https://www.explorationpub.com/Journals/ent Most Recent Articles : Exploration of Neuroprotective Therapy. en-us Tue, 26 May 2026 23:47:07 GMT https://www.explorationpub.com/Journals/ent/Article/1004106 Background: High-intensity training (HIT) increases walking speed for individuals with chronic stroke. Several recent studies have examined its application for those in the subacute phase following a stroke. This systematic review examines the application of HIT in the subacute phase following a stroke. Methods: A systematic search for studies that compared HIT (defined as 60–84% heart rate reserve or 77–93% heart rate maximum) to lower-intensity training, conventional physical therapy, placebo, or no intervention in adults 0–6 months post stroke. Randomized or quasi-randomized controlled trials, cohort studies, and case-controlled studies published in peer-reviewed journals in English were included. The primary outcome of interest was walking speed; the secondary outcome was walking endurance. Two independent evaluators performed literature selection, data extraction, and assessed study quality using the revised Cochrane risk-of-bias tool. Reporting followed PRISMA guidelines. Results: Of 1,642 studies initially retrieved, 10 studies with a total of 677 participants were included. All experimental groups showed an average positive change in self-selected walking speed (range: 0.20–0.56 m/s). HIT resulted in statistically significant improvements in walking speed versus comparison interventions in 4 studies. Eight studies that measured walking endurance found an average increase of 60 to 197 m following HIT. Discussion: HIT demonstrated superior outcomes in self-selected walking speed and walking endurance for individuals in the subacute phase post stroke, both immediately following intervention and at follow-up. These findings align with the clinical practice guideline (CPG) for chronic stroke patients. Further randomized clinical trials are needed to strengthen the evidence. Systematic Review Fri, 23 May 2025 00:00:00 GMT AlejandroOjeda-Manzano, Elsy ArlenePérez-Padilla, Sergio IvánSanguino-Suárez, ChristineCabelka, HumbertoSalgado, AlexandraBorstad, Fri, 23 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004106 https://www.explorationpub.com/Journals/ent/Article/10041 Not applicable. Editorial Mon, 25 Jan 2021 00:00:00 GMT RafaelFranco, Mon, 25 Jan 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/10041 https://www.explorationpub.com/Journals/ent/Article/10042 Not applicable. Letter to the Editor Tue, 20 Apr 2021 00:00:00 GMT PeterIlles, Tue, 20 Apr 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/10042 https://www.explorationpub.com/Journals/ent/Article/10043 The autism spectrum disorder (ASD) comprises a series of neurological diseases that share serious alterations of the development of the central nervous system. The degree of disability may vary so that Asperger’s may have a relatively normal life and get positions of responsibility in corporations and even in Governments, whereas other ASD sufferers are fully dependent on caregivers and have serious cognitive deficits. Although the first cases of autism were detected by looking at failures in metabolism, e.g., phenylketonuria, to later identify the faulty gene, today the trend is the opposite, first obtaining the exome and minimizing the look for altered parameters in blood, urine, etc. Cholesterol is key for neural development as it is not able to cross the blood brain barrier. Therefore, any gene or environmental factor that affects cholesterol synthesis will impact early developmental stages eventually leading to a disease within the autism spectrum and/or schizophrenia. This review provides data of the relevance of cholesterol dyshomeostasis in autism spectrum disorders. Determining biochemical parameters in body fluids should help to provide new therapeutic approaches in some cases of autism. Review Mon, 21 Jun 2021 00:00:00 GMT RafaelFranco, RafaelRivas-Santisteban, GemmaNavarro, IreneReyes-Resina, Mon, 21 Jun 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/10043 https://www.explorationpub.com/Journals/ent/Article/10044 Early in the course of infection, human immunodeficiency virus (HIV) is able to enter the central nervous system where it stablishes a permanent reservoir. Current antiretroviral therapies do not efficiently cross the blood-brain barrier and therefore do not reach the HIV located in the central nervous system. Consequently, HIV infection can often be associated with neurocognitive impairment and HIV-associated dementia. The purpose of this review is to brief the reader into the world of neurological complications arising from HIV infection. Mechanisms by which HIV directly or indirectly impairs the central nervous system are discussed, as well as other factors influencing or contributing to the impairment, and the animal models currently used to perform research on the topic. Review Wed, 30 