood. Our study investigates the neuroprotective properties [...] Read more.

Stroke affects over 12 million people annually, leading to high mortality, long-term disability, and substantial healthcare costs. Although East Asian herbal medicines are widely used for stroke treatment, the pathways of operation they use remain poorly understood. Our study investigates the neuroprotective properties of Astragalus mongholicus (AM) in acute ischemic stroke using photothrombotic (PTB) and transient middle cerebral artery occlusion (tMCAO) mouse models, as well as an in vitro oxygen-glucose deprivation (OGD) model. Post-OGD treatment with AM improved cell viability in mouse neuroblastoma cells, likely by reducing reactive oxygen species (ROS). Mice received short-term (0–2 days) or long-term (0–27 days) AM treatment post-stroke. Infarct size was assessed using a 2,3,5-triphenyl tetrazolium chloride (TTC) staining procedure alongside magnetic resonance imaging (MRI). Neuroprotective metabolites including inositol (Ins), glycerophosphocholine+phosphocholine (GPc+ PCh), N-acetylaspartate+N-acetylaspartylglutamate (NAA+NAAG), creatine + phosphocreatine (Cr+PCr), and glutamine+glutamate (Glx) were analyzed via magnetic resonance spectroscopy (MRS). Gliosis was assessed using GFAP and Iba-1 immunohistochemical markers, while neurological deficits were quantified with modified neurological severity scores (mNSS). Motor and cognitive functions were assessed using cylinder, rotarod, and novel object recognition (NOR) tests. AM treatment significantly reduced ischemic damage and improved neurological outcomes in both acute and chronic stages of PTB and tMCAO models. Additionally, AM increased neuroprotective metabolites levels, reduced gliosis, and decreased oxidative stress, as evidenced by reduced inducible nitric oxide synthase (iNOS). These findings highlight the antioxidant properties of AM and its strong therapeutic potential for promoting recovery after ischemic stroke by alleviating neurological deficits, reducing gliosis, and mitigating oxidative stress. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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19 pages, 3461 KiB

Open AccessArticle

Sex Differences in Depression: Insights from Multimodal Gray Matter Morphology and Peripheral Inflammatory Factors

by Wenjun Wang, Wenjia Liang, Chenxi Sun and Shuwei Liu

Int. J. Mol. Sci. 2024, 25(24), 13412; https://doi.org/10.3390/ijms252413412 - 14 Dec 2024

Viewed by 1048

Abstract

Major depressive disorder (MDD) exhibits notable sex differences in prevalence and clinical and neurobiological manifestations. Though the relationship between peripheral inflammation and MDD-related brain changes is well studied, the role of sex as a modifying factor is underexplored. This study aims to assess [...] Read more.

Major depressive disorder (MDD) exhibits notable sex differences in prevalence and clinical and neurobiological manifestations. Though the relationship between peripheral inflammation and MDD-related brain changes is well studied, the role of sex as a modifying factor is underexplored. This study aims to assess how sex influences brain and inflammatory markers in MDD. We utilized voxel-based and surface-based morphometry to analyze gray matter (GM) structure, along with GM-based spatial statistics (GBSS) to examine GM microstructure among treatment-naive patients with depression (n = 174) and age-matched healthy controls (n = 133). We uncovered sex-by-diagnosis interactions in several limbic system structures, the frontoparietal operculum and temporal regions. Post hoc analyses revealed that male patients exhibit pronounced brain abnormalities, while no significant differences were noted in females despite their higher depressive scores. Additionally, heightened inflammation levels in MDD were observed in both sexes, with sex-specific effects on sex-specific brain phenotypes, particularly including a general negative correlation in males. Intriguingly, mediation analyses highlight the specific role of the parahippocampal gyrus (PHG) in mediating interleukin (IL)-8 and depression in men. The findings suggest that in clinical practice, it would be beneficial to prioritize sex-specific assessments and interventions for MDD. This includes recognizing the possibility that male patients may experience significant brain alterations, especially when identifying male patients who may underreport symptoms. Possible limitations encompass a small sample size and the cross-sectional design. In future research, the incorporation of longitudinal studies or diverse populations, while considering illness duration, will enhance our understanding of how inflammation interacts with brain changes in depression. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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19 pages, 4454 KiB

Open AccessArticle

Construction of a Dataset for All Expressed Transcripts for Alzheimer’s Disease Research

by Zhenyu Huang, Bocheng Shi, Xuechen Mu, Siyu Qiao, Gangyi Xiao, Yan Wang and Ying Xu

Brain Sci. 2024, 14(12), 1180; https://doi.org/10.3390/brainsci14121180 - 25 Nov 2024

Cited by 1 | Viewed by 1038

Abstract

Accurate identification and functional annotation of splicing isoforms and non-coding RNAs (lncRNAs), alongside full-length protein-encoding transcripts, are critical for understanding gene (mis)regulation and metabolic reprogramming in Alzheimer’s disease (AD). This study aims to provide a comprehensive and accurate transcriptome resource to improve existing [...] Read more.

Accurate identification and functional annotation of splicing isoforms and non-coding RNAs (lncRNAs), alongside full-length protein-encoding transcripts, are critical for understanding gene (mis)regulation and metabolic reprogramming in Alzheimer’s disease (AD). This study aims to provide a comprehensive and accurate transcriptome resource to improve existing AD transcript databases. Background/Objectives: Gene mis-regulation and metabolic reprogramming play a key role in AD, yet existing transcript databases lack accurate and comprehensive identification of splicing isoforms and lncRNAs. This study aims to generate a refined transcriptome dataset, expanding the understanding of AD onset and progression. Methods: Publicly available RNA-seq data from pre-AD and AD tissues were utilized. Advanced bioinformatics tools were applied to assemble and annotate full-length transcripts, including splicing isoforms and lncRNAs, with an emphasis on correcting errors and enhancing annotation accuracy. Results: A significantly improved transcriptome dataset was generated, which includes detailed annotations of splicing isoforms and lncRNAs. This dataset expands the scope of existing AD transcript databases and provides new insights into the molecular mechanisms underlying AD. The findings demonstrate that the refined dataset captures more relevant details about AD progression compared to publicly available data. Conclusions: The newly developed transcriptome resource and the associated analysis tools offer a valuable contribution to AD research, providing deeper insights into the disease’s molecular mechanisms. This work supports future research into gene regulation and metabolic reprogramming in AD and serves as a foundation for exploring novel therapeutic targets. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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10 pages, 4456 KiB

Open AccessArticle

Photobiomodulation Therapy at 660 nm Inhibits Hippocampal Neuroinflammation in a Lipopolysaccharide-Challenged Rat Model

by Tae-Mi Jung, Jong-Ha Lee, Jin-Chul Heo and Chang-Hyun Kim

Biomedicines 2024, 12(11), 2514; https://doi.org/10.3390/biomedicines12112514 - 3 Nov 2024

Viewed by 1785

Abstract

Background/Objectives: Neuroinflammation is associated with the progression of various brain diseases, and the management of neuroinflammation-induced neural damage is a crucial aspect of treating neurological disorders. This study investigated the anti-inflammatory efficacy of photobiomodulation therapy (PBMT) using 660 nm phototherapy in a rat [...] Read more.

Background/Objectives: Neuroinflammation is associated with the progression of various brain diseases, and the management of neuroinflammation-induced neural damage is a crucial aspect of treating neurological disorders. This study investigated the anti-inflammatory efficacy of photobiomodulation therapy (PBMT) using 660 nm phototherapy in a rat model with lipopolysaccharide (LPS)-induced neuroinflammation. Methods: We induced inflammation in rat brains via intraperitoneal injection of LPS and subjected the treatment group to 660 nm phototherapy to examine its protective effect against hippocampal damage based on pathological, histological, and immunohistochemical tissue analyses. Results: The 660 nm treated rats showed a significant decrease in hippocampal structural damage and cell death compared to the LPS-treated group. We observed reduced expression of the inflammation markers GFAP, TNF-α, and IL-1β in the hippocampus of the treatment group, and an increase in SIRT1 expression across all hippocampal regions. Conclusions: This study presents a promising method for controlling neuroinflammation and providing neuroprotection and inflammation relief. PBMT represents a non-invasive therapeutic approach with minimal side effects ensured through the proper control of light irradiation. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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16 pages, 6383 KiB

Open AccessArticle

From Diabetes to Dementia: Identifying Key Genes in the Progression of Cognitive Impairment

by Zhaoming Cao, Yage Du, Guangyi Xu, He Zhu, Yinchao Ma, Ziyuan Wang, Shaoying Wang and Yanhui Lu

Brain Sci. 2024, 14(10), 1035; https://doi.org/10.3390/brainsci14101035 - 18 Oct 2024

Viewed by 1446

Abstract

Objectives: To provide a basis for further research on the molecular mechanisms underlying type 2 diabetes-associated mild cognitive impairment (DCI) using two bioinformatics methods to screen key genes involved in the progression of mild cognitive impairment (MCI) and type 2 diabetes. Methods: RNA [...] Read more.

Objectives: To provide a basis for further research on the molecular mechanisms underlying type 2 diabetes-associated mild cognitive impairment (DCI) using two bioinformatics methods to screen key genes involved in the progression of mild cognitive impairment (MCI) and type 2 diabetes. Methods: RNA sequencing data of MCI and normal cognition groups, as well as expression profile and sample information data of clinical characteristic data of GSE63060, which contains 160 MCI samples and 104 normal samples, were downloaded from the GEO database. Hub genes were identified using weighted gene co-expression network analysis (WGCNA). Protein–protein interaction (PPI) analysis, combined with least absolute shrinkage and selection operator (LASSO) and receiver operating characteristic (ROC) curve analyses, was used to verify the genes. Moreover, RNA sequencing and clinical characteristic data for GSE166502 of 13 type 2 diabetes samples and 13 normal controls were downloaded from the GEO database, and the correlation between the screened genes and type 2 diabetes was verified by difference and ROC curve analyses. In addition, we collected clinical biopsies to validate the results. Results: Based on WGCNA, 10 modules were integrated, and six were correlated with MCI. Six hub genes associated with MCI (TOMM7, SNRPG, COX7C, UQCRQ, RPL31, and RPS24) were identified using the LASSO algorithm. The ROC curve was screened by integrating the GEO database, and revealed COX7C, SNRPG, TOMM7, and RPS24 as key genes in the progression of type 2 diabetes. Conclusions: COX7C, SNRPG, TOMM7, and RPS24 are involved in MCI and type 2 diabetes progression. Therefore, the molecular mechanisms of these four genes in the development of type 2 diabetes-associated MCI should be studied. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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15 pages, 2415 KiB

Open AccessArticle

Adenosine Metabolism Pathway Alterations in Frontal Cortical Neurons in Schizophrenia

by Smita Sahay, Emily A. Devine, Christina F.-A. Vargas, Robert E. McCullumsmith and Sinead M. O’Donovan

Cells 2024, 13(19), 1657; https://doi.org/10.3390/cells13191657 - 6 Oct 2024

Cited by 1 | Viewed by 3384

Abstract

Schizophrenia is a neuropsychiatric illness characterized by altered neurotransmission, in which adenosine, a modulator of glutamate and dopamine, plays a critical role that is relatively unexplored in the human brain. In the present study, postmortem human brain tissue from the anterior cingulate cortex [...] Read more.

Schizophrenia is a neuropsychiatric illness characterized by altered neurotransmission, in which adenosine, a modulator of glutamate and dopamine, plays a critical role that is relatively unexplored in the human brain. In the present study, postmortem human brain tissue from the anterior cingulate cortex (ACC) of individuals with schizophrenia (n = 20) and sex- and age-matched control subjects without psychiatric illness (n = 20) was obtained from the Bronx–Mount Sinai NIH Brain and Tissue Repository. Enriched populations of ACC pyramidal neurons were isolated using laser microdissection (LMD). The mRNA expression levels of six key adenosine pathway components—adenosine kinase (ADK), equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), ectonucleoside triphosphate diphosphohydrolases 1 and 3 (ENTPD1 and ENTPD3), and ecto-5′-nucleotidase (NT5E)—were quantified using real-time PCR (qPCR) in neurons from these individuals. No significant mRNA expression differences were observed between the schizophrenia and control groups (p > 0.05). However, a significant sex difference was found in ADK mRNA expression, with higher levels in male compared with female subjects (Mann–Whitney U = 86; p < 0.05), a finding significantly driven by disease (t₍₁₇₎ = 3.289; p < 0.05). Correlation analyses also demonstrated significant associations (n = 12) between the expression of several adenosine pathway components (p < 0.05). In our dementia severity analysis, ENTPD1 mRNA expression was significantly higher in males in the “mild” clinical dementia rating (CDR) bin compared with males in the “none” CDR bin (F_{(2, 13)} = 5.212; p < 0.05). Lastly, antipsychotic analysis revealed no significant impact on the expression of adenosine pathway components between medicated and non-medicated schizophrenia subjects (p > 0.05). The observed sex-specific variations and inter-component correlations highlight the value of investigating sex differences in disease and contribute to the molecular basis of schizophrenia’s pathology. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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15 pages, 700 KiB

Open AccessReview

Towards New Methodology for Cross-Validation of Clinical Evaluation Scales and Functional MRI in Psychiatry

by Diyana Najar, Julian Dichev and Drozdstoy Stoyanov

J. Clin. Med. 2024, 13(15), 4363; https://doi.org/10.3390/jcm13154363 - 25 Jul 2024

Cited by 5 | Viewed by 1673

Abstract

Objective biomarkers have been a critical challenge for the field of psychiatry, where diagnostic, prognostic, and theranostic assessments are still based on subjective narratives. Psychopathology operates with idiographic knowledge and subjective evaluations incorporated into clinical assessment inventories, but is considered to be a [...] Read more.

Objective biomarkers have been a critical challenge for the field of psychiatry, where diagnostic, prognostic, and theranostic assessments are still based on subjective narratives. Psychopathology operates with idiographic knowledge and subjective evaluations incorporated into clinical assessment inventories, but is considered to be a medical discipline and, as such, uses medical intervention methods (e.g., pharmacological, ECT; rTMS; tDCS) and, therefore, is supposed to operate with the language and methods of nomothetic networks. The idiographic assessments are provisionally “quantified” into “structured clinical scales” to in some way resemble nomothetic measures. Instead of fostering data merging and integration, this approach further encapsulates the clinical psychiatric methods, as all other biological tests (molecular, neuroimaging) are performed separately, only after the clinical assessment has provided diagnosis. Translational cross-validation of clinical assessment instruments and fMRI is an attempt to address the gap. The aim of this approach is to investigate whether there exist common and specific neural circuits, which underpin differential item responses to clinical self-rating scales during fMRI sessions in patients suffering from the two main spectra of mental disorders: schizophrenia and major depression. The current status of this research program and future implications to promote the development of psychiatry as a medical discipline are discussed. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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17 pages, 2771 KiB

Open AccessArticle

Neuroprotective Potentials of Berberine in Rotenone-Induced Parkinson’s Disease-like Motor Symptoms in Rats

by Hsiang-Chien Tseng, Mao-Hsien Wang, Chih-Hsiang Fang, Yi-Wen Lin and Hung-Sheng Soung

Brain Sci. 2024, 14(6), 596; https://doi.org/10.3390/brainsci14060596 - 13 Jun 2024

Cited by 3 | Viewed by 2000

Abstract

Rotenone (RTN) induces neurotoxicity and motor dysfunction in rats, mirroring the pathophysiological traits of Parkinson’s disease (PD), including striatal oxidative stress, mitochondrial dysfunction, and changes in neural structure. This makes RTN a valuable model for PD research. Berberine (BBR), an isoquinoline alkaloid recognized [...] Read more.

Rotenone (RTN) induces neurotoxicity and motor dysfunction in rats, mirroring the pathophysiological traits of Parkinson’s disease (PD), including striatal oxidative stress, mitochondrial dysfunction, and changes in neural structure. This makes RTN a valuable model for PD research. Berberine (BBR), an isoquinoline alkaloid recognized for its antioxidative, anti-inflammatory, and neuroprotective properties, was evaluated for its ability to counteract RTN-induced impairments. Rats received subcutaneous RTN at 0.5 mg/kg for 21 days, resulting in weight loss and significant motor deficits assessed through open-field, bar catalepsy, beam-crossing, rotarod, and grip strength tests. BBR, administered orally at 30 or 100 mg/kg doses, one hour prior to RTN exposure for the same duration, effectively mitigated many of the RTN-induced motor impairments. Furthermore, BBR treatment reduced RTN-induced nitric oxide (NO) and lipid peroxidation (LPO) levels, bolstered antioxidative capacity, enhanced mitochondrial enzyme activities (e.g., succinate dehydrogenase (SDH), ATPase, and the electron transport chain (ETC)), and diminished striatal neuroinflammation and apoptosis markers. Notably, the co-administration of trigonelline (TGN), an inhibitor of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway, significantly attenuated BBR’s protective effects, indicating that BBR’s neuroprotective actions are mediated via the Nrf2 pathway. These results underscore BBR’s potential in ameliorating motor impairments akin to PD, suggesting its promise in potentially delaying or managing PD symptoms. Further research is warranted to translate these preclinical findings into clinical settings, enhancing our comprehension of BBR’s therapeutic prospects in PD. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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28 pages, 1175 KiB

Open AccessReview

Neurodegenerative Diseases: Unraveling the Heterogeneity of Astrocytes

by Alberto Santiago-Balmaseda, Annai Aguirre-Orozco, Irais E. Valenzuela-Arzeta, Marcos M. Villegas-Rojas, Isaac Pérez-Segura, Natalie Jiménez-Barrios, Ernesto Hurtado-Robles, Luis Daniel Rodríguez-Hernández, Erick R. Rivera-German, Magdalena Guerra-Crespo, Daniel Martinez-Fong, Carlos Ledesma-Alonso, Sofía Diaz-Cintra and Luis O. Soto-Rojas

Cells 2024, 13(11), 921; https://doi.org/10.3390/cells13110921 - 27 May 2024

Cited by 7 | Viewed by 4356

Abstract

The astrocyte population, around 50% of human brain cells, plays a crucial role in maintaining the overall health and functionality of the central nervous system (CNS). Astrocytes are vital in orchestrating neuronal development by releasing synaptogenic molecules and eliminating excessive synapses. They also [...] Read more.

