Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 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

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

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

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

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

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

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

(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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(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

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

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

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

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

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

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

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