Jun 2021 00:00:00 GMT Jose M.Martinez-Navio, Wed, 30 Jun 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/10044 https://www.explorationpub.com/Journals/ent/Article/10045 The pathogenic basis behind some of the most prevalent neurodegenerative diseases in advanced societies, known as proteinopathies, deals with alterations in protein homeostasis. Despite the broad diversity of clinical symptoms, they share a remarkably common feature that is the serious neuronal loss in several disease-specific brain regions due to the presence of toxic aggregations of misfolded proteins. So far, research efforts have been insufficient to decipher the exact molecular mechanisms that trigger the conformational change from a functional healthy protein to its pathological version. This is a sine qua non condition to progress in developing new approaches and treatments for these diseases for which there is no cure. Currently, it is well accepted that perturbations in gut microbiota composition negatively impact a wide range of brain processes via the gut-brain axis which increases host susceptibility to neurodegenerative disorders. In this context, modulate the microbial ecosystem colonizing the gastrointestinal tract may be a promising therapeutic approach in the management of proteinopathies. This review aims to provide an updated view of the role that gut microbiota poses in the pathogenesis of Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, the most common neurodegenerative proteinopathies, and of the possibility of translating this knowledge into effective and safe clinical microbiota-based interventions, especially those designed to afford neuroprotection. Review Wed, 28 Jul 2021 00:00:00 GMT PaulaAlonso-García, RebecaMartín, EvaMartínez-Pinilla, Wed, 28 Jul 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/10045 https://www.explorationpub.com/Journals/ent/Article/10046 Since the identification and cloning of the cannabinoid receptor 2 (CB2R), several studies focused on the characterization of its physiological and pathological role. Initially, CB2R was considered as the peripheral cannabinoid receptor due to its detection in the rat spleen and leukocyte subpopulation in humans. Later, CB2R was identified in different brain regions significantly modifying the landscape and pointing out its role in a wide variety of central physiological functions and pathological conditions. Additional research also detected the expression of CB2R in neurons, microglia, and astroglia in different brain regions. Indeed, the findings collected to date support a significant function of CB2R in anxiety, depression, schizophrenia, and additional neuropsychiatric disorders. This review gathers the most relevant literature regarding new advances about the role of CB2R in a variety of neuropsychiatric conditions, with special emphasis on its potential as a new therapeutic target for the treatment of different psychiatric disorders. Review Tue, 03 Aug 2021 00:00:00 GMT María S.García-Gutiérrez, FranciscoNavarrete, AniGasparyan, JorgeManzanares, Tue, 03 Aug 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/10046 https://www.explorationpub.com/Journals/ent/Article/10047 Current evidence indicates that neurodegeneration of dopaminergic neurons of the substantia nigra associated to Parkinson’s disease is a consequence of a neuroinflammatory process in which microglial cells play a central role. The initial activation of microglial cells is triggered by pathogenic protein inclusions, which are mainly composed by α-synuclein. Importantly, these pathogenic forms of α-synuclein subsequently induce a T-cell-mediated autoimmune response to dopaminergic neurons. Depending on their functional phenotype, these autoreactive T-cells might shape the functional features of activated microglia. T-cells bearing pro-inflammatory phenotypes such as T-helper (Th)1 or Th17 promote a chronic inflammatory behaviour on microglia, whilst anti-inflammatory T-cells, such as regulatory T-cells (Treg) favour the acquisition of neuroprotective features by microglia. Thus, T-cells play a fundamental role in the development of neuroinflammation and neurodegeneration involved in Parkinson’s disease. This review summarizes the evidence indicating that not only CD4+ T-cells, but also CD8+ T-cells play an important role in the physiopathology of Parkinson’s disease. Next, this review analyses the different T-cell epitopes derived from the pathogenic forms of α-synuclein involved in the autoimmune response associated to Parkinson’s disease in animal models and humans. It also summarizes the requirement of specific alleles of major histocompatibility complexes (MHC) class I and class II necessaries for the presentation of CD8+ and CD4+ T-cell epitopes from the pathogenic forms of α-synuclein in both humans and animal models. Finally, this work summarizes and discusses a number of experimental immunotherapies that aim to strengthen the Treg response or