The astrocyte population, around 50% of human brain cells, plays a crucial role in maintaining the overall health and functionality of the central nervous system (CNS). Astrocytes are vital in orchestrating neuronal development by releasing synaptogenic molecules and eliminating excessive synapses. They also modulate neuronal excitability and contribute to CNS homeostasis, promoting neuronal survival by clearance of neurotransmitters, transporting metabolites, and secreting trophic factors. Astrocytes are highly heterogeneous and respond to CNS injuries and diseases through a process known as reactive astrogliosis, which can contribute to both inflammation and its resolution. Recent evidence has revealed remarkable alterations in astrocyte transcriptomes in response to several diseases, identifying at least two distinct phenotypes called A1 or neurotoxic and A2 or neuroprotective astrocytes. However, due to the vast heterogeneity of these cells, it is limited to classify them into only two phenotypes. This review explores the various physiological and pathophysiological roles, potential markers, and pathways that might be activated in different astrocytic phenotypes. Furthermore, we discuss the astrocyte heterogeneity in the main neurodegenerative diseases and identify potential therapeutic strategies. Understanding the underlying mechanisms in the differentiation and imbalance of the astrocytic population will allow the identification of specific biomarkers and timely therapeutic approaches in various neurodegenerative diseases. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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13 pages, 2080 KiB

Open AccessArticle

Sex-Specific Differences and the Role of Environmental Enrichment in the Expression of Hippocampal CB₁ Receptors following Chronic Unpredictable Stress

by Evgenia Dandi, Evangelia Kesidou, Constantina Simeonidou, Evangelia Spandou, Nikolaos Grigoriadis and Despina A. Tata

Brain Sci. 2024, 14(4), 357; https://doi.org/10.3390/brainsci14040357 - 3 Apr 2024

Cited by 3 | Viewed by 1879

Abstract

Stress-related mental disorders have become increasingly prevalent, thus endangering mental health worldwide. Exploring stress-associated brain alterations is vital for understanding the possible neurobiological mechanisms underlying these changes. Based on existing evidence, the brain endogenous cannabinoid system (ECS) plays a significant role in the [...] Read more.

Stress-related mental disorders have become increasingly prevalent, thus endangering mental health worldwide. Exploring stress-associated brain alterations is vital for understanding the possible neurobiological mechanisms underlying these changes. Based on existing evidence, the brain endogenous cannabinoid system (ECS) plays a significant role in the stress response, and disruptions in its function are associated with the neurobiology of various stress-related disorders. This study primarily focuses on investigating the impact of chronic unpredictable stress (CUS) on the expression of hippocampal cannabinoid type 1 (CB₁) receptors, part of the ECS, in adult male and female Wistar rats. Additionally, it explores whether environmental enrichment (EE) initiated during adolescence could mitigate the CUS-associated alterations in CB₁ expression. Wistar rats, shortly after weaning, were placed in either standard housing (SH) or EE conditions for a duration of 10 weeks. On postnatal day 66, specific subgroups of SH or EE animals underwent a 4-week CUS protocol. Western blot (WB) analysis was conducted in the whole hippocampus of the left brain hemisphere to assess total CB₁ protein expression, while immunohistochemistry (IHC) was performed on the right hemisphere to estimate the expression of CB₁ receptors in certain hippocampal areas (i.e., CA1, CA3 and dentate gyrus-DG). The WB analysis revealed no statistically significant differences in total CB₁ protein levels among the groups; however, reduced CB₁ expression was found in specific hippocampal sub-regions using IHC. Specifically, CUS significantly decreased CB₁ receptor expression in the CA1 and DG of both sexes, whereas in CA3 the CUS-associated decrease was limited to SH males. Interestingly, EE housing proved protective against these reductions. These findings suggest a region and sex-specific endocannabinoid response to chronic stress, emphasizing the role of positive early experiences in the protection of the adolescent brain against adverse conditions later in life. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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14 pages, 2418 KiB

Open AccessArticle

Resveratrol Alleviates the Early Challenges of Implant-Based Drug Delivery in a Human Glial Cell Model

by Luise Schlotterose, François Cossais, Ralph Lucius and Kirsten Hattermann

Int. J. Mol. Sci. 2024, 25(4), 2078; https://doi.org/10.3390/ijms25042078 - 8 Feb 2024

Viewed by 1537

Abstract

Brain diseases are oftentimes life-threatening and difficult to treat. The local administration of drug substances using brain implants can increase on-site concentrations and decrease systemic side effects. However, the biocompatibility of potential brain implant materials needs to be evaluated carefully as implants can [...] Read more.

Brain diseases are oftentimes life-threatening and difficult to treat. The local administration of drug substances using brain implants can increase on-site concentrations and decrease systemic side effects. However, the biocompatibility of potential brain implant materials needs to be evaluated carefully as implants can trigger foreign body reactions, particularly by increasing the microglia and astrocyte reactivity. To date, these tests have been frequently conducted in very simple in vitro models, in particular not respecting the key players in glial cell reactions and the challenges of surgical implantation characterized by the disruption of oxygen and nutrient supply. Thus, we established an in vitro model in which we treated human glial cell lines with reduced oxygen and glucose levels. The model displayed cytokine and reactive oxygen species release from reactive microglia and an increase in a marker of reactive astrocytes, galectin-3. Moreover, the treatment caused changes in the cell survival and triggered the production of hypoxia-inducible factor 1α. In this comprehensive platform, we demonstrated the protective effect of the natural polyphenol resveratrol as a model substance, which might be included in brain implants to ease the undesired glial cell response. Overall, a glial-cell-based in vitro model of the initial challenges of local brain disease treatment may prove useful for investigating new therapy options. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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13 pages, 1947 KiB

Open AccessArticle

Dopamine Synthesis in the Nigrostriatal Dopaminergic System in Patients at Risk of Developing Parkinson’s Disease at the Prodromal Stage

by Victor Blokhin, Ekaterina N. Pavlova, Elena A. Katunina, Marina R. Nodel, Galina V. Kataeva, Elina R. Moskalets, Tatiana S. Pronina and Michael V. Ugrumov

J. Clin. Med. 2024, 13(3), 875; https://doi.org/10.3390/jcm13030875 - 2 Feb 2024

Cited by 3 | Viewed by 2155

Abstract

Parkinson’s disease (PD) is diagnosed by the onset of motor symptoms and treated long after its onset. Therefore, the development of the early diagnosis of PD is a priority for neurology. Advanced methodologies for this include (1) searching for patients at risk of [...] Read more.

Parkinson’s disease (PD) is diagnosed by the onset of motor symptoms and treated long after its onset. Therefore, the development of the early diagnosis of PD is a priority for neurology. Advanced methodologies for this include (1) searching for patients at risk of developing prodromal PD based on premotor symptoms; (2) searching for changes in the body fluids in these patients as diagnostic biomarkers; (3) verifying the diagnosis of prodromal PD and diagnostic-value biomarkers using positron emission tomography (PET); (4) anticipating the development of motor symptoms. According to our data, the majority of patients (n = 14) at risk of developing PD selected in our previous study show pronounced interhemispheric asymmetry in the incorporation of 18F-DOPA into dopamine synthesis in the striatum. This was assessed for the caudate nucleus and putamen separately using the specific binding coefficient, asymmetry index, and putamen/caudate nucleus ratio. Interhemispheric asymmetry in the incorporation of 18F-DOPA into the striatum provides strong evidence for its dopaminergic denervation and the diagnostic value of previously identified blood biomarkers. Of the 17 patients at risk of developing prodromal PD studied using PET, 3 patients developed motor symptoms within a year. Thus, our study shows the promise of using the described methodology for the development of early diagnosis of PD. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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32 pages, 2585 KiB

Open AccessReview

Epigallocatechin-3-Gallate and Genistein for Decreasing Gut Dysbiosis, Inhibiting Inflammasomes, and Aiding Autophagy in Alzheimer’s Disease

by Ahalya Muraleedharan and Swapan K. Ray

Brain Sci. 2024, 14(1), 96; https://doi.org/10.3390/brainsci14010096 - 19 Jan 2024

Cited by 5 | Viewed by 3415

Abstract

There are approximately 24 million cases of Alzheimer’s disease (AD) worldwide, and the number of cases is expected to increase four-fold by 2050. AD is a neurodegenerative disease that leads to severe dementia in most patients. There are several neuropathological signs of AD, [...] Read more.

There are approximately 24 million cases of Alzheimer’s disease (AD) worldwide, and the number of cases is expected to increase four-fold by 2050. AD is a neurodegenerative disease that leads to severe dementia in most patients. There are several neuropathological signs of AD, such as deposition of amyloid beta (Aβ) plaques, formation of neurofibrillary tangles (NFTs), neuronal loss, activation of inflammasomes, and declining autophagy. Several of these hallmarks are linked to the gut microbiome. The gastrointestinal (GI) tract contains microbial diversity, which is important in regulating several functions in the brain via the gut-brain axis (GBA). The disruption of the balance in the gut microbiota is known as gut dysbiosis. Recent studies strongly support that targeting gut dysbiosis with selective bioflavonoids is a highly plausible solution to attenuate activation of inflammasomes (contributing to neuroinflammation) and resume autophagy (a cellular mechanism for lysosomal degradation of the damaged components and recycling of building blocks) to stop AD pathogenesis. This review is focused on two bioflavonoids, specifically epigallocatechin-3-gallate (EGCG) and genistein (GS), as a possible new paradigm of treatment for maintaining healthy gut microbiota in AD due to their implications in modulating crucial AD signaling pathways. The combination of EGCG and GS has a higher potential than either agent alone to attenuate the signaling pathways implicated in AD pathogenesis. The effects of EGCG and GS on altering gut microbiota and GBA were also explored, along with conclusions from various delivery methods to increase the bioavailability of these bioflavonoids in the body. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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18 pages, 3612 KiB

Open AccessArticle

Amyloidogenic and Neuroinflammatory Molecular Pathways Are Contrasted Using Menaquinone 4 (MK4) and Reduced Menaquinone 7 (MK7R) in Association with Increased DNA Methylation in SK-N-BE Neuroblastoma Cell Line

by Michela Orticello, Rosaria A. Cavallaro, Daniele Antinori, Tiziana Raia, Marco Lucarelli and Andrea Fuso

Cells 2024, 13(1), 58; https://doi.org/10.3390/cells13010058 - 27 Dec 2023

Cited by 2 | Viewed by 2844

Abstract

Besides its role in coagulation, vitamin K seems to be involved in various other mechanisms, including inflammation and age-related diseases, also at the level of gene expression. This work examined the roles of two vitamin K2 (menaquinones) vitamers, namely, menaquinone-4 (MK4) and reduced [...] Read more.

Besides its role in coagulation, vitamin K seems to be involved in various other mechanisms, including inflammation and age-related diseases, also at the level of gene expression. This work examined the roles of two vitamin K2 (menaquinones) vitamers, namely, menaquinone-4 (MK4) and reduced menaquinone-7 (MK7R), as gene modulator compounds, as well as their potential role in the epigenetic regulation of genes involved in amyloidogenesis and neuroinflammation. The SK-N-BE human neuroblastoma cells provided a “first-line” model for screening the neuroinflammatory and neurodegenerative molecular pathways. MK7R, being a new vitamin K form, was first tested in terms of solubilization, uptake and cell viability, together with MK4 as an endogenous control. We assessed the expression of key factors in amyloidogenesis and neuroinflammation, observing that the MK7R treatment was associated with the downregulation of neurodegeneration- (PSEN1 and BACE1) and neuroinflammation- (IL-1β and IL-6) associated genes, whereas genes retaining protective roles toward amiloidogenesis were upregulated (ADAM10 and ADAM17). By profiling the DNA methylation patterns of genes known to be epigenetically regulated, we observed a correlation between hypermethylation and the downregulation of PSEN1, IL-1β and IL-6. These results suggest a possible role of MK7R in the treatment of cognitive impairment, giving a possible base for further preclinical experiments in animal models of neurodegenerative disease. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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12 pages, 1700 KiB

Open AccessArticle

Association between Gray and White Matter Lesions and Its Involvement in Clinical Symptoms of Alzheimer’s-Type Dementia

by Taizen Nakase, Benjamin Thyreau, Yasuko Tatewaki, Naoki Tomita, Yumi Takano, Michiho Muranaka and Yasuyuki Taki

J. Clin. Med. 2023, 12(24), 7642; https://doi.org/10.3390/jcm12247642 - 12 Dec 2023

Cited by 2 | Viewed by 1772

Abstract

Background: Not only gray matter lesions (GMLs) but also white matter lesions (WMLs) can play important roles in the pathology of Alzheimer’s disease (AD). The progression of cognitive impairment (CI) and behavioral and psychological symptoms of dementia (BPSD) might be caused by a [...] Read more.

Background: Not only gray matter lesions (GMLs) but also white matter lesions (WMLs) can play important roles in the pathology of Alzheimer’s disease (AD). The progression of cognitive impairment (CI) and behavioral and psychological symptoms of dementia (BPSD) might be caused by a concerted effect of both GML and WML. Objective: This study aimed to investigate the association between GML and WML and how they are involved in the symptoms of CI and BPSD in dementia patients by means of imaging technology. Methods: Patients in our memory clinic, who were diagnosed with AD-type dementia or amnestic mild cognitive impairment (aMCI) and had undergone both single-photon emission computed tomography (SPECT) and brain MRI, were consecutively enrolled (n = 156; 61 males and 95 females; 79.8 ± 7.4 years old). Symptoms of CI and BPSD were obtained from patients’ medical records. For the analysis of GMLs and WMLs, SPECT data and MRI T1-weighted images were used, respectively. This study followed the Declaration of Helsinki, and all procedures were approved by the institutional ethics committee. Results: According to a multivariate analysis, disorientation and disturbed attention demonstrated a relationship between the precuneus and WMLs in both hemispheres. Hyperactivity in BPSD showed multiple correlations between GMLs on both sides of the frontal cortex and WMLs. Patients with aMCI presented more multiple correlations between GMLs and WMLs compared with those with AD-type dementia regarding dementia symptoms including BPSD. Conclusion: The interaction between GMLs and WMLs may vary depending on the symptoms of CI and BPSD. Hyperactivity in BPSD may be affected by the functional relationship between GMLs and WMLs in the left and right hemispheres. The correlation between GMLs and WMLs may be changing in AD-type dementia and aMCI. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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12 pages, 1276 KiB

Open AccessArticle

LRP1 and RAGE Genes Transporting Amyloid and Tau Protein in the Hippocampal CA3 Area in an Ischemic Model of Alzheimer’s Disease with 2-Year Survival

by Ryszard Pluta, Janusz Kocki, Jacek Bogucki, Anna Bogucka-Kocka and Stanisław J. Czuczwar

Cells 2023, 12(23), 2763; https://doi.org/10.3390/cells12232763 - 4 Dec 2023

Cited by 9 | Viewed by 2147

Abstract

Explaining changes at the gene level that occur during neurodegeneration in the CA3 area is crucial from the point of view of memory impairment and the development of post-ischemic dementia. An ischemic model of Alzheimer’s disease was used to evaluate changes in the [...] Read more.

Explaining changes at the gene level that occur during neurodegeneration in the CA3 area is crucial from the point of view of memory impairment and the development of post-ischemic dementia. An ischemic model of Alzheimer’s disease was used to evaluate changes in the expression of genes related to amyloid transport in the CA3 region of the hippocampus after 10 min of brain ischemia with survival of 2, 7 and 30 days and 12, 18 and 24 months. The quantitative reverse transcriptase PCR assay revealed that the expression of the LRP1 and RAGE genes involved in amyloid transport was dysregulated from 2 days to 24 months post-ischemia in the CA3 area of the hippocampus. LRP1 gene expression 2 and 7 days after ischemia was below control values. However, its expression from day 30 to 24 months, survival after an ischemic episode was above control values. RAGE gene expression 2 days after ischemia was below control values, reaching a maximum increase 7 and 30 days post-ischemia. Then, after 12, 18 and 24 months, it was again below the control values. The data indicate that in the CA3 area of the hippocampus, an episode of brain ischemia causes the increased expression of the RAGE gene for 7–30 days during the acute phase and that of LRP1 from 1 to 24 months after ischemia during the chronic stage. In other words, in the early post-ischemic stage, the expression of the gene that transport amyloid to the brain increases (7–30 days). Conversely, in the late post-ischemic stage, amyloid scavenging/cleaning gene activity increases, reducing and/or preventing further neuronal damage or facilitating the healing of damaged sites. This is how the new phenomenon of pyramidal neuronal damage in the CA3 area after ischemia is defined. In summary, post-ischemic modification of the LRP1 and RAGE genes is useful in the study of the ischemic pathways and molecular factors involved in the development of Alzheimer’s disease. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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24 pages, 3427 KiB

Open AccessReview

Advancing Alzheimer’s Therapeutics: Exploring the Impact of Physical Exercise in Animal Models and Patients

by Jesús Andrade-Guerrero, Paola Rodríguez-Arellano, Nayeli Barron-Leon, Erika Orta-Salazar, Carlos Ledesma-Alonso, Sofía Díaz-Cintra and Luis O. Soto-Rojas

Cells 2023, 12(21), 2531; https://doi.org/10.3390/cells12212531 - 27 Oct 2023

Cited by 11 | Viewed by 3777

Abstract

Alzheimer’s disease (AD) is the main neurodegenerative disorder characterized by several pathophysiological features, including the misfolding of the tau protein and the amyloid beta (Aβ) peptide, neuroinflammation, oxidative stress, synaptic dysfunction, metabolic alterations, and cognitive impairment. These mechanisms collectively contribute to neurodegeneration, necessitating [...] Read more.

Alzheimer’s disease (AD) is the main neurodegenerative disorder characterized by several pathophysiological features, including the misfolding of the tau protein and the amyloid beta (Aβ) peptide, neuroinflammation, oxidative stress, synaptic dysfunction, metabolic alterations, and cognitive impairment. These mechanisms collectively contribute to neurodegeneration, necessitating the exploration of therapeutic approaches with multiple targets. Physical exercise has emerged as a promising non-pharmacological intervention for AD, with demonstrated effects on promoting neurogenesis, activating neurotrophic factors, reducing Aβ aggregates, minimizing the formation of neurofibrillary tangles (NFTs), dampening inflammatory processes, mitigating oxidative stress, and improving the functionality of the neurovascular unit (NVU). Overall, the neuroprotective effects of exercise are not singular, but are multi-targets. Numerous studies have investigated physical exercise’s potential in both AD patients and animal models, employing various exercise protocols to elucidate the underlying neurobiological mechanisms and effects. The objective of this review is to analyze the neurological therapeutic effects of these exercise protocols in animal models and compare them with studies conducted in AD patients. By translating findings from different approaches, this review aims to identify opportune, specific, and personalized therapeutic windows, thus advancing research on the use of physical exercise with AD patients. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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27 pages, 1460 KiB

Open AccessArticle

Phenomenological Changes Associated with Deep Brain Stimulation for Obsessive Compulsive Disorder: A Cognitive Appraisal Model of Recovery

by Nicola Acevedo, David Castle, Peter Bosanac and Susan Rossell

Brain Sci. 2023, 13(10), 1444; https://doi.org/10.3390/brainsci13101444 - 10 Oct 2023

Cited by 3 | Viewed by 2136

Abstract

The current scientific enquiry of deep brain stimulation (DBS) does not capture the breadth of DBS-induced changes to an individual’s life. Considering that DBS is applied in severe and complex cases, it is ethically and clinically necessary to consider the patient perspective and [...] Read more.

The current scientific enquiry of deep brain stimulation (DBS) does not capture the breadth of DBS-induced changes to an individual’s life. Considering that DBS is applied in severe and complex cases, it is ethically and clinically necessary to consider the patient perspective and personally relevant outcomes. This lived experience investigation of people with obsessive compulsive disorder (OCD) undergoing DBS aims to provide a comprehensive evaluation of DBS-induced effects associated with OCD psychopathology. Six patients and six carers completed semi-structured open-ended interviews. A blended approach of interpretative phenomenological, inductive, and thematic analysis techniques was employed. Profound psychopathological changes were expressed; individuals felt more alive, had improved cognitive affective control, greater engagement in the world, and were able to manage their OCD. Through suppression of the condition, self-constructs were able to re-emerge and develop. A framework describing the progression of phenomenological changes, and a theoretical model describing changes in the cognitive appraisal of intrusions influencing recovery are proposed. This is the first identified qualitative investigation of DBS-induced changes in psychiatric patients and carers. Findings have implications for patient education and recovery models of OCD, and scientific understanding of DBS effects. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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15 pages, 4172 KiB

Open AccessArticle

The Effects of Early-Life Stress on Liver Transcriptomics and the Protective Role of EPA in a Mouse Model of Early-Life-Stress-Induced Adolescent Depression

by Jinlan Zhao, Lihong Ye, Zuyi Liu, Jiayi Wu, Di Deng, Lin An, Shasha Bai, Lei Yang, Binjie Liu, Yafei Shi, Zhongqiu Liu and Rong Zhang

Int. J. Mol. Sci. 2023, 24(17), 13131; https://doi.org/10.3390/ijms241713131 - 23 Aug 2023

Cited by 4 | Viewed by 2472

Abstract

Early-life stress (ELS) was found to increase the risk of adolescent depression, and clinical evidence indicated that eicosapentaenoic acid (EPA) was decreased in patients with adolescent depression, but the underlying mechanisms are unclear. Here, we utilized an ELS model of maternal separation with [...] Read more.

Early-life stress (ELS) was found to increase the risk of adolescent depression, and clinical evidence indicated that eicosapentaenoic acid (EPA) was decreased in patients with adolescent depression, but the underlying mechanisms are unclear. Here, we utilized an ELS model of maternal separation with early weaning to explore the protective role of EPA in adolescent depression. We found that that ELS induced depression-like behavior rather than anxiety-like behavior in adolescent mice. RNA-sequencing results showed that ELS changed the transcription pattern in the liver, including 863 upregulated genes and 971 downregulated genes, especially those related to the biosynthesis of unsaturated fatty acids metabolism in the liver. Moreover, ELS decreased the expression of the rate-limiting enzymes, fatty acid desaturases 1/2 (FADS1/2), involved in the biosynthesis of EPA in the liver. Additionally, ELS reduced the levels of EPA in the liver, serum, and hippocampus, and EPA administration improved depression-like behavior-induced by ELS. Our results provide transcriptomic evidence that ELS increases the risk of adolescent depression by reducing the synthesis of unsaturated fatty acids in the liver, especially EPA, and suggest that supplementation with EPA should be investigated as a potential treatment for adolescent depression. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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18 pages, 6695 KiB

Open AccessArticle

Screening for Mild Cognitive Impairment with Speech Interaction Based on Virtual Reality and Wearable Devices

by Ruixuan Wu, Aoyu Li, Chen Xue, Jiali Chai, Yan Qiang, Juanjuan Zhao and Long Wang

Brain Sci. 2023, 13(8), 1222; https://doi.org/10.3390/brainsci13081222 - 21 Aug 2023

Cited by 8 | Viewed by 3169

Abstract

Significant advances in sensor technology and virtual reality (VR) offer new possibilities for early and effective detection of mild cognitive impairment (MCI), and this wealth of data can improve the early detection and monitoring of patients. In this study, we proposed a non-invasive [...] Read more.

Significant advances in sensor technology and virtual reality (VR) offer new possibilities for early and effective detection of mild cognitive impairment (MCI), and this wealth of data can improve the early detection and monitoring of patients. In this study, we proposed a non-invasive and effective MCI detection protocol based on electroencephalogram (EEG), speech, and digitized cognitive parameters. The EEG data, speech data, and digitized cognitive parameters of 86 participants (44 MCI patients and 42 healthy individuals) were monitored using a wearable EEG device and a VR device during the resting state and task (the VR-based language task we designed). Regarding the features selected under different modality combinations for all language tasks, we performed leave-one-out cross-validation for them using four different classifiers. We then compared the classification performance under multimodal data fusion using features from a single language task, features from all tasks, and using a weighted voting strategy, respectively. The experimental results showed that the collaborative screening of multimodal data yielded the highest classification performance compared to single-modal features. Among them, the SVM classifier using the RBF kernel obtained the best classification results with an accuracy of 87%. The overall classification performance was further improved using a weighted voting strategy with an accuracy of 89.8%, indicating that our proposed method can tap into the cognitive changes of MCI patients. The MCI detection scheme based on EEG, speech, and digital cognitive parameters proposed in this study provides a new direction and support for effective MCI detection, and suggests that VR and wearable devices will be a promising direction for easy-to-perform and effective MCI detection, offering new possibilities for the exploration of VR technology in the field of language cognition. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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13 pages, 2039 KiB

Open AccessReview

The Dynamic Relationship between the Glymphatic System, Aging, Memory, and Sleep

by Konstantinos I. Voumvourakis, Eleni Sideri, Georgios N. Papadimitropoulos, Ioanna Tsantzali, Paul Hewlett, Dimitrios Kitsos, Marianna Stefanou, Anastasios Bonakis, Sotirios Giannopoulos, Georgios Tsivgoulis and George P. Paraskevas

Biomedicines 2023, 11(8), 2092; https://doi.org/10.3390/biomedicines11082092 - 25 Jul 2023

Cited by 21 | Viewed by 11051

Abstract

The process of memory entails the activation of numerous neural networks and biochemical pathways throughout the brain. The phenomenon of memory decline in relation to aging has been the subject of extensive research for several decades. The correlation between the process of aging [...] Read more.

The process of memory entails the activation of numerous neural networks and biochemical pathways throughout the brain. The phenomenon of memory decline in relation to aging has been the subject of extensive research for several decades. The correlation between the process of aging and memory is intricate and has various aspects to consider. Throughout the aging process, there are various alterations that take place within the brain and, as expected, affect other functions that have already been linked to memory and its function such as involving microcirculation and sleep. Recent studies provide an understanding of how these mechanisms may be interconnected through the relatively new concept of the glymphatic system. The glymphatic system is strongly correlated to sleep processes. Sleep helps the glymphatic system remove brain waste solutes. Astrocytes expand and contract to form channels for cerebrospinal fluid (CSF) to wash through the brain and eliminate waste. However, the details have not been totally elusive, but the discovery of what we call the glymphatic system enables us to connect many pieces of physiology to understand how such factors are interconnected and the interplay between them. Thus, the purpose of this review is to discuss how the glymphatic system, sleep, memory, and aging are interconnected through a network of complex mechanisms and dynamic interactions. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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15 pages, 1796 KiB

Open AccessReview

Transcranial Magnetic Stimulation as a Tool to Promote Smoking Cessation and Decrease Drug and Alcohol Use

by Tal Harmelech, Colleen A. Hanlon and Aron Tendler

Brain Sci. 2023, 13(7), 1072; https://doi.org/10.3390/brainsci13071072 - 14 Jul 2023

Cited by 8 | Viewed by 4598

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, drug-free, neural-circuit-based therapeutic tool that was recently cleared by the United States Food and Drug Associate for the treatment of smoking cessation. TMS has been investigated as a tool to reduce consumption and craving for [...] Read more.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, drug-free, neural-circuit-based therapeutic tool that was recently cleared by the United States Food and Drug Associate for the treatment of smoking cessation. TMS has been investigated as a tool to reduce consumption and craving for many other substance use disorders (SUDs). This review starts with a discussion of neural networks involved in the addiction process. It then provides a framework for the therapeutic efficacy of TMS describing the role of executive control circuits, default mode, and salience circuits as putative targets for neuromodulation (via targeting the DLPFC, MPFC, cingulate, and insula bilaterally). A series of the largest studies of TMS in SUDs are listed and discussed in the context of this framework. Our review concludes with an assessment of the current state of knowledge regarding the use of rTMS as a therapeutic tool in reducing drug, alcohol, and nicotine use and identifies gaps in the literature that need to be addressed in future studies. Namely, while the presumed mechanism through which TMS exerts its effects is by modulating the functional connectivity circuits involved in executive control and salience of drug-related cues, it is also possible that TMS has direct effects on subcortical dopamine, a hypothesis that could be explored in greater detail with PET imaging. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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33 pages, 2943 KiB

Open AccessArticle

Effects of Maternal Separation and Subsequent Stress on Behaviors and Brain Monoamines in Rats

by Polina V. Mavrenkova, Nadezhda N. Khlebnikova, Irina B. Alchinova, Marina S. Demorzhi, Batozhab B. Shoibonov and Mikhail Yu. Karganov

Brain Sci. 2023, 13(6), 956; https://doi.org/10.3390/brainsci13060956 - 15 Jun 2023

Cited by 2 | Viewed by 3078

Abstract

Childhood adversity can induce maladaptive behaviors and increase risk for affective disorders, post-traumatic stress disorder, personality disorders, and vulnerability to stress in adulthood. Deprivation of maternal care interrupts brain development through the disturbance of various neurotransmitters, however, the details remain unclear. The features [...] Read more.

Childhood adversity can induce maladaptive behaviors and increase risk for affective disorders, post-traumatic stress disorder, personality disorders, and vulnerability to stress in adulthood. Deprivation of maternal care interrupts brain development through the disturbance of various neurotransmitters, however, the details remain unclear. The features of the symptoms of disorders are largely determined by early stress protocol, genetic characteristics (line), and the sex of the animals. The purpose of current study was (1) to assess behavioral changes in adult Wistar rats of both sexes after early life stress; (2) to determine the levels of monoamines in brain structures involved in the motor, emotional, and social reactions in rats aged 1 and 2 months; and (3) to determine the level of monoamines after physical or emotional stress in adult rats. The rat pups were separated from their dams and isolated from siblings in tight boxes at a temperature of 22–23 °C for 6 h during postnatal days 2–18. The data were processed predominantly using two-way analysis of variance and the Newman–Keys test as the post hoc analysis. The adult rats demonstrated an increase in motor activity and aggressiveness and a decrease in levels of anxiety and sociability. Behavioral disturbances were accompanied by region-, sex-, and age-dependent changes in the levels of monoamines and their metabolites. The dopaminergic and noradrenergic systems were found to be sensitive to psycho-emotional stress. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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20 pages, 21626 KiB

Open AccessArticle

Neuroanatomical Alterations in the CNTNAP2 Mouse Model of Autism Spectrum Disorder

by Tanya Gandhi, Cade R. Canepa, Tolulope T. Adeyelu, Philip A. Adeniyi and Charles C. Lee

Brain Sci. 2023, 13(6), 891; https://doi.org/10.3390/brainsci13060891 - 31 May 2023

Cited by 5 | Viewed by 2988

Abstract

Autism spectrum disorder (ASD) is associated with neurodevelopmental alterations, including atypical forebrain cellular organization. Mutations in several ASD-related genes often result in cerebral cortical anomalies, such as the abnormal developmental migration of excitatory pyramidal cells and the malformation of inhibitory neuronal circuitry. Notably [...] Read more.

Autism spectrum disorder (ASD) is associated with neurodevelopmental alterations, including atypical forebrain cellular organization. Mutations in several ASD-related genes often result in cerebral cortical anomalies, such as the abnormal developmental migration of excitatory pyramidal cells and the malformation of inhibitory neuronal circuitry. Notably here, mutations in the CNTNAP2 gene result in ectopic superficial cortical neurons stalled in lower cortical layers and alterations to the balance of cortical excitation and inhibition. However, the broader circuit-level implications of these findings have not been previously investigated. Therefore, we assessed whether ectopic cortical neurons in CNTNAP2 mutant mice form aberrant connections with higher-order thalamic nuclei, potentially accounting for some autistic behaviors, such as repetitive and hyperactive behaviors. Furthermore, we assessed whether the development of parvalbumin-positive (PV) cortical interneurons and their specialized matrix support structures, called perineuronal nets (PNNs), were altered in these mutant mice. We found alterations in both ectopic neuronal connectivity and in the development of PNNs, PV neurons and PNNs enwrapping PV neurons in various sensory cortical regions and at different postnatal ages in the CNTNAP2 mutant mice, which likely lead to some of the cortical excitation/inhibition (E/I) imbalance associated with ASD. These findings suggest neuroanatomical alterations in cortical regions that underlie the emergence of ASD-related behaviors in this mouse model of the disorder. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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23 pages, 1414 KiB

Open AccessReview

Towards Novel Potential Molecular Targets for Antidepressant and Antipsychotic Pharmacotherapies

by Yuriy M. Kositsyn, Murilo S. de Abreu, Tatiana O. Kolesnikova, Alexey A. Lagunin, Vladimir V. Poroikov, Hasmik S. Harutyunyan, Konstantin B. Yenkoyan and Allan V. Kalueff

Int. J. Mol. Sci. 2023, 24(11), 9482; https://doi.org/10.3390/ijms24119482 - 30 May 2023

Cited by 8 | Viewed by 6005

Abstract

Depression and schizophrenia are two highly prevalent and severely debilitating neuropsychiatric disorders. Both conventional antidepressant and antipsychotic pharmacotherapies are often inefficient clinically, causing multiple side effects and serious patient compliance problems. Collectively, this calls for the development of novel drug targets for treating [...] Read more.

Depression and schizophrenia are two highly prevalent and severely debilitating neuropsychiatric disorders. Both conventional antidepressant and antipsychotic pharmacotherapies are often inefficient clinically, causing multiple side effects and serious patient compliance problems. Collectively, this calls for the development of novel drug targets for treating depressed and schizophrenic patients. Here, we discuss recent translational advances, research tools and approaches, aiming to facilitate innovative drug discovery in this field. Providing a comprehensive overview of current antidepressants and antipsychotic drugs, we also outline potential novel molecular targets for treating depression and schizophrenia. We also critically evaluate multiple translational challenges and summarize various open questions, in order to foster further integrative cross-discipline research into antidepressant and antipsychotic drug development. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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11 pages, 915 KiB

Open AccessArticle

Excellent Interrater Reliability for Manual Segmentation of the Medial Perirhinal Cortex

by Nicolas A. Henzen, Julia Reinhardt, Maria Blatow, Reto W. Kressig and Sabine Krumm

Brain Sci. 2023, 13(6), 850; https://doi.org/10.3390/brainsci13060850 - 24 May 2023

Viewed by 1885

Abstract

Objective: Evaluation of interrater reliability for manual segmentation of brain structures that are affected first by neurofibrillary tau pathology in Alzheimer’s disease. Method: Medial perirhinal cortex, lateral perirhinal cortex, and entorhinal cortex were manually segmented by two raters on structural magnetic resonance images [...] Read more.

Objective: Evaluation of interrater reliability for manual segmentation of brain structures that are affected first by neurofibrillary tau pathology in Alzheimer’s disease. Method: Medial perirhinal cortex, lateral perirhinal cortex, and entorhinal cortex were manually segmented by two raters on structural magnetic resonance images of 44 adults (20 men; mean age = 69.2 ± 10.4 years). Intraclass correlation coefficients (ICC) of cortical thickness and volumes were calculated. Results: Very high ICC values of manual segmentation for the cortical thickness of all regions (0.953–0.986) and consistently lower ICC values for volume estimates of the medial and lateral perirhinal cortex (0.705–0.874). Conclusions: The applied manual segmentation protocol allows different raters to achieve remarkably similar cortical thickness estimates for regions of the parahippocampal gyrus. In addition, the results suggest a preference for cortical thickness over volume as a reliable measure of atrophy, especially for regions affected by collateral sulcus variability (i.e., medial and lateral perirhinal cortex). The results provide a basis for future automated segmentation and collection of normative data. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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18 pages, 3875 KiB

Open AccessArticle

Organotypic Hippocampal Slice Cultures from Adult Tauopathy Mice and Theragnostic Evaluation of Nanomaterial Phospho-TAU Antibody-Conjugates

by Susanna Kemppainen, Nadine Huber, Roosa-Maria Willman, Ana Zamora, Petra Mäkinen, Henna Martiskainen, Mari Takalo, Annakaisa Haapasalo, Tomás Sobrino, Manuel Antonio González Gómez, Yolanda Piñeiro, José Rivas, Uwe Himmelreich and Mikko Hiltunen

Cells 2023, 12(10), 1422; https://doi.org/10.3390/cells12101422 - 18 May 2023

Viewed by 3631

Abstract

Organotypic slice culture models surpass conventional in vitro methods in many aspects. They retain all tissue-resident cell types and tissue hierarchy. For studying multifactorial neurodegenerative diseases such as tauopathies, it is crucial to maintain cellular crosstalk in an accessible model system. Organotypic slice [...] Read more.