to dampen the inflammatory T-cell response as a therapeutic approach in animal models of Parkinson’s disease. Review Sun, 03 Oct 2021 00:00:00 GMT RodrigoPacheco, Sun, 03 Oct 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/10047 https://www.explorationpub.com/Journals/ent/Article/10049 Spinal cord injury (SCI) induces several destructive events that develop immediately after the primary insult. These phenomena increase tissue damage; that is why, numerous therapeutic approaches are studied in order to neutralize these destructive mechanisms. In line with this, several studies indicate that after injury, neural tissue could be protected by an adaptive immune response directed against self-antigens. Immunization with neural-derived peptides (INDP) reduces secondary degeneration of neurons after spinal cord insult and promotes a significant motor recovery. The combination of antioxidants or other immunomodulatory peptides after SCI can improve the protective effect induced by INDP. INDP in acute SCI is a promising strategy, so further studies should be addressed to be able to formulate the best strategy. Review Tue, 12 Oct 2021 00:00:00 GMT Andrea PaolaIbarra-García, AntonioIbarra, Tue, 12 Oct 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/10049 https://www.explorationpub.com/Journals/ent/Article/10048 Phosphoinositides are membrane phospholipids involved in a variety of cellular processes like growth, development, metabolism, and transport. This review focuses on the maintenance of cellular homeostasis of phosphatidylinositol 4,5-bisphosphate (PIP2), and phosphatidylinositol 3,4,5-trisphosphate (PIP3). The critical balance of these PIPs is crucial for regulation of neuronal form and function. The activity of PIP2 and PIP3 can be regulated through kinases, phosphatases, phospholipases and cholesterol microdomains. PIP2 and PIP3 carry out their functions either indirectly through their effectors activating integral signaling pathways, or through direct regulation of membrane channels, transporters, and cytoskeletal proteins. Any perturbations to the balance between PIP2 and PIP3 signaling result in neurodevelopmental and neurodegenerative disorders. This review will discuss the upstream modulators and downstream effectors of the PIP2 and PIP3 signaling, in the context of neuronal health and disease. Review Sat, 09 Oct 2021 00:00:00 GMT KamranTariq, Bryan W.Luikart, Sat, 09 Oct 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/10048 https://www.explorationpub.com/Journals/ent/Article/100410 Familial early-onset Alzheimer’s disease (AD) is more probable in individuals coming from mothers diagnosed with AD than from fathers diagnosed with AD. Studies in animal models have shown maternal imprinting due to the transmission to the embryo of altered material in the ovum. In the case of transgenic animals harboring a mutated form of the human amyloid precursor protein (APP), offspring from crosses with wild-type (WT) fathers and transgenic mothers display more abnormalities than offspring from crosses with transgenic fathers and WT mothers. Expression of the mutated APP in the ovum may lead to alterations that may be genetic and/or epigenetic in the nuclear and/or the mitochondrial DNA. These modifications that are transmitted to the new living beings affect more mitochondrial proteins and, therefore, the mitochondrial function may be affected in adulthood by trends present in the ovum. Perspective Fri, 29 Oct 2021 00:00:00 GMT AlbertoPérez-Mediavilla, MartaZamarbide, Fri, 29 Oct 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100410 https://www.explorationpub.com/Journals/ent/Article/100411 Peroxisomes are actively involved in the metabolism of various lipids including fatty acids, ether phospholipids, bile acids as well as the processing of reactive oxygen and nitrogen species. Recent studies show that peroxisomes can regulate cholesterol homeostasis by mediating cholesterol transport from the lysosomes to the endoplasmic reticulum and towards primary cilium as well. Disruptions of peroxisome biogenesis or functions lead to peroxisomal disorders that usually involve neurological deficits. Peroxisomal dysfunction is also linked to several neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In many peroxisomal disorders and neurodegenerative diseases, aberrant cholesterol accumulation is frequently encountered yet largely neglected. This review discusses the current understanding of the mechanisms by which peroxisomes facilitate cholesterol trafficking within the cell and the pathological conditions related to impaired cholesterol transport by peroxisomes, with the hope to inspire future development of the treatments for peroxisomal disorders and neurodegenerative diseases. Review Tue, 07 Dec 2021 00:00:00 GMT JianXiao, Bao-LiangSong, JieLuo, Tue, 07 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100411 https://www.explorationpub.com/Journals/ent/Article/100412 Niemann-