Organotypic slice culture models surpass conventional in vitro methods in many aspects. They retain all tissue-resident cell types and tissue hierarchy. For studying multifactorial neurodegenerative diseases such as tauopathies, it is crucial to maintain cellular crosstalk in an accessible model system. Organotypic slice cultures from postnatal tissue are an established research tool, but adult tissue-originating systems are missing, yet necessary, as young tissue-originating systems cannot fully model adult or senescent brains. To establish an adult-originating slice culture system for tauopathy studies, we made hippocampal slice cultures from transgenic 5-month-old hTau.P301S mice. In addition to the comprehensive characterization, we set out to test a novel antibody for hyperphosphorylated TAU (pTAU, B6), with and without a nanomaterial conjugate. Adult hippocampal slices retained intact hippocampal layers, astrocytes, and functional microglia during culturing. The P301S-slice neurons expressed pTAU throughout the granular cell layer and secreted pTAU to the culture medium, whereas the wildtype slices did not. Additionally, cytotoxicity and inflammation-related determinants were increased in the P301S slices. Using fluorescence microscopy, we showed target engagement of the B6 antibody to pTAU-expressing neurons and a subtle but consistent decrease in intracellular pTAU with the B6 treatment. Collectively, this tauopathy slice culture model enables measuring the extracellular and intracellular effects of different mechanistic or therapeutic manipulations on TAU pathology in adult tissue without the hindrance of the blood–brain barrier. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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16 pages, 13221 KiB

Open AccessArticle

Combined Use of Frameless Neuronavigation and In Situ Optical Guidance in Brain Tumor Needle Biopsies

by Elisabeth Klint, Johan Richter and Karin Wårdell

Brain Sci. 2023, 13(5), 809; https://doi.org/10.3390/brainsci13050809 - 16 May 2023

Cited by 3 | Viewed by 2596

Abstract

Brain tumor needle biopsies are performed to retrieve tissue samples for neuropathological analysis. Although preoperative images guide the procedure, there are risks of hemorrhage and sampling of non-tumor tissue. This study aimed to develop and evaluate a method for frameless one-insertion needle biopsies [...] Read more.

Brain tumor needle biopsies are performed to retrieve tissue samples for neuropathological analysis. Although preoperative images guide the procedure, there are risks of hemorrhage and sampling of non-tumor tissue. This study aimed to develop and evaluate a method for frameless one-insertion needle biopsies with in situ optical guidance and present a processing pipeline for combined postoperative analysis of optical, MRI, and neuropathological data. An optical system for quantified feedback on tissue microcirculation, gray–whiteness, and the presence of a tumor (protoporphyrin IX (PpIX) accumulation) with a one-insertion optical probe was integrated into a needle biopsy kit that was used for frameless neuronavigation. In Python, a pipeline for signal processing, image registration, and coordinate transformation was set up. The Euclidian distances between the pre- and postoperative coordinates were calculated. The proposed workflow was evaluated on static references, a phantom, and three patients with suspected high-grade gliomas. In total, six biopsy samples that overlapped with the region of the highest PpIX peak without increased microcirculation were taken. The samples were confirmed as being tumorous and postoperative imaging was used to define the biopsy locations. A 2.5 ± 1.2 mm difference between the pre- and postoperative coordinates was found. Optical guidance in frameless brain tumor biopsies could offer benefits such as quantified in situ indication of high-grade tumor tissue and indications of increased blood flow along the needle trajectory before the tissue is removed. Additionally, postoperative visualization enables the combined analysis of MRI, optical, and neuropathological data. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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11 pages, 630 KiB

Open AccessArticle

Diagnostic Effectiveness of [¹²³I]Ioflupane Single Photon Emission Computed Tomography (SPECT) in Multiple System Atrophy

by Javier Villena-Salinas, Simeón José Ortega-Lozano, Tomader Amrani-Raissouni, Eduardo Agüera and Javier Caballero-Villarraso

J. Clin. Med. 2023, 12(10), 3478; https://doi.org/10.3390/jcm12103478 - 15 May 2023

Cited by 3 | Viewed by 1549

Abstract

Background: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder that has no curative treatment. Diagnosis is based on a set of criteria established by Gilman (1998 and 2008) and recently updated by Wenning (2022). We aim to determine the effectiveness of [...] Read more.

Background: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder that has no curative treatment. Diagnosis is based on a set of criteria established by Gilman (1998 and 2008) and recently updated by Wenning (2022). We aim to determine the effectiveness of [¹²³I]Ioflupane SPECT in MSA, especially at the initial clinical suspicion. Methods: A cross-sectional study of patients at the initial clinical suspicion of MSA, referred for [¹²³I]Ioflupane SPECT. Results: Overall, 139 patients (68 men, 71 women) were included, 104 being MSA-probable and 35 MSA-possible. MRI was normal in 89.2%, while SPECT was positive in 78.45%. SPECT showed high sensitivity (82.46%) and positive predictive value (86.24), reaching maximum sensitivity in MSA-P (97.26%). Significant differences were found when relating both SPECT assessments in the healthy–sick and inconclusive–sick groups. We also found an association when relating SPECT to the subtype (MSA-C or MSA-P), as well as to the presence of parkinsonian symptoms. Lateralization of striatal involvement was detected (left side). Conclusions: [¹²³I]Ioflupane SPECT is a useful and reliable tool for diagnosing MSA, with good effectiveness and accuracy. Qualitative assessment shows a clear superiority when distinguishing between the healthy–sick categories, as well as between the parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes at initial clinical suspicion. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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13 pages, 3780 KiB

Open AccessArticle

Microisolation of Spatially Characterized Single Populations of Neurons for RNA Sequencing from Mouse and Postmortem Human Brain Tissues

by Melissa J. Alldred and Stephen D. Ginsberg

J. Clin. Med. 2023, 12(9), 3304; https://doi.org/10.3390/jcm12093304 - 5 May 2023

Cited by 5 | Viewed by 2476

Abstract

Single-cell and single-population RNA sequencing (RNA-seq) is a rapidly evolving new field of intense investigation. Recent studies indicate unique transcriptomic profiles are derived based on the spatial localization of neurons within circuits and regions. Individual neuronal subtypes can have vastly different transcriptomic fingerprints, [...] Read more.

Single-cell and single-population RNA sequencing (RNA-seq) is a rapidly evolving new field of intense investigation. Recent studies indicate unique transcriptomic profiles are derived based on the spatial localization of neurons within circuits and regions. Individual neuronal subtypes can have vastly different transcriptomic fingerprints, well beyond the basic excitatory neuron and inhibitory neuron designations. To study single-population gene expression profiles of spatially characterized neurons, we have developed a methodology combining laser capture microdissection (LCM), RNA purification of single populations of neurons, and subsequent library preparation for downstream applications, including RNA-seq. LCM provides the benefit of isolating single neurons characterized by morphology or via transmitter-identified and/or receptor immunoreactivity and enables spatial localization within the sample. We utilize unfixed human postmortem and mouse brain tissue that is frozen to preserve RNA quality in order to isolate the desired neurons of interest. Microisolated neurons are then pooled for RNA purification utilizing as few as 250 individual neurons from a tissue section, precluding extraneous nonspecific tissue contaminants. Library preparation is performed from picogram RNA quantities extracted from LCM-captured neurons. Single-population RNA-seq analysis demonstrates that microisolated neurons from both postmortem human and mouse brain tissues are viable for transcriptomic profiling, including differential gene expression assessment and bioinformatic pathway inquiry. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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13 pages, 1188 KiB

Open AccessSystematic Review

GFAP as a Potential Biomarker for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

by Ka Young Kim, Ki Young Shin and Keun-A Chang

Cells 2023, 12(9), 1309; https://doi.org/10.3390/cells12091309 - 4 May 2023

Cited by 99 | Viewed by 8276

Abstract

Blood biomarkers have been considered tools for the diagnosis, prognosis, and monitoring of Alzheimer’s disease (AD). Although amyloid-β peptide (Aβ) and tau are primarily blood biomarkers, recent studies have identified other reliable candidates that can serve as measurable indicators of pathological conditions. One [...] Read more.

Blood biomarkers have been considered tools for the diagnosis, prognosis, and monitoring of Alzheimer’s disease (AD). Although amyloid-β peptide (Aβ) and tau are primarily blood biomarkers, recent studies have identified other reliable candidates that can serve as measurable indicators of pathological conditions. One such candidate is the glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal protein that can be detected in blood samples. Increasing evidence suggests that blood GFAP levels can be used to detect early-stage AD. In this systematic review and meta-analysis, we aimed to evaluate GFAP in peripheral blood as a biomarker for AD and provide an overview of the evidence regarding its utility. Our analysis revealed that the GFAP level in the blood was higher in the Aβ-positive group than in the negative groups, and in individuals with AD or mild cognitive impairment (MCI) compared to the healthy controls. Therefore, we believe that the clinical use of blood GFAP measurements has the potential to accelerate the diagnosis and improve the prognosis of AD. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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24 pages, 5730 KiB

Open AccessArticle

Multi-Targeting Neuroprotective Effects of Syzygium aromaticum Bud Extracts and Their Key Phytocompounds against Neurodegenerative Diseases

by Himadri Sharma, Dan Yeong Kim, Kyu Hwan Shim, Niti Sharma and Seong Soo A. An

Int. J. Mol. Sci. 2023, 24(9), 8148; https://doi.org/10.3390/ijms24098148 - 2 May 2023

Cited by 16 | Viewed by 3380

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that causes a gradual loss of normal motor and cognitive function. The complex AD pathophysiology involves various factors such as oxidative stress, neuroinflammation, amyloid-beta (Aβ) aggregation, disturbed neurotransmission, and apoptosis. The available drugs suffer from a [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease that causes a gradual loss of normal motor and cognitive function. The complex AD pathophysiology involves various factors such as oxidative stress, neuroinflammation, amyloid-beta (Aβ) aggregation, disturbed neurotransmission, and apoptosis. The available drugs suffer from a range of side effects and are not able to cover different aspects of the disease. Therefore, finding a safer therapeutic approach that can affect multiple targets at a time is highly desirable. In the present study, the underlying neuroprotective mechanism of an important culinary spice, Syzygium aromaticum (Clove) extract, and major bioactive compounds were studied in hydrogen peroxide-induced oxidative stress in human neuroblastoma SH-SY5Y cell lines as a model. The extracts were subjected to GC-MS to identify important bioactive components. The extracts and key bio-actives reduced reactive oxygen species (ROS), restored mitochondrial membrane potential (MMP), and provided neuroprotection from H₂O₂-induced oxidative stress in cell-based assays due to the antioxidant action. They also reduced lipid peroxidation significantly and restored GSH content. Clove extracts have also displayed anti-acetylcholinesterase (AChE) activity, anti-glycation potential, and Aβ aggregation/fibrilization inhibition. The multitarget neuroprotective approach displayed by Clove makes it a potential candidate for AD drug development. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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12 pages, 2328 KiB

Open AccessArticle

D2 Receptors and Sodium Ion Channel Blockades of the Basolateral Amygdala Attenuate Lithium Chloride-Induced Conditioned Taste Aversion Applying to Cancer Chemotherapy Nausea and Vomiting

by Zhi-Yue Gao, Chung Ming Huang, Cai-N Cheng and Andrew Chih-Wei Huang

Brain Sci. 2023, 13(4), 697; https://doi.org/10.3390/brainsci13040697 - 21 Apr 2023

Cited by 1 | Viewed by 2451

Abstract

Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned [...] Read more.

Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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9 pages, 2222 KiB

Open AccessArticle

Exploring the Pathological Effect of Aβ42 Oligomers on Neural Networks in Primary Cortical Neuron Culture

by Dulguun Ganbat, Jae Kyong Jeon, Yunjong Lee and Sang Seong Kim

Int. J. Mol. Sci. 2023, 24(7), 6641; https://doi.org/10.3390/ijms24076641 - 2 Apr 2023

Cited by 5 | Viewed by 2879

Abstract

Alzheimer’s disease (AD) is a multifactorial disorder that affects cognitive functioning, behavior, and neuronal properties. The neuronal dysfunction is primarily responsible for cognitive decline in AD patients, with many causal factors including plaque accumulation of Aβ42. Neural hyperactivity induced by Aβ42 deposition causes [...] Read more.

Alzheimer’s disease (AD) is a multifactorial disorder that affects cognitive functioning, behavior, and neuronal properties. The neuronal dysfunction is primarily responsible for cognitive decline in AD patients, with many causal factors including plaque accumulation of Aβ42. Neural hyperactivity induced by Aβ42 deposition causes abnormalities in neural networks, leading to alterations in synaptic activity and interneuron dysfunction. Even though neuroimaging techniques elucidated the underlying mechanism of neural connectivity, precise understanding at the cellular level is still elusive. Previous multielectrode array studies have examined the neuronal network modulation in in vitro cultures revealing the relevance of ion channels and the chemical modulators in the presence of Aβ42. In this study, we investigated neuronal connectivity and dynamic changes using a high-density multielectrode array, particularly looking at network-wide parameter changes over time. By comparing the neuronal network between normal and Aβ42treated neuronal cultures, it was possible to discover the direct pathological effect of the Aβ42 oligomer altering the network characteristics. The detrimental effects of the Aβ42 oligomer included not only a decline in spike activation but also a qualitative impairment in neural connectivity as well as a disorientation of dispersibility. As a result, this will improve our understanding of how neural networks are modified during AD progression. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)
(This article belongs to the Section Molecular Biology)

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13 pages, 2060 KiB

Open AccessArticle

Effects of Methylone Pre-Exposure on Fluoxetine-Induced Conditioned Taste Avoidance in Male and Female Sprague-Dawley Rats

by Hayley N. Manke, Kenner C. Rice and Anthony L. Riley

Brain Sci. 2023, 13(4), 585; https://doi.org/10.3390/brainsci13040585 - 30 Mar 2023

Cited by 3 | Viewed by 2173

Abstract

Background: Prior work has reported that a drug’s aversive effects (as indexed by taste avoidance conditioning) are attenuated when the pre-exposure and conditioning drugs are the same or different. The latter, otherwise known as cross-drug pre-exposure, is especially interesting as it has been [...] Read more.

Background: Prior work has reported that a drug’s aversive effects (as indexed by taste avoidance conditioning) are attenuated when the pre-exposure and conditioning drugs are the same or different. The latter, otherwise known as cross-drug pre-exposure, is especially interesting as it has been used as a tool to assess mechanisms underlying the aversive effects of drugs. We previously reported that methylone pre-exposure differentially impacted the aversive effects of MDPV and MDMA (MDPV > MDMA), a difference consistent with the dopaminergic mediation of methylone’s aversive effects. To examine the possible role of serotonin (5-HT) in methylone’s aversive effects, the present study assessed the effects of methylone pre-exposure on taste avoidance induced by the 5-HT reuptake inhibitor fluoxetine. Methods: Male and female Sprague-Dawley rats were exposed to 10 mg/kg of methylone every 4th day (for a total of 5 injections) prior to taste avoidance training with 10 mg/kg of fluoxetine. Results: Fluoxetine induced significant taste avoidance (each p < 0.05) that was independent of sex. Methylone pre-exposure had no impact on avoidance produced by fluoxetine in either males or females (each p > 0.05). Conclusions: Methylone pre-exposure had no impact on fluoxetine-induced avoidance. These findings suggest that it is unlikely that 5-HT mediates the aversive effects of methylone. The implications of the present results for the mechanisms mediating methylone’s aversive effects were discussed. Understanding such mechanisms is important in predictions relevant to drug history and abuse liability as a variety of subject and experiential factors known to affect (reduce) a drug’s aversive effects may increase its use and potential for abuse. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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23 pages, 1223 KiB

Open AccessSystematic Review

Cardiorespiratory Assessments in Panic Disorder Facilitated by Wearable Devices: A Systematic Review and Brief Comparison of the Wearable Zephyr BioPatch with the Quark-b2 Stationary Testing System

by Daniela Caldirola, Silvia Daccò, Massimiliano Grassi, Alessandra Alciati, William M. Sbabo, Domenico De Donatis, Giovanni Martinotti, Domenico De Berardis and Giampaolo Perna

Brain Sci. 2023, 13(3), 502; https://doi.org/10.3390/brainsci13030502 - 16 Mar 2023

Cited by 1 | Viewed by 3190

Abstract

Abnormalities in cardiorespiratory measurements have repeatedly been found in patients with panic disorder (PD) during laboratory-based assessments. However, recordings performed outside laboratory settings are required to test the ecological validity of these findings. Wearable devices, such as sensor-imbedded garments, biopatches, and smartwatches, are [...] Read more.

Abnormalities in cardiorespiratory measurements have repeatedly been found in patients with panic disorder (PD) during laboratory-based assessments. However, recordings performed outside laboratory settings are required to test the ecological validity of these findings. Wearable devices, such as sensor-imbedded garments, biopatches, and smartwatches, are promising tools for this purpose. We systematically reviewed the evidence for wearables-based cardiorespiratory assessments in PD by searching for publications on the PubMed, PsycINFO, and Embase databases, from inception to 30 July 2022. After the screening of two-hundred and twenty records, eight studies were included. The limited number of available studies and critical aspects related to the uncertain reliability of wearables-based assessments, especially concerning respiration, prevented us from drawing conclusions about the cardiorespiratory function of patients with PD in daily life. We also present preliminary data on a pilot study conducted on volunteers at the Villa San Benedetto Menni Hospital for evaluating the accuracy of heart rate (HR) and breathing rate (BR) measurements by the wearable Zephyr BioPatch compared with the Quark-b2 stationary testing system. Our exploratory results suggested possible BR and HR misestimation by the wearable Zephyr BioPatch compared with the Quark-b2 system. Challenges of wearables-based cardiorespiratory assessment and possible solutions to improve their reliability and optimize their significant potential for the study of PD pathophysiology are presented. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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18 pages, 4193 KiB

Open AccessArticle

Modulation of Melatonin in Pain Behaviors Associated with Oxidative Stress and Neuroinflammation Responses in an Animal Model of Central Post-Stroke Pain

by Tavleen Kaur, Andrew Chih-Wei Huang and Bai-Chuang Shyu

Int. J. Mol. Sci. 2023, 24(6), 5413; https://doi.org/10.3390/ijms24065413 - 12 Mar 2023

Cited by 9 | Viewed by 2565

Abstract

Central post-stroke pain is a severe persistent pain disease that affects 12% of stroke survivors (CPSP). These patients may have a cognitive impairment, depression, and sleep apnea, which leave them open to misdiagnosis and mistreatment. However, there has been little research on whether [...] Read more.

Central post-stroke pain is a severe persistent pain disease that affects 12% of stroke survivors (CPSP). These patients may have a cognitive impairment, depression, and sleep apnea, which leave them open to misdiagnosis and mistreatment. However, there has been little research on whether the neurohormone melatonin can effectively reduce pain in CPSP conditions. In the present study, we labeled melatonin receptors in various brain regions of rats. Later, we established a CPSP animal model by intra-thalamic collagenase lesions. After a rehabilitation period of three weeks, melatonin was administered using different doses (i.e., 30 mg/kg, 60 mg/kg, 120 mg/kg) for the following three weeks. Mechanical allodynia, thermal hyperalgesia, and cold allodynia behavioral tests were performed. Immediately after behavioral parameters were tested, animals were sacrificed, and the thalamus and cortex were isolated for biochemical (mitochondrial complexes/enzyme assays and LPO, GSH levels) and neuroinflammatory (TNF-α, IL-1β, IL-6) assessments. The results show that melatonin receptors were abundant in VPM/VPL regions. The thalamic lesion significantly induced pain behaviors in the mechanical, thermal planters, and cold allodynia tests. A significant decrease in mitochondrial chain complexes (C-I, II, III, IV) and enzymes (SOD, CAT, Gpx, SDH) was observed after the thalamic lesion. While there were significant increases in reactive oxygen species levels, including increases in LPO, the levels of reduced GSH were decreased in both the cortex and thalamus. Proinflammatory infiltration was noticed after the thalamic lesion, as there was a significant elevation in levels of TNF-α, IL-1β, and IL-6. Administration of melatonin has been shown to reverse the injury effect dose-dependently. Moreover, a significant increase in C-I, IV, SOD, CAT, and Gpx levels occurred in the CPSP group. Proinflammatory cytokines were significantly reduced by melatonin treatments. Melatonin seems to mediate its actions through MT1 receptors by preserving mitochondrial homeostasis, reducing free radical generation, enhancing mitochondrial glutathione levels, safeguarding the proton potential in the mitochondrial ETC by stimulating complex I and IV activities, and protecting the neuronal damage. In summary, exogenous melatonin can ameliorate pain behaviors in CPSP. The present findings may provide a novel neuromodulatory treatment in the clinical aspects of CPSP. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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17 pages, 2019 KiB

Open AccessFeature PaperArticle

Electrophysiological Activity of Primary Cortical Neuron-Glia Mixed Cultures

by Noah Goshi, Hyehyun Kim, Gregory Girardi, Alexander Gardner and Erkin Seker

Cells 2023, 12(5), 821; https://doi.org/10.3390/cells12050821 - 6 Mar 2023

Cited by 7 | Viewed by 4717

Abstract

Neuroinflammation plays a central role in many neurological disorders, ranging from traumatic brain injuries to neurodegeneration. Electrophysiological activity is an essential measure of neuronal function, which is influenced by neuroinflammation. In order to study neuroinflammation and its electrophysiological fingerprints, there is a need [...] Read more.

Neuroinflammation plays a central role in many neurological disorders, ranging from traumatic brain injuries to neurodegeneration. Electrophysiological activity is an essential measure of neuronal function, which is influenced by neuroinflammation. In order to study neuroinflammation and its electrophysiological fingerprints, there is a need for in vitro models that accurately capture the in vivo phenomena. In this study, we employed a new tri-culture of primary rat neurons, astrocytes, and microglia in combination with extracellular electrophysiological recording techniques using multiple electrode arrays (MEAs) to determine the effect of microglia on neural function and the response to neuroinflammatory stimuli. Specifically, we established the tri-culture and its corresponding neuron-astrocyte co-culture (lacking microglia) counterpart on custom MEAs and monitored their electrophysiological activity for 21 days to assess culture maturation and network formation. As a complementary assessment, we quantified synaptic puncta and averaged spike waveforms to determine the difference in excitatory to inhibitory neuron ratio (E/I ratio) of the neurons. The results demonstrate that the microglia in the tri-culture do not disrupt neural network formation and stability and may be a better representation of the in vivo rat cortex due to its more similar E/I ratio as compared to more traditional isolated neuron and neuron-astrocyte co-cultures. In addition, only the tri-culture displayed a significant decrease in both the number of active channels and spike frequency following pro-inflammatory lipopolysaccharide exposure, highlighting the critical role of microglia in capturing electrophysiological manifestations of a representative neuroinflammatory insult. We expect the demonstrated technology to assist in studying various brain disease mechanisms. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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23 pages, 1955 KiB

Open AccessEditor’s ChoiceReview

Extracellular Vesicles, Cell-Penetrating Peptides and miRNAs as Future Novel Therapeutic Interventions for Parkinson’s and Alzheimer’s Disease

by Cameron Noah Keighron, Sahar Avazzadeh, Katarzyna Goljanek-Whysall, Brian McDonagh, Linda Howard, Thomas Ritter and Leo R. Quinlan

Biomedicines 2023, 11(3), 728; https://doi.org/10.3390/biomedicines11030728 - 28 Feb 2023

Cited by 13 | Viewed by 5742

Abstract

Neurodegeneration is hallmarked by the progressive loss of dopaminergic neurons and/or a significant increase in protein aggregates in the brain. Neurodegenerative diseases are a leading cause of death worldwide with over 15 million people currently suffering from either Parkinson’s disease (PD) or Alzheimer’s [...] Read more.

Neurodegeneration is hallmarked by the progressive loss of dopaminergic neurons and/or a significant increase in protein aggregates in the brain. Neurodegenerative diseases are a leading cause of death worldwide with over 15 million people currently suffering from either Parkinson’s disease (PD) or Alzheimer’s disease (AD). PD is often characterized by both motor and non-motor symptoms, including muscle rigidity, tremors and bradykinesia, with AD displaying symptoms of confusion and dementia. The current mainstay of therapeutics includes pharmacological approaches such as levodopa to replace dopamine in PD patients, deep brain stimulation in affected regions of the brain and physical therapy. However, these treatments are typically not disease-modifying, though they do help at least for some time with symptom management. These treatments often also fail due to their inability to cross the blood–brain barrier. There is a need to develop new strategies to target neurodegeneration in an ever-ageing population. First, we review the current PD and AD treatments and their limitations. Second, we review the current use of extracellular vesicles (EVs), cell-penetrating peptides (CPPs) and miRNAs as neuroprotective agents. Finally, we discuss the possibility of exploiting these as a combinatory therapeutic, alongside some potential drawbacks. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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17 pages, 1455 KiB

Open AccessArticle

The Resting State of Taiwan EEG Normative Database: Z-Scores of Patients with Major Depressive Disorder as the Cross-Validation

by Yin-Chen Wu and I-Mei Lin

Brain Sci. 2023, 13(2), 351; https://doi.org/10.3390/brainsci13020351 - 18 Feb 2023

Cited by 3 | Viewed by 3066

Abstract

This study referred to the standard of electroencephalography (EEG) collection of normative databases and collected the Taiwan normative database to examine the reliability and validation of the Taiwan EEG normative database. We included 260 healthy participants and divided them into five groups in [...] Read more.

This study referred to the standard of electroencephalography (EEG) collection of normative databases and collected the Taiwan normative database to examine the reliability and validation of the Taiwan EEG normative database. We included 260 healthy participants and divided them into five groups in 10-year age-group segments and calculated the EEG means, standard deviation, and z-scores. Internal consistency reliability was verified at different frequencies between the three electrode locations in the Taiwan normative database. We recruited 221 major depressive disorder (MDD) patients for cross-validation between the Taiwan and NeuroGuide normative databases. There were high internal consistency reliabilities for delta, theta, alpha, beta, and high-beta at C3, Cz, and C4 in the HC group. There were high correlations between the two z-scores of the Taiwan and NeuroGuide normative databases in the frontal, central, parietal, temporal, and occipital lobes from MDD patients. The beta z-scores in the frontal lobe and central area, and the high-beta z-scores in the frontal, central, parietal, temporal, and occipital lobes were greater than one for MDD patients; in addition, the beta and high-beta absolute value z-scores in the whole brain were greater than the ones of MDD patients. The Taiwan EEG normative database has good psychometric characteristics of internal consistency reliability and cross-validation. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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19 pages, 3760 KiB

Open AccessArticle

Embryoid Body Cells from Human Embryonic Stem Cells Overexpressing Dopaminergic Transcription Factors Survive and Initiate Neurogenesis via Neural Rosettes in the Substantia Nigra

by Rodrigo Ramos-Acevedo, Carmen Alejandra Morato-Torres, Francisco J. Padilla-Godínez, Luis Daniel Bernal-Conde, Marcela Palomero-Rivero, Faria Zafar, Omar Collazo-Navarrete, Luis O. Soto-Rojas, Birgitt Schüle and Magdalena Guerra-Crespo

Brain Sci. 2023, 13(2), 329; https://doi.org/10.3390/brainsci13020329 - 14 Feb 2023

Cited by 2 | Viewed by 3662

Abstract

Transplantation of immature dopaminergic neurons or neural precursors derived from embryonic stem cells (ESCs) into the substantia nigra pars compacta (SNpc) is a potential therapeutic approach for functional restitution of the nigrostriatal pathway in Parkinson’s disease (PD). However, further studies are needed to [...] Read more.

Transplantation of immature dopaminergic neurons or neural precursors derived from embryonic stem cells (ESCs) into the substantia nigra pars compacta (SNpc) is a potential therapeutic approach for functional restitution of the nigrostriatal pathway in Parkinson’s disease (PD). However, further studies are needed to understand the effects of the local microenvironment on the transplanted cells to improve survival and specific differentiation in situ. We have previously reported that the adult SNpc sustains a neurogenic microenvironment. Non-neuralized embryoid body cells (EBCs) from mouse ESCs (mESCs) overexpressing the dopaminergic transcription factor Lmx1a gave rise to many tyrosine hydroxylase (Th⁺) cells in the intact and damaged adult SNpc, although only for a short-term period. Here, we extended our study by transplanting EBCs from genetically engineered naive human ESC (hESC), overexpressing the dopaminergic transcription factors LMX1A, FOXA2, and OTX2 (hESC-LFO), in the SNpc. Unexpectedly, no graft survival was observed in wild-type hESC EBCs transplants, whereas hESC-LFO EBCs showed viability in the SNpc. Interestingly, neural rosettes, a developmental hallmark of neuroepithelial tissue, emerged at 7- and 15-days post-transplantation (dpt) from the hESC-LFO EBCs. Neural rosettes expressed specification dopaminergic markers (Lmx1a, Otx2), which gave rise to several Th⁺ cells at 30 dpt. Our results suggest that the SNpc enables the robust initiation of neural differentiation of transplanted human EBCs prompted to differentiate toward the midbrain dopaminergic phenotype. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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14 pages, 2588 KiB

Open AccessArticle

Effects of Binaural Beat Stimulation in Adults with Stuttering

by Dmytro Chernetchenko, Pramax Prasolov, Sam Aganov, Andrii Voropai, Yuliia Polishchuk, Dmytro Lituiev and Eugene Nayshtetik

Brain Sci. 2023, 13(2), 309; https://doi.org/10.3390/brainsci13020309 - 11 Feb 2023

Cited by 2 | Viewed by 3951

Abstract

In recent decades, several studies have demonstrated a link between stuttering and abnormal electroencephalographic (EEG) β-power in cortex. Effects of exposure to binaural stimuli were studied in adults with stuttering (AWS, n = 6) and fluent participants (n = 6) using EEG, [...] Read more.

In recent decades, several studies have demonstrated a link between stuttering and abnormal electroencephalographic (EEG) β-power in cortex. Effects of exposure to binaural stimuli were studied in adults with stuttering (AWS, n = 6) and fluent participants (n = 6) using EEG, ECG, and speech analysis. During standard reading tasks without stimulation, in controls but not in the AWS group, EEG β-power was significantly higher in the left hemisphere than in the right hemisphere. After stimulation, the power of the β-band in AWS participants in the left hemisphere increased 1.54-fold. The average β-band power within the left frontotemporal area and temporoparietal junction of the cortex after stimulation in AWS participants shows an increase by 1.65-fold and 1.72-fold, respectively. The rate of disfluency dropped significantly immediately after stimulation (median 74.70% of the baseline). Similarly, the speech rate significantly increased immediately after stimulation (median 133.15%). We show for the first time that auditory binaural beat stimulation can improve speech fluency in AWS, and its effect is proportional to boost in EEG β-band power in left frontotemporal and temporoparietal junction of cortex. Changes in β-power were detected immediately after exposure and persisted for 10 min. Additionally, these effects were accompanied by a reduction in stress levels. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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17 pages, 1770 KiB

Open AccessArticle

The Efficacity of the NeuroAssist Robotic System for Motor Rehabilitation of the Upper Limb—Promising Results from a Pilot Study

by Nicoleta Tohanean, Paul Tucan, Oana-Maria Vanta, Cristian Abrudan, Sebastian Pintea, Bogdan Gherman, Alin Burz, Alexandru Banica, Calin Vaida, Deborah Alice Neguran, Andreea Ordog, Daniela Tarnita and Doina Pisla

J. Clin. Med. 2023, 12(2), 425; https://doi.org/10.3390/jcm12020425 - 4 Jan 2023

Cited by 10 | Viewed by 3196

Abstract

The research aimed to evaluate the efficacy of the NeuroAssist, a parallel robotic system comprised of three robotic modules equipped with human–robot interaction capabilities, an internal sensor system for torque monitoring, and an external sensor system for real-time patient monitoring for the motor [...] Read more.

The research aimed to evaluate the efficacy of the NeuroAssist, a parallel robotic system comprised of three robotic modules equipped with human–robot interaction capabilities, an internal sensor system for torque monitoring, and an external sensor system for real-time patient monitoring for the motor rehabilitation of the shoulder, elbow, and wrist. The study enrolled 10 consecutive patients with right upper limb paresis caused by stroke, traumatic spinal cord disease, or multiple sclerosis admitted to the Neurology I Department of Cluj-Napoca Emergency County Hospital. The patients were evaluated clinically and electrophysiologically before (T1) and after the intervention (T2). The intervention consisted of five consecutive daily sessions of 30–45 min each of 30 passive repetitive movements performed with the robot. There were significant differences (Wilcoxon signed-rank test) between baseline and end-point clinical parameters, specifically for the Barthel Index (53.00 ± 37.72 vs. 60.50 ± 36.39, p = 0.016) and Activities of Daily Living Index (4.70 ± 3.43 vs. 5.50 ± 3.80, p = 0.038). The goniometric parameters improved: shoulder flexion (70.00 ± 56.61 vs. 80.00 ± 63.59, p = 0.026); wrist flexion/extension (34.00 ± 28.75 vs. 42.50 ± 33.7, p = 0.042)/(30.00 ± 22.97 vs. 41.00 ± 30.62, p = 0.042); ulnar deviation (23.50 ± 19.44 vs. 33.50 ± 24.15, p = 0.027); and radial deviation (17.50 ± 18.14 vs. 27.00 ± 24.85, p = 0.027). There was a difference in muscle activation of the extensor digitorum communis muscle (1.00 ± 0.94 vs. 1.40 ± 1.17, p = 0.046). The optimized and dependable NeuroAssist Robotic System improved shoulder and wrist range of motion and functional scores, regardless of the cause of the motor deficit. However, further investigations are necessary to establish its definite role in motor recovery. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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23 pages, 7749 KiB

Open AccessArticle

Cutaneous Injection of Resiniferatoxin Completely Alleviates and Prevents Nerve-Injury-Induced Neuropathic Pain

by Hayate Javed, Aishwarya Mary Johnson, Anil Kumar Challagandla, Bright Starling Emerald and Safa Shehab

Cells 2022, 11(24), 4049; https://doi.org/10.3390/cells11244049 - 14 Dec 2022

Cited by 9 | Viewed by 3264

Abstract

Fifth lumbar (L5) nerve injury in rodent produces neuropathic manifestations in the corresponding hind paw. The aim of this study was to investigate the effect of cutaneous injection of resiniferatoxin (RTX), a TRPV1 receptor agonist, in the rat’s hind paw on the neuropathic [...] Read more.

Fifth lumbar (L5) nerve injury in rodent produces neuropathic manifestations in the corresponding hind paw. The aim of this study was to investigate the effect of cutaneous injection of resiniferatoxin (RTX), a TRPV1 receptor agonist, in the rat’s hind paw on the neuropathic pain induced by L5 nerve injury. The results showed that intraplantar injection of RTX (0.002%, 100 µL) (1) completely reversed the development of chronic thermal and mechanical hypersensitivity; (2) completely prevented the development of nerve-injury-induced thermal and mechanical hypersensitivity when applied one week earlier; (3) caused downregulation of nociceptive pain markers, including TRPV1, IB4 and CGRP, and upregulation of VIP in the ipsilateral dorsal horn of spinal cord and dorsal root ganglion (DRG) immunohistochemically and a significant reduction in the expression of TRPV1 mRNA and protein in the ipsilateral DRG using Western blot and qRT-PCR techniques; (4) caused downregulation of PGP 9.5- and CGRP-immunoreactivity in the injected skin; (5) produced significant suppression of c-fos expression, as a neuronal activity marker, in the spinal neurons in response to a second intraplantar RTX injection two weeks later. This work identifies the ability of cutaneous injection of RTX to completely alleviate and prevent the development of different types of neuropathic pain in animals and humans. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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14 pages, 297 KiB

Open AccessArticle

Application of Grey Relational Analysis to Predict Dementia Tendency by Cognitive Function, Sleep Disturbances, and Health Conditions of Diabetic Patients

by Chiung-Yu Huang, Yu-Ching Lin, Yung-Chuan Lu and Chun-I Chen

Brain Sci. 2022, 12(12), 1642; https://doi.org/10.3390/brainsci12121642 - 30 Nov 2022

Cited by 7 | Viewed by 2102

Abstract

Background: The number of elderly diabetic patients has been increasing recently, and these patients have a higher morbidity of dementia than those without diabetes. Diabetes is associated with an increased risk for the development of dementia in elderly individuals, which is a [...] Read more.

Background: The number of elderly diabetic patients has been increasing recently, and these patients have a higher morbidity of dementia than those without diabetes. Diabetes is associated with an increased risk for the development of dementia in elderly individuals, which is a serious health problem. Objectives: The primary aim was to examine whether diabetes is a risk factor for dementia among elderly individuals. The secondary aim was to apply grey theory to integrate the results and how they relate to cognitive impairments in elderly diabetic patients and to predict which participants are at high risk of developing dementia. Methods: Two hundred and twenty patients aged 50 years or older who were diagnosed with diabetes mellitus were recruited. Information on demographics, disease characteristics, activities of daily living, Mini Mental State Examination, sleep quality, depressive symptoms, and health-related quality of life was collected via questionnaires. The grey relational analysis approach was applied to evaluate the relationship between the results and health outcomes. Results: A total of 13.6% of participants had cognitive disturbances, of whom 1.4% had severe cognitive dysfunction. However, with regard to sleep disorders, 56.4% had sleep disturbances of varying degrees from light to severe. Further investigation is needed to address this problem. A higher prevalence of sleep disturbances among diabetic patients translates to a higher degree of depressive symptoms and a worse physical and mental health-related quality of life. Furthermore, based on the grey relational analysis, the grey relation coefficient varies from 0.6217~0.7540. Among the subjects, Participant 101 had the highest value, suggesting a need for immediate medical care. In this study, we observed that 20% of the total participants, for whom the grey relation coefficient was 0.6730, needed further and immediate medical care. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

25 pages, 13066 KiB

Open AccessArticle

Alterations in Cerebellar Microtubule Cytoskeletal Network in a ValproicAcid-Induced Rat Model of Autism Spectrum Disorders

by Magdalena Gąssowska-Dobrowolska, Agnieszka Kolasa, David Q. Beversdorf and Agata Adamczyk

Biomedicines 2022, 10(12), 3031; https://doi.org/10.3390/biomedicines10123031 - 24 Nov 2022

Cited by 9 | Viewed by 3043

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental diseases characterised by deficits in social communication, restricted interests, and repetitive behaviours. The growing body of evidence points to a role for cerebellar changes in ASD pathology. Some of the findings suggest that not only motor problems [...] Read more.

Autism spectrum disorders (ASD) are neurodevelopmental diseases characterised by deficits in social communication, restricted interests, and repetitive behaviours. The growing body of evidence points to a role for cerebellar changes in ASD pathology. Some of the findings suggest that not only motor problems but also social deficits, repetitive behaviours, and mental inflexibility associated with ASD are connected with damage to the cerebellum. However, the understanding of this brain structure’s functions in ASD pathology needs future investigations. Therefore, in this study, we generated a rodent model of ASD through a single prenatal administration of valproic acid (VPA) into pregnant rats, followed by cerebellar morphological studies of the offspring, focusing on the alterations of key cytoskeletal elements. The expression (Western blot) of α/β-tubulin and the major neuronal MT-associated proteins (MAP) such as MAP-Tau and MAP1B, MAP2, MAP6 (STOP) along with actin-crosslinking αII-spectrin and neurofilament light polypeptide (NF-L) was investigated. We found that maternal exposure to VPA induces a significant decrease in the protein levels of α/β-tubulin, MAP-Tau, MAP1B, MAP2, and αII-spectrin. Moreover, excessive MAP-Tau phosphorylation at (Ser396) along with key Tau-kinases activation was indicated. Immunohistochemical staining showed chromatolysis in the cerebellum of autistic-like rats and loss of Purkinje cells shedding light on one of the possible molecular mechanisms underpinning neuroplasticity alterations in the ASD brain. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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11 pages, 1500 KiB

Open AccessArticle

Elevated Serum CCL23 Levels at Admission Predict Delayed Cerebral Ischemia and Functional Outcome after Aneurysmal Subarachnoid Hemorrhage

by Hongwei Lin, Jie Shen, Yu Zhu, Lihui Zhou, Fan Wu, Zongchi Liu, Shengxiang Zhang and Renya Zhan

J. Clin. Med. 2022, 11(23), 6879; https://doi.org/10.3390/jcm11236879 - 22 Nov 2022

Cited by 3 | Viewed by 1934

Abstract

(1) Background: CC chemokine ligand 23 (CCL23) is a chemokine implicated in the inflammatory response following brain damage. The aim of this study is to identify the change in serum CCL23 levels within 24 h after aSAH and whether serum CCL23 levels are [...] Read more.

(1) Background: CC chemokine ligand 23 (CCL23) is a chemokine implicated in the inflammatory response following brain damage. The aim of this study is to identify the change in serum CCL23 levels within 24 h after aSAH and whether serum CCL23 levels are associated with initial clinical severity, delayed cerebral ischemia (DCI), and functional outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). (2) Methods: 102 patients with aSAH and 61 controls were included in this prospective observational study. All clinical data were collected prospectively, and their serum CCL23 levels were measured. Initial clinical severity was reflected by the Hunt–Hess score and mFisher score. Functional outcome was evaluated in terms of the Glasgow Outcome Scale (GOS) score at 6-month follow-up. (3) Results: Patients with aSAH had higher serum CCL23 levels than controls. The temporal profile of serum CCL23 levels and neutrophils count exhibited a sustained increase within 24 h after aSAH. Serum CCL23 levels were related to blood neutrophils count, blood CRP levels, and initial clinical severity. Serum CCL23 level was an independent predictor of DCI and 6-month poor outcome in aSAH patients. (4) Conclusions: Serum CCL23 levels emerged as an independent predictor for DCI and poor outcome in patients with aSAH. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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18 pages, 10917 KiB

Open AccessArticle

Comprehensive Analysis of the Prognostic Value and Molecular Function of CRNDE in Glioma at Bulk and Single-Cell Levels

by Lairong Song, Xiaojie Li, Xiaoying Xu, Xulei Huo, Yi Zheng, Xiaomin Wang, Da Li, Junting Zhang, Ke Wang, Liang Wang and Zhen Wu

Cells 2022, 11(22), 3669; https://doi.org/10.3390/cells11223669 - 18 Nov 2022

Cited by 2 | Viewed by 2496

Abstract

Colorectal neoplasia differentially expressed (CRNDE) is an oncogenic long noncoding RNA (lncRNA) overexpressed in diverse malignancies. Here, we comprehensively analyze the prognostic value and molecular function of CRNDE in glioma. Bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome [...] Read more.

Colorectal neoplasia differentially expressed (CRNDE) is an oncogenic long noncoding RNA (lncRNA) overexpressed in diverse malignancies. Here, we comprehensively analyze the prognostic value and molecular function of CRNDE in glioma. Bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA), and single-cell RNA-sequencing data from the Tumor Immune Single-Cell Hub (TISCH) were analyzed. Kaplan–Meier survival analysis was applied to verify the prognostic value of CRNDE. Then, a nomogram based on multivariate Cox regression was established for individualized survival prediction. Subsequently, the expression characteristic and biological function of CRNDE were analyzed at the single-cell level. Lastly, the effects of CRNDE on the proliferation and invasion of glioma cell were explored in vitro. We discovered that CRNDE was a powerful marker for risk stratification of glioma patients. Regardless of the status of IDH and 1p/19q, CRNDE could effectively stratify patients’ prognosis. The nomogram that incorporated the CRNDE expression was proved to be a reliable tool for survival prediction. In addition, epithelial–mesenchymal transition may be the most important biological process regulated by CRNDE, which was identified at both the bulk and single-cell levels. Moreover, CRNDE knockdown significantly inhibited the proliferation and invasion of glioma cell. Overall, CRNDE is a vital oncogene and may be a valuable supplement to improve the clinical stratification of glioma. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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16 pages, 2741 KiB

Open AccessArticle

α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors’ Gating Modules

by Mohammad Qneibi, Safa’ Nassar, Sosana Bdir and Adel Hidmi

Cells 2022, 11(22), 3608; https://doi.org/10.3390/cells11223608 - 15 Nov 2022

Cited by 3 | Viewed by 3503

Abstract

The ionotropic glutamate receptor subtype α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) is responsible for most excitatory transmission in the brain. AMPA receptor function is altered in numerous neurological illnesses, making AMPA receptors appealing therapeutic targets for clinical intervention. Alpha-Lipoic acid (α-LA) is a naturally occurring [...] Read more.

The ionotropic glutamate receptor subtype α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) is responsible for most excitatory transmission in the brain. AMPA receptor function is altered in numerous neurological illnesses, making AMPA receptors appealing therapeutic targets for clinical intervention. Alpha-Lipoic acid (α-LA) is a naturally occurring compound, which functions as a co-factor in metabolism and energy production. α-LA is an antioxidant with various benefits in treating diabetes, including managing symptomatic diabetic neuropathy. This study will test a novel and innovative strategy to synthesize a new isomer of lipoic acid (R-LA) derivatives (bifunctional NO-donor/antioxidant) in one chemical on homomeric and heteromeric AMPA receptor subunits. We used patch-clamp electrophysiology to examine LA derivatives expressed in human embryonic kidney 293 cells (HEK293) for inhibition and changes in desensitization or deactivation rates. LA derivatives were shown to be potent antagonists of AMPA receptors, with an 8–11-fold reduction in AMPA receptor currents seen following the delivery of the compounds. Furthermore, the LA derivatives influenced the rates of desensitization and deactivation of AMPA receptors. Based on our results, especially given that α-LA is closely connected to the nervous system, we may better understand using AMPA receptors and innovative drugs to treat neurological diseases associated with excessive activation of AMPA receptors. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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16 pages, 2181 KiB

Open AccessArticle

Applying Deep Learning on a Few EEG Electrodes during Resting State Reveals Depressive States: A Data Driven Study

by Damián Jan, Manuel de Vega, Joana López-Pigüi and Iván Padrón

Brain Sci. 2022, 12(11), 1506; https://doi.org/10.3390/brainsci12111506 - 6 Nov 2022

Cited by 3 | Viewed by 2332

Abstract

The growing number of depressive people and the overload in primary care services make it necessary to identify depressive states with easily accessible biomarkers such as mobile electroencephalography (EEG). Some studies have addressed this issue by collecting and analyzing EEG resting state in [...] Read more.

The growing number of depressive people and the overload in primary care services make it necessary to identify depressive states with easily accessible biomarkers such as mobile electroencephalography (EEG). Some studies have addressed this issue by collecting and analyzing EEG resting state in a search of appropriate features and classification methods. Traditionally, EEG resting state classification methods for depression were mainly based on linear or a combination of linear and non-linear features. We hypothesize that participants with ongoing depressive states differ from controls in complex patterns of brain dynamics that can be captured in EEG resting state data, using only nonlinear measures on a few electrodes, making it possible to develop cheap and wearable devices that could be even monitored through smartphones. To validate such a perspective, a resting-state EEG study was conducted with 50 participants, half with depressive state (DEP) and half controls (CTL). A data-driven approach was applied to select the most appropriate time window and electrodes for the EEG analyses, as suggested by Giacometti, as well as the most efficient nonlinear features and classifiers, to distinguish between CTL and DEP participants. Nonlinear features showing temporo-spatial and spectral complexity were selected. The results confirmed that computing nonlinear features from a few selected electrodes in a 15 s time window are sufficient to classify DEP and CTL participants accurately. Finally, after training and testing internally the classifier, the trained machine was applied to EEG resting state data (CTL and DEP) from a publicly available database, validating the capacity of generalization of the classifier with data from different equipment, population, and environment obtaining an accuracy near 100%. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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11 pages, 265 KiB

Open AccessArticle

Serum Zinc and Long-Term Prognosis after Acute Traumatic Brain Injury with Intracranial Injury: A Multicenter Prospective Study

by Ki Hong Kim, Young Sun Ro, Hanna Yoon, Stephen Gyung Won Lee, Eujene Jung, Sung Bae Moon, Gwan Jin Park and Sang Do Shin

J. Clin. Med. 2022, 11(21), 6496; https://doi.org/10.3390/jcm11216496 - 1 Nov 2022

Cited by 5 | Viewed by 2393

Abstract

Serum zinc levels in the acute stages after traumatic brain injury (TBI) may be capable of predicting cinical and functional prognoses. This study aimed to evaluate the association between serum zinc levels and long-term survival and neurological outcomes in TBI patients with intracranial [...] Read more.

Serum zinc levels in the acute stages after traumatic brain injury (TBI) may be capable of predicting cinical and functional prognoses. This study aimed to evaluate the association between serum zinc levels and long-term survival and neurological outcomes in TBI patients with intracranial injury. This multicenter prospective cohort study enrolled adult TBI patients with intracranial injury who visited emergency departments between December 2018 and June 2020. Serum zinc levels drawn within 24 h after injury were categorized into four groups: low (<80.0 mcg/dL), low–normal (80.0–100.0 mcg/dL), high–normal (100.1–120.0 mcg/dL), and high (>120.0 mcg/dL). The study outcomes were 6-month mortality and disability (Glasgow Outcome Scale, 1–3). A multilevel multivariable logistic regression analysis was conducted to estimate associations between serum zinc and study outcomes. From the eligible TBI patients (N = 487), the median (interquartile range) serum zinc level was 112.0 mcg/dL (95.0–142.0). Six-month mortality and disability were 21.1% (103/487) and 29.6% (144/487), respectively. Compared to the high–normal zinc group, there were significant associations with 6-month mortality and disability observed in the low zinc group (aORs (95% CIs): 1.91 (1.60–2.28) and 1.95 (1.62–2.36) for the low group; 1.14 (0.67–1.94) and 1.15 (0.91–1.46) for the low–normal group; and 0.72 (0.44–1.16) and 0.88 (0.61–1.27) for the high group, respectively). Among the 122 TBI patients with diabetes mellitus, the low zinc group showed a higher incidence of 6-month mortality (aOR (95% CI): 9.13 (4.01–20.81)) compared to the high–normal zinc group. Moreover, the low and low–normal groups had higher odds for 6-month disability (aORs (95% CIs): 6.63 (3.61–12.15) for the low group and 2.37 (1.38–4.07) for the low–normal group). Serum zinc deficiency is associated with a higher incidence of 6-month mortality and disability after injury for TBI patients with intracranial injury. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

13 pages, 4149 KiB

Open AccessArticle

Efficient Gene Expression in Human Stem Cell Derived-Cortical Organoids Using Adeno Associated Virus

by Ann-Na Cho, Fiona Bright, Nicolle Morey, Carol Au, Lars M. Ittner and Yazi D. Ke

Cells 2022, 11(20), 3194; https://doi.org/10.3390/cells11203194 - 11 Oct 2022

Cited by 7 | Viewed by 5242

Abstract

Cortical organoids are 3D structures derived either from human embryonic stem cells or human induced pluripotent stem cells with their use exploding in recent years due to their ability to better recapitulate the human brain in vivo in respect to organization; differentiation; and [...] Read more.

Cortical organoids are 3D structures derived either from human embryonic stem cells or human induced pluripotent stem cells with their use exploding in recent years due to their ability to better recapitulate the human brain in vivo in respect to organization; differentiation; and polarity. Adeno-associated viruses (AAVs) have emerged in recent years as the vectors of choice for CNS-targeted gene therapy. Here; we compare the use of AAVs as a mode of gene expression in cortical organoids; over traditional methods such as lipofectamine and electroporation and demonstrate its ease-of-use in generating quick disease models through expression of different variants of the central gene—TDP-43—implicated in amyotrophic lateral sclerosis and frontotemporal dementia. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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20 pages, 2511 KiB

Open AccessArticle

Attenuation of Autism-like Behaviors by an Anthocyanin-Rich Extract from Portuguese Blueberries via Microbiota–Gut–Brain Axis Modulation in a Valproic Acid Mouse Model

by Diana Serra, Joana F. Henriques, Fábio J. Sousa, Mariana Laranjo, Rosa Resende, Marisa Ferreira-Marques, Victor de Freitas, Gabriela Silva, João Peça, Teresa C. P. Dinis and Leonor M. Almeida

Int. J. Mol. Sci. 2022, 23(16), 9259; https://doi.org/10.3390/ijms23169259 - 17 Aug 2022

Cited by 17 | Viewed by 4700

Abstract

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental pathologies whose current treatment is neither curative nor effective. Anthocyanins are naturally occurring compounds abundant in blueberries and in other red fruits which have been shown to be successful in the treatment of several [...] Read more.

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental pathologies whose current treatment is neither curative nor effective. Anthocyanins are naturally occurring compounds abundant in blueberries and in other red fruits which have been shown to be successful in the treatment of several neurological diseases, at least in in vitro and in vivo disease models. The aim of the present work was to study the ability of an anthocyanin-rich extract (ARE) obtained from Portuguese blueberries to alleviate autism-like symptoms in a valproic acid (VPA) mouse model of ASD and to get insights into the underlying molecular mechanisms of such benefits. Therefore, pregnant BALB/c females were treated subcutaneously with a single dose of VPA (500 mg/kg) or saline on gestational day 12.5. Male offspring mice were orally treated with the ARE from Portuguese blueberries (30 mg/kg/day) or the vehicle for three weeks, and further subjected to behavioral tests and biochemical analysis. Our data suggested that the ARE treatment alleviated autism-like behaviors in in utero VPA-exposed mice and, at the same time, decreased both neuroinflammation and gut inflammation, modulated the gut microbiota composition, increased serotonin levels in cerebral prefrontal cortex and gut, and reduced the synaptic dysfunction verified in autistic mice. Overall, our work suggests that anthocyanins extracted from Portuguese blueberries could constitute an effective strategy to ameliorate typical autistic behaviors through modulation of the microbiota–gut–brain axis. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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11 pages, 1033 KiB

Open AccessBrief Report

Application of Network Analysis to Uncover Variables Contributing to Functional Recovery after Stroke

by Xiao Xi, Qianfeng Li, Lisa J. Wood, Eliezer Bose, Xi Zeng, Jun Wang, Xun Luo and Qing Mei Wang

Brain Sci. 2022, 12(8), 1065; https://doi.org/10.3390/brainsci12081065 - 11 Aug 2022

Viewed by 2136

Abstract

To estimate network structures to discover the interrelationships among variables and distinguish the difference between networks. Three hundred and forty-eight stroke patients were enrolled in this retrospective study. A network analysis was used to investigate the association between those variables. A Network Comparison [...] Read more.

To estimate network structures to discover the interrelationships among variables and distinguish the difference between networks. Three hundred and forty-eight stroke patients were enrolled in this retrospective study. A network analysis was used to investigate the association between those variables. A Network Comparison Test was performed to compare the correlation of variables between networks. Three hundred and twenty-five connections were identified, and 22 of these differed significantly between the high- and low-Functional Independence Measurement (FIM) groups. In the high-FIM network structure, brain-derived neurotrophic factor (BDNF) and length of stay (LOS) had associations with other nodes. However, there was no association with BDNF and LOS in the low-FIM network. In addition, the use of amantadine was associated with shorter LOS and lower FIM motor subscores in the high-FIM network, but there was no such connection in the low-FIM network. Centrality indices revealed that amantadine use had high centrality with others in the high-FIM network but not the low-FIM network. Coronary artery disease (CAD) had high centrality in the low-FIM network structure but not the high-FIM network. Network analysis revealed a new correlation of variables associated with stroke recovery. This approach might be a promising method to facilitate the discovery of novel factors important for stroke recovery. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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29 pages, 10007 KiB

Open AccessArticle

The Relationship between the Aberrant Long Non-Coding RNA-Mediated Competitive Endogenous RNA Network and Alzheimer’s Disease Pathogenesis

by Zhongdi Cai, Kaiyue Zhao, Li Zeng, Mimin Liu, Ting Sun, Zhuorong Li and Rui Liu

Int. J. Mol. Sci. 2022, 23(15), 8497; https://doi.org/10.3390/ijms23158497 - 31 Jul 2022

Cited by 11 | Viewed by 2715

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by cognitive dysfunction. The role of long non-coding RNAs (lncRNAs) with the action of competitive endogenous RNA (ceRNA) in AD remains unclear. The present study aimed to identify significantly differentially expressed lncRNAs (SDELs) and [...] Read more.

Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by cognitive dysfunction. The role of long non-coding RNAs (lncRNAs) with the action of competitive endogenous RNA (ceRNA) in AD remains unclear. The present study aimed to identify significantly differentially expressed lncRNAs (SDELs) and establish lncRNA-associated ceRNA networks via RNA sequencing analysis and a quantitative real-time Polymerase Chain Reaction (qPCR) assay using transgenic mice with five familial AD mutations. A total of 53 SDELs in the cortex and 51 SDELs in the hippocampus were identified, including seven core SDELs common to both regions. The functions and pathways were then investigated through the potential target genes of SDELs via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, which indicate biological effects, action distributions, and pathological transductions associated with AD. Based on the ceRNA hypothesis, integrated ceRNA networks in the cortex and hippocampus of lncRNA-miRNA-mRNA were constructed. The core SDEL-mediated ceRNA relationship was established and the expression of these RNAs was verified by qPCR. The results identified lncRNA ENSMUST00000127786 and highlighted miRNAs and mRNAs as potential key mediators in AD. These findings provide AD-derived lncRNA-mediated ceRNA profiles, and further experimental evidence is needed to confirm these identified ceRNA regulatory relationships. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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12 pages, 4195 KiB

Open AccessArticle

Elevated Hexose-6-Phosphate Dehydrogenase Regulated by OSMR-AS1/hsa-miR-516b-5p Axis Correlates with Poor Prognosis and Dendritic Cells Infiltration of Glioblastoma

by Yi-Bin Zhang, Shu-Fa Zheng, Lin-Jie Ma, Peng Lin, Huang-Cheng Shang-Guan, Yuan-Xiang Lin, De-Zhi Kang and Pei-Sen Yao

Brain Sci. 2022, 12(8), 1012; https://doi.org/10.3390/brainsci12081012 - 30 Jul 2022

Cited by 2 | Viewed by 2788

Abstract

Objective Glioblastoma (GBM), a type of malignant glioma, is the most aggressive type of brain tumor and is associated with high mortality. Hexose-6-phosphate dehydrogenase (H6PD) has been detected in multiple tumors and is involved in tumor initiation and progression. However, the specific role [...] Read more.

Objective Glioblastoma (GBM), a type of malignant glioma, is the most aggressive type of brain tumor and is associated with high mortality. Hexose-6-phosphate dehydrogenase (H6PD) has been detected in multiple tumors and is involved in tumor initiation and progression. However, the specific role and mechanism of H6PD in GBM remain unclear. Methods We performed pan-cancer analysis of expression and prognosis of H6PD in GBM using the Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA). Subsequently, noncoding RNAs regulating H6PD expression were obtained by comprehensive analysis, including gene expression, prognosis, correlation, and immune infiltration. Finally, tumor immune infiltrates related to H6PD and survival were performed. Results Higher expression of H6PD was statistically significantly associated with an unfavorable outcome in GBM. Downregulation of hsa-miR-124-3p and hsa-miR-516b-5p in GBM was detected from GSE90603. Subsequently, OSMR-AS1 was observed in the regulation of H6PD via hsa-miR-516b-5p. Moreover, higher H6PD expression significantly correlated with immune infiltration of dendritic cells, immune checkpoint expression, and biomarkers of dendritic cells. Conclusions The OSMR-AS1/ miR-516b-5p axis was identified as the highest-potential upstream ncRNA-related pathway of H6PD in GBM. Furthermore, the present findings demonstrated that H6PD blockading might possess antitumor roles via regulating dendritic cell infiltration and immune checkpoint expression. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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17 pages, 7522 KiB

Open AccessArticle

Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework

by Juan Javier López-Rivera, Luna Rodríguez-Salazar, Alejandro Soto-Ospina, Carlos Estrada-Serrato, David Serrano, Henry Mauricio Chaparro-Solano, Olga Londoño, Paula A. Rueda, Geraldine Ardila, Andrés Villegas-Lanau, Marcela Godoy-Corredor, Mauricio Cuartas, Jorge I. Vélez, Oscar M. Vidal, Mario A. Isaza-Ruget and Mauricio Arcos-Burgos

Brain Sci. 2022, 12(7), 871; https://doi.org/10.3390/brainsci12070871 - 30 Jun 2022

Cited by 11 | Viewed by 3901

Abstract

A whole-exome capture and next-generation sequencing was applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, and severe cognitive deficit, and without any identifiable Syndromic pattern, and to her parents, we disclosed a [...] Read more.

A whole-exome capture and next-generation sequencing was applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, and severe cognitive deficit, and without any identifiable Syndromic pattern, and to her parents, we disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated with Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated sequence, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURAwt and the PURA–Phe233del showed that the occurrence of the Phe233del affects between 220–320 amino acids. The distortion in the PURA structural conformation in the ~5 Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein–DNA docking corroborated these results in an in silico analysis that showed a loss of the contact of the PURA–Phe233del III repeat domain model with the DNA. Together, (i) the energetic and stereochemical, (ii) the hydropathic indexes and polarity surfaces, and (iii) the hybrid Quantum Mechanics–Molecular Mechanics (QM–MM) analyses of the PURA molecular models demarcate, at the atomic resolution, the specific surrounding region affected by these mutations and pave the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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9 pages, 2189 KiB

Open AccessCommunication

Diffusion Tensor Imaging Radiomics for Diagnosis of Parkinson’s Disease

by Jingwen Li, Xiaoming Liu, Xinyi Wang, Hanshu Liu, Zhicheng Lin and Nian Xiong

Brain Sci. 2022, 12(7), 851; https://doi.org/10.3390/brainsci12070851 - 29 Jun 2022

Cited by 8 | Viewed by 3055

Abstract

Background: Diagnosis of Parkinson’s Disease (PD) based on clinical symptoms and scale scores is mostly objective, and the accuracy of neuroimaging for PD diagnosis remains controversial. This study aims to introduce a radiomic tool to improve the sensitivity and specificity of diagnosis based [...] Read more.

Background: Diagnosis of Parkinson’s Disease (PD) based on clinical symptoms and scale scores is mostly objective, and the accuracy of neuroimaging for PD diagnosis remains controversial. This study aims to introduce a radiomic tool to improve the sensitivity and specificity of diagnosis based on Diffusion Tensor Imaging (DTI) metrics. Methods: In this machine learning-based retrospective study, we collected basic clinical information and DTI images from 54 healthy controls (HCs) and 56 PD patients. Among them, 60 subjects (30 PD patients and 30 HCs) were assigned to the training group, whereas the test cohort was 26 PD patients and 24 HCs. After the feature extraction and selection using newly developed image processing software Ray-plus, LASSO regression was used to finalize radiomic features. Results: A total of 4600 radiomic features were extracted, of which 12 were finally selected. The values of the AUC (area under the subject operating curve) in the training group, the validation group, and overall were 0.911, 0.931, and 0.919, respectively. Conclusion: This study introduced a novel radiometric and computer algorithm based on DTI images, which can help increase the sensitivity and specificity of PD screening. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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16 pages, 2736 KiB

Open AccessArticle

Glioblastoma Extracellular Vesicle-Specific Peptides Inhibit EV-Induced Neuronal Cytotoxicity

by Wenbo Zhou, Julia Craft, Alex Ojemann, Luke Bergen, Arin Graner, Aitana Gonzales, Qianbin He, Timothy Kopper, Marie Smith, Michael W. Graner and Xiaoli Yu

Int. J. Mol. Sci. 2022, 23(13), 7200; https://doi.org/10.3390/ijms23137200 - 28 Jun 2022

Cited by 11 | Viewed by 3940

Abstract

WHO Grade 4 IDH-wild type astrocytoma (GBM) is the deadliest brain tumor with a poor prognosis. Meningioma (MMA) is a more common “benign” central nervous system tumor but with significant recurrence rates. There is an urgent need for brain tumor biomarkers for early [...] Read more.

WHO Grade 4 IDH-wild type astrocytoma (GBM) is the deadliest brain tumor with a poor prognosis. Meningioma (MMA) is a more common “benign” central nervous system tumor but with significant recurrence rates. There is an urgent need for brain tumor biomarkers for early diagnosis and effective treatment options. Extracellular vesicles (EVs) are tiny membrane-enclosed vesicles that play essential functions in cell-to-cell communications among tumor cells. We aimed to identify epitopes of brain tumor EVs by phage peptide libraries. EVs from GBM plasma, MMA plasma, or brain tumor cell lines were used to screen phage-displayed random peptide libraries to identify high-affinity peptides. We purified EVs from three GBM plasma pools (23 patients), one MMA pool (10 patients), and four brain tumor cell lines. We identified a total of 21 high-affinity phage peptides (12 unique) specific to brain tumor EVs. The peptides shared high sequence homologies among those selected by the same EVs. Dose–response ELISA demonstrated that phage peptides were specific to brain tumor EVs compared to controls. Peptide affinity purification identified unique brain tumor EV subpopulations. Significantly, GBM EV peptides inhibit brain tumor EV-induced complement-dependent cytotoxicity (necrosis) in neurons. We conclude that phage display technology could identify specific peptides to isolate and characterize tumor EVs. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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11 pages, 708 KiB

Open AccessArticle

DYRK1A and Activity-Dependent Neuroprotective Protein Comparative Diagnosis Interest in Cerebrospinal Fluid and Plasma in the Context of Alzheimer-Related Cognitive Impairment in Down Syndrome Patients

by Manon Moreau, Maria Carmona-Iragui, Miren Altuna, Lorraine Dalzon, Isabel Barroeta, Marie Vilaire, Sophie Durand, Juan Fortea, Anne-Sophie Rebillat and Nathalie Janel

Biomedicines 2022, 10(6), 1380; https://doi.org/10.3390/biomedicines10061380 - 10 Jun 2022

Cited by 5 | Viewed by 3381

Abstract

Down syndrome (DS) is a complex genetic condition due to an additional copy of human chromosome 21, which results in the deregulation of many genes. In addition to the intellectual disability associated with DS, adults with DS also have an ultrahigh risk of [...] Read more.

Down syndrome (DS) is a complex genetic condition due to an additional copy of human chromosome 21, which results in the deregulation of many genes. In addition to the intellectual disability associated with DS, adults with DS also have an ultrahigh risk of developing early onset Alzheimer’s disease dementia. DYRK1A, a proline-directed serine/threonine kinase, whose gene is located on chromosome 21, has recently emerged as a promising plasma biomarker in patients with sporadic Alzheimer’s disease (AD). The protein DYRK1A is truncated in symptomatic AD, the increased truncated form being associated with a decrease in the level of full-length form. Activity-dependent neuroprotective protein (ADNP), a key protein for the brain development, has been demonstrated to be a useful marker for symptomatic AD and disease progression. In this study, we evaluated DYRK1A and ADNP in CSF and plasma of adults with DS and explored the relationship between these proteins. We used mice models to evaluate the effect of DYRK1A overexpression on ADNP levels and then performed a dual-center cross-sectional human study in adults with DS in Barcelona (Spain) and Paris (France). Both cohorts included adults with DS at different stages of the continuum of AD: asymptomatic AD (aDS), prodromal AD (pDS), and AD dementia (dDS). Non-trisomic controls and patients with sporadic AD dementia were included for comparison. Full-form levels of DYRK1A were decreased in plasma and CSF in adults with DS and symptomatic AD (pDS and dDS) compared to aDS, and in patients with sporadic AD compared to controls. On the contrary, the truncated form of DYRK1A was found to increase both in CSF and plasma in adults with DS and symptomatic AD and in patients with sporadic AD with respect to aDS and controls. ADNP levels showed a more complex structure. ADNP levels increased in aDS groups vs. controls, in agreement with the increase in levels found in the brains of mice overexpressing DYRK1A. However, symptomatic individuals had lower levels than aDS individuals. Our results show that the comparison between full-length and truncated-form levels of DYRK1A coupled with ADNP levels could be used in trials targeting pathophysiological mechanisms of dementia in individuals with DS. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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13 pages, 4269 KiB

Open AccessArticle

A Multi-Modal and Multi-Atlas Integrated Framework for Identification of Mild Cognitive Impairment

by Zhuqing Long, Jie Li, Haitao Liao, Li Deng, Yukeng Du, Jianghua Fan, Xiaofeng Li, Jichang Miao, Shuang Qiu, Chaojie Long and Bin Jing

Brain Sci. 2022, 12(6), 751; https://doi.org/10.3390/brainsci12060751 - 8 Jun 2022

Cited by 8 | Viewed by 3947

Abstract

Background: Multi-modal neuroimaging with appropriate atlas is vital for effectively differentiating mild cognitive impairment (MCI) from healthy controls (HC). Methods: The resting-state functional magnetic resonance imaging (rs-fMRI) and structural MRI (sMRI) of 69 MCI patients and 61 HC subjects were collected. Then, the [...] Read more.

Background: Multi-modal neuroimaging with appropriate atlas is vital for effectively differentiating mild cognitive impairment (MCI) from healthy controls (HC). Methods: The resting-state functional magnetic resonance imaging (rs-fMRI) and structural MRI (sMRI) of 69 MCI patients and 61 HC subjects were collected. Then, the gray matter volumes obtained from the sMRI and Hurst exponent (HE) values calculated from rs-fMRI data in the Automated Anatomical Labeling (AAL-90), Brainnetome (BN-246), Harvard–Oxford (HOA-112) and AAL3-170 atlases were extracted, respectively. Next, these characteristics were selected with a minimal redundancy maximal relevance algorithm and a sequential feature collection method in single or multi-modalities, and only the optimal features were retained after this procedure. Lastly, the retained characteristics were served as the input features for the support vector machine (SVM)-based method to classify MCI patients, and the performance was estimated with a leave-one-out cross-validation (LOOCV). Results: Our proposed method obtained the best 92.00% accuracy, 94.92% specificity and 89.39% sensitivity with the sMRI in AAL-90 and the fMRI in HOA-112 atlas, which was much better than using the single-modal or single-atlas features. Conclusion: The results demonstrated that the multi-modal and multi-atlas integrated method could effectively recognize MCI patients, which could be extended into various neurological and neuropsychiatric diseases. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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11 pages, 2406 KiB

Open AccessArticle

Lower Posterior Cingulate N-Acetylaspartate to Creatine Level in Early Detection of Biologically Defined Alzheimer’s Disease

by Qianyun Chen, Jill Abrigo, Wanting Liu, Elyia Yixun Han, David Ka Wai Yeung, Lin Shi, Lisa Wing Chi Au, Min Deng, Sirong Chen, Eric Yim Lung Leung, Chi Lai Ho, Vincent Chung Tong Mok and Winnie Chiu Wing Chu

Brain Sci. 2022, 12(6), 722; https://doi.org/10.3390/brainsci12060722 - 31 May 2022

Cited by 11 | Viewed by 3088

Abstract

Alzheimer’s disease (AD) was recently defined as a biological construct to reflect neuropathologic status, and both abnormal amyloid and tau are required for a diagnosis of AD. We aimed to determine the proton MR spectroscopic (¹H-MRS) patterns of the posterior cingulate [...] Read more.

Alzheimer’s disease (AD) was recently defined as a biological construct to reflect neuropathologic status, and both abnormal amyloid and tau are required for a diagnosis of AD. We aimed to determine the proton MR spectroscopic (¹H-MRS) patterns of the posterior cingulate in biologically defined AD. A total of 68 participants were included in this study, comprising 37 controls, 16 early AD, and 15 late AD, who were classified according to their amyloid and tau status and presence of hippocampal atrophy. Compared with controls, early AD showed lower N-acetylaspartate (NAA)/creatine (Cr) (p = 0.003), whereas late AD showed lower NAA/Cr and higher myoInositol (mI)/Cr (all with p < 0.05). Lower NAA/Cr correlated with a greater global amyloid load (r = −0.47, p < 0.001) and tau load (r = −0.51, p < 0.001) and allowed a discrimination of early AD from controls (p < 0.001). Subgroup analysis showed that NAA/Cr also allowed a differentiation of early AD from controls in the cognitively unimpaired subjects, with an area under the receiver operating characteristics curve, sensitivity, and specificity of 0.96, 100%, and 83.8%, respectively. Lower posterior cingulate NAA levels may help to inform underlying neuropathologic changes in the early stage of AD. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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16 pages, 3574 KiB

Open AccessArticle

Atp11b Deletion Affects the Gut Microbiota and Accelerates Brain Aging in Mice

by Cuiping Liu, Shibo Zhang, Hongwei Shi, Haicong Zhou, Junyi Zhuang, Yiyang Cao, Natalie Ward and Jiao Wang

Brain Sci. 2022, 12(6), 709; https://doi.org/10.3390/brainsci12060709 - 30 May 2022

Cited by 6 | Viewed by 3546

Abstract

The microbiota-gut-brain axis has attracted significant attention with respect to studying the mechanisms of brain aging; however, the specific connection between gut microbiota and aging remains unclear. The abnormal expression and mutation of proteins belonging to the P4-ATPase family, including Atp11b, results [...] Read more.

The microbiota-gut-brain axis has attracted significant attention with respect to studying the mechanisms of brain aging; however, the specific connection between gut microbiota and aging remains unclear. The abnormal expression and mutation of proteins belonging to the P4-ATPase family, including Atp11b, results in a variety of neurological diseases. The results of our analysis demonstrate that there was a shift in the abundance of certain gut microbiota in Atp11b-knockout (KO) mice. Specifically, there was an increase in pro-inflammatory bacteria that accelerate aging and a decrease in probiotics that delay aging. Consequently, an enhanced oxidative stress response was observed, which was characterized by a reduction in the superoxide dismutase (SOD) activity and an increase in malondialdehyde (MDA) and reactive oxygen species (ROS) levels. In addition, our data demonstrate that there was a decrease in the number of cells in the dentate gyrus (DG) region of the hippocampus, and aggravation of aging-related pathological features such as senescence β-galactosidase (SA-β-Gal), p-HistoneH2AX (Ser139), and p16^INK4. Moreover, KO mice show typical aging-associated behavior, such as memory impairment and slow pain perception. Taken together, we demonstrate a possible mechanism of aging induced by gut microbiota in Atp11b-KO mice, which provides a novel perspective for the treatment of aging through the microbiota-gut-brain axis. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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11 pages, 27226 KiB

Open AccessArticle

Olfactory Ensheathing Cells Alleviate Facial Pain in Rats with Trigeminal Neuralgia by Inhibiting the Expression of P2X7 Receptor

by Jiafeng Lu, Baolin Yang, Jiayi Liao, Baokang Chen, Mingxin Lu, Wenjun Zhang, Jingnan Zeng, Hui Cheng and Zengxu Liu

Brain Sci. 2022, 12(6), 706; https://doi.org/10.3390/brainsci12060706 - 30 May 2022

Cited by 6 | Viewed by 3349

Abstract

Trigeminal neuralgia (TN) is a common facial neuropathic pain that is mainly characterized by spontaneous or induced needling or electric shock pain in the innervation area of the trigeminal nerve. It is also referred to as “the cancer that never dies”. The olfactory [...] Read more.

Trigeminal neuralgia (TN) is a common facial neuropathic pain that is mainly characterized by spontaneous or induced needling or electric shock pain in the innervation area of the trigeminal nerve. It is also referred to as “the cancer that never dies”. The olfactory ensheathing cell (OEC) is a special glial cell in the nervous system that has a strong supportive function in nerve regeneration. Cell transplantation therapy is a useful treatment modality that we believe can be applied in TN management. In this study, OECs were transplanted into the ligation site of the infraorbital nerve of rats. We found that after the OEC transplantation, mechanical pain threshold in the face of the rats was significantly increased. Western blotting, immunofluorescence assay, and reverse transcription-quantitative polymerase chain reaction were performed on the trigeminal ganglia (TG) of model rats. The results revealed a decrease in the expression of P2X7 receptor (P2X7R) in the trigeminal ganglia. Our findings show that OEC transplantation has a good therapeutic effect on TN in rats, and that can reduce the expression of P2X7R in trigeminal ganglia. Therefore, we think that OEC transplantation may be a suitable treatment for TN. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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22 pages, 6029 KiB

Open AccessReview

Neuroimaging Modalities in Alzheimer’s Disease: Diagnosis and Clinical Features

by JunHyun Kim, Minhong Jeong, Wesley R. Stiles and Hak Soo Choi

Int. J. Mol. Sci. 2022, 23(11), 6079; https://doi.org/10.3390/ijms23116079 - 28 May 2022

Cited by 60 | Viewed by 8104

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease causing progressive cognitive decline until eventual death. AD affects millions of individuals worldwide in the absence of effective treatment options, and its clinical causes are still uncertain. The onset of dementia symptoms indicates severe neurodegeneration has [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease causing progressive cognitive decline until eventual death. AD affects millions of individuals worldwide in the absence of effective treatment options, and its clinical causes are still uncertain. The onset of dementia symptoms indicates severe neurodegeneration has already taken place. Therefore, AD diagnosis at an early stage is essential as it results in more effective therapy to slow its progression. The current clinical diagnosis of AD relies on mental examinations and brain imaging to determine whether patients meet diagnostic criteria, and biomedical research focuses on finding associated biomarkers by using neuroimaging techniques. Multiple clinical brain imaging modalities emerged as potential techniques to study AD, showing a range of capacity in their preciseness to identify the disease. This review presents the advantages and limitations of brain imaging modalities for AD diagnosis and discusses their clinical value. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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9 pages, 1772 KiB

Open AccessArticle

Structural Integrity and Functional Neural Activity Associated with Oral Language Function after Stroke

by Sunghyon Kyeong, Hyunkoo Kang and Dae Hyun Kim

J. Clin. Med. 2022, 11(11), 3028; https://doi.org/10.3390/jcm11113028 - 27 May 2022

Cited by 2 | Viewed by 2301

Abstract

(1) Background: The impairment of language function after a stroke is common. It is unclear how the brain reorganizes for language function after cerebral infarction. The aim of this observational study is to investigate the association of structural integrity and functional neural activity [...] Read more.

(1) Background: The impairment of language function after a stroke is common. It is unclear how the brain reorganizes for language function after cerebral infarction. The aim of this observational study is to investigate the association of structural integrity and functional neural activity with language function in aphasic patients with middle cerebral artery infarction. (2) Methods: Magnetic resonance images and scores from the Western Aphasia Battery on 20 patients were retrieved from medical records. A Voxel-wise linear regression analysis was performed using fractional anisotropy maps or the fractional amplitude of low-frequency fluctuation maps as dependent variables and scores of oral language function as independent variables while controlling for age and time elapsed after stroke. (3) Results: Spontaneous speech was positively associated with fractional anisotropy in the left dorsal stream and the right posterior corpus callosum and with the fractional amplitude of the low-frequency fluctuation of cranial nuclei in the pontomedullary junction. Comprehension was positively associated with the left ventral stream. Naming was positively associated with the left ventral stream and the bilateral occipitofrontal fasciculus, as well as with the fractional amplitude of low-frequency fluctuation of the supramarginal gyrus in the left hemisphere. (4) Conclusions: The dorsal and ventral streams are important for articulation and meaning after the reorganization of neural circuits following stroke. Subdomains of oral language function with a visual component are dependent on the visual association areas located in the right hemisphere. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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9 pages, 1559 KiB

Open AccessArticle

Pre-Interventional 3D-Printing-Assisted Planning of Flow Disrupter Implantation for the Treatment of an Intracranial Aneurysm

by Guillaume Charbonnier, Panagiotis Primikiris, Benjamin Billottet, Aurélien Louvrier, Sergio Vancheri, Serine Ferhat and Alessandra Biondi

J. Clin. Med. 2022, 11(11), 2950; https://doi.org/10.3390/jcm11112950 - 24 May 2022

Cited by 5 | Viewed by 2467

Abstract

Intrasaccular flow disrupter devices (ISFD) have opened up new ways to treat intracranial aneurysms but choosing the correct size of ISFD can be challenging. We describe the first use of 3D printing to assist in the choice of ISFD, and we report an [...] Read more.

Intrasaccular flow disrupter devices (ISFD) have opened up new ways to treat intracranial aneurysms but choosing the correct size of ISFD can be challenging. We describe the first use of 3D printing to assist in the choice of ISFD, and we report an illustrative case. We developed a technique that uses preoperative angiography to make a plastic model of the aneurysm. We tested the deployment of different sizes of intrasaccular flow disruptor on the 3D model under fluoroscopy. The best devices were then used as the first-line strategy to treat the patient. The preoperative 3D printing helped in the successful selection of a first-line ISFD, which was not the one recommended by the manufacturer. Three-dimensional printing can provide interesting information regarding the treatment of intracranial aneurysms using ISFD. Further studies are needed to fully assess its benefits. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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13 pages, 1958 KiB

Open AccessArticle

A Depression Prediction Algorithm Based on Spatiotemporal Feature of EEG Signal

by Wei Liu, Kebin Jia, Zhuozheng Wang and Zhuo Ma

Brain Sci. 2022, 12(5), 630; https://doi.org/10.3390/brainsci12050630 - 11 May 2022

Cited by 29 | Viewed by 5589

Abstract

Depression has gradually become the most common mental disorder in the world. The accuracy of its diagnosis may be affected by many factors, while the primary diagnosis seems to be difficult to define. Finding a way to identify depression by satisfying both objective [...] Read more.

Depression has gradually become the most common mental disorder in the world. The accuracy of its diagnosis may be affected by many factors, while the primary diagnosis seems to be difficult to define. Finding a way to identify depression by satisfying both objective and effective conditions is an urgent issue. In this paper, a strategy for predicting depression based on spatiotemporal features is proposed, and is expected to be used in the auxiliary diagnosis of depression. Firstly, electroencephalogram (EEG) signals were denoised through the filter to obtain the power spectra of the three corresponding frequency ranges, Theta, Alpha and Beta. Using orthogonal projection, the spatial positions of the electrodes were mapped to the brainpower spectrum, thereby obtaining three brain maps with spatial information. Then, the three brain maps were superimposed on a new brain map with frequency domain and spatial characteristics. A Convolutional Neural Network (CNN) and Gated Recurrent Unit (GRU) were applied to extract the sequential feature. The proposed strategy was validated with a public EEG dataset, achieving an accuracy of 89.63% and an accuracy of 88.56% with the private dataset. The network had less complexity with only six layers. The results show that our strategy is credible, less complex and useful in predicting depression using EEG signals. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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15 pages, 851 KiB

Open AccessArticle

Reduced Glx and GABA Inductions in the Anterior Cingulate Cortex and Caudate Nucleus Are Related to Impaired Control of Attention in Attention-Deficit/Hyperactivity Disorder

by Ping C. Mamiya, Todd L. Richards, Richard A. E. Edden, Adrian K. C. Lee, Mark A. Stein and Patricia K. Kuhl

Int. J. Mol. Sci. 2022, 23(9), 4677; https://doi.org/10.3390/ijms23094677 - 23 Apr 2022

Cited by 8 | Viewed by 3893

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that impairs the control of attention and behavioral inhibition in affected individuals. Recent genome-wide association findings have revealed an association between glutamate and GABA gene sets and ADHD symptoms. Consistently, people with ADHD show altered glutamate [...] Read more.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that impairs the control of attention and behavioral inhibition in affected individuals. Recent genome-wide association findings have revealed an association between glutamate and GABA gene sets and ADHD symptoms. Consistently, people with ADHD show altered glutamate and GABA content in the brain circuitry that is important for attention control function. Yet, it remains unknown how glutamate and GABA content in the attention control circuitry change when people are controlling their attention, and whether these changes can predict impaired attention control in people with ADHD. To study these questions, we recruited 18 adults with ADHD (31–51 years) and 16 adults without ADHD (28–54 years). We studied glutamate + glutamine (Glx) and GABA content in the fronto-striatal circuitry while participants performed attention control tasks. We found that Glx and GABA concentrations at rest did not differ between participants with ADHD or without ADHD. However, while participants were performing the attention control tasks, participants with ADHD showed smaller Glx and GABA increases than participants without ADHD. Notably, smaller GABA increases in participants with ADHD significantly predicted their poor task performance. Together, these findings provide the first demonstration showing that attention control deficits in people with ADHD may be related to insufficient responses of the GABAergic system in the fronto-striatal circuitry. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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22 pages, 1484 KiB

Open AccessSystematic Review

Raman Spectroscopy as a Neuromonitoring Tool in Traumatic Brain Injury: A Systematic Review and Clinical Perspectives

by Andrew R. Stevens, Clarissa A. Stickland, Georgia Harris, Zubair Ahmed, Pola Goldberg Oppenheimer, Antonio Belli and David J. Davies

Cells 2022, 11(7), 1227; https://doi.org/10.3390/cells11071227 - 5 Apr 2022

Cited by 13 | Viewed by 4395

Abstract

Traumatic brain injury (TBI) is a significant global health problem, for which no disease-modifying therapeutics are currently available to improve survival and outcomes. Current neuromonitoring modalities are unable to reflect the complex and changing pathophysiological processes of the acute changes that occur after [...] Read more.

Traumatic brain injury (TBI) is a significant global health problem, for which no disease-modifying therapeutics are currently available to improve survival and outcomes. Current neuromonitoring modalities are unable to reflect the complex and changing pathophysiological processes of the acute changes that occur after TBI. Raman spectroscopy (RS) is a powerful, label-free, optical tool which can provide detailed biochemical data in vivo. A systematic review of the literature is presented of available evidence for the use of RS in TBI. Seven research studies met the inclusion/exclusion criteria with all studies being performed in pre-clinical models. None of the studies reported the in vivo application of RS, with spectral acquisition performed ex vivo and one performed in vitro. Four further studies were included that related to the use of RS in analogous brain injury models, and a further five utilised RS in ex vivo biofluid studies for diagnosis or monitoring of TBI. RS is identified as a potential means to identify injury severity and metabolic dysfunction which may hold translational value. In relation to the available evidence, the translational potentials and barriers are discussed. This systematic review supports the further translational development of RS in TBI to fully ascertain its potential for enhancing patient care. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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21 pages, 33240 KiB

Open AccessArticle

Expression of Calbindin, a Marker of Gamma-Aminobutyric Acid Neurons, Is Reduced in the Amygdala of Oestrogen Receptor β-Deficient Female Mice

by Daniel Kalinowski, Krystyna Bogus-Nowakowska, Anna Kozłowska and Maciej Równiak

J. Clin. Med. 2022, 11(7), 1760; https://doi.org/10.3390/jcm11071760 - 22 Mar 2022

Cited by 6 | Viewed by 3895

Abstract

Oestrogen receptor β (ERβ) knock-out female mice display increased anxiety and decreased threshold for synaptic plasticity induction in the basolateral amygdala. This may suggest that the γ-aminobutyric acid (GABA) inhibitory system is altered. Therefore, the immunoreactivity of main GABAergic markers—i.e., calbindin, parvalbumin, calretinin, [...] Read more.

Oestrogen receptor β (ERβ) knock-out female mice display increased anxiety and decreased threshold for synaptic plasticity induction in the basolateral amygdala. This may suggest that the γ-aminobutyric acid (GABA) inhibitory system is altered. Therefore, the immunoreactivity of main GABAergic markers—i.e., calbindin, parvalbumin, calretinin, somatostatin, α1 subunit-containing GABA_A receptor and vesicular GABA transporter—were compared in the six subregions (LA, BL, BM, ME, CE and CO) of the amygdala of adult female wild-type and ERβ knock-out mice using immunohistochemistry and quantitative methods. The influence of ERβ knock-out on neuronal loss and glia was also elucidated using pan-neuronal and astrocyte markers. The results show severe neuronal deficits in all main amygdala regions in ERβ knock-out mice accompanied by astroglia overexpression only in the medial, basomedial and cortical nuclei and a decrease in calbindin-expressing neurons (CB+) in the amygdala in ERβ knock-out mice compared with controls, while other markers of the GABAergic system remain unchanged. Concluding, the lack of ERβ led to failure in the structural integrity of the CB+ subpopulation, reducing interneuron firing and resulting in a disinhibitory effect over pyramidal function. This fear-promoting excitatory/inhibitory alteration may lead to the increased anxiety observed in these mice. The impact of neuronal deficits and astroglia overexpression on the amygdala functions remains unknown. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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19 pages, 2571 KiB

Open AccessArticle

Krüppel-like Transcription Factor 7 Is a Causal Gene in Autism Development

by Hui Tian, Shupei Qiao, Yufang Zhao, Xiyun Jin, Cao Wang, Ruiqi Wang, Yilin Wang, Yanwen Jiao, Ying Liu, Bosong Zhang, Jiaming Jin, Yue Chen, Qinghua Jiang and Weiming Tian

Int. J. Mol. Sci. 2022, 23(6), 3376; https://doi.org/10.3390/ijms23063376 - 21 Mar 2022

Cited by 3 | Viewed by 3897

Abstract

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disease. To date, more than 1000 genes have been shown to be associated with ASD, and only a few of these genes account for more than 1% of autism cases. Klf7 is an important [...] Read more.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disease. To date, more than 1000 genes have been shown to be associated with ASD, and only a few of these genes account for more than 1% of autism cases. Klf7 is an important transcription factor of cell proliferation and differentiation in the nervous system, but whether klf7 is involved in autism is unclear. Methods: We first performed ChIP-seq analysis of klf7 in N2A cells, then performed behavioral tests and RNA-seq in klf7^+/− mice, and finally restored mice with adeno-associated virus (AAV)-mediated overexpression of klf7 in klf7^+/− mice. Results: Klf7 targeted genes are enriched with ASD genes, and 631 ASD risk genes are also differentially expressed in klf7^+/− mice which exhibited the core symptoms of ASD. When klf7 levels were increased in the central nervous system (CNS) in klf7^+/− adult mice, deficits in social interaction, repetitive behavior and majority of dysregulated ASD genes were rescued in the adults, suggesting transcriptional regulation. Moreover, knockdown of klf7 in human brain organoids caused dysregulation of 517 ASD risk genes, 344 of which were shared with klf7^+/− mice, including some high-confidence ASD genes. Conclusions: Our findings highlight a klf7 regulation of ASD genes and provide new insights into the pathogenesis of ASD and promising targets for further research on mechanisms and treatments. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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14 pages, 319 KiB

Open AccessReview

Stroke Genomics: Current Knowledge, Clinical Applications and Future Possibilities

by Sandeep Appunni, Muni Rubens, Venkataraghavan Ramamoorthy, Anshul Saxena, Peter McGranaghan and Emir Veledar

Brain Sci. 2022, 12(3), 302; https://doi.org/10.3390/brainsci12030302 - 23 Feb 2022

Cited by 7 | Viewed by 4980

Abstract

The pathophysiology of stoke involves many complex pathways and risk factors. Though there are several ongoing studies on stroke, treatment options are limited, and the prevalence of stroke is continuing to increase. Understanding the genomic variants and biological pathways associated with stroke could [...] Read more.

The pathophysiology of stoke involves many complex pathways and risk factors. Though there are several ongoing studies on stroke, treatment options are limited, and the prevalence of stroke is continuing to increase. Understanding the genomic variants and biological pathways associated with stroke could offer novel therapeutic alternatives in terms of drug targets and receptor modulations for newer treatment methods. It is challenging to identify individual causative mutations in a single gene because many alleles are responsible for minor effects. Therefore, multiple factorial analyses using single nucleotide polymorphisms (SNPs) could be used to gain new insight by identifying potential genetic risk factors. There are many studies, such as Genome-Wide Association Studies (GWAS) and Phenome-Wide Association Studies (PheWAS) which have identified numerous independent loci associated with stroke, which could be instrumental in developing newer drug targets and novel therapies. Additionally, using analytical techniques, such as meta-analysis and Mendelian randomization could help in evaluating stroke risk factors and determining treatment priorities. Combining SNPs into polygenic risk scores and lifestyle risk factors could detect stroke risk at a very young age and help in administering preventive interventions. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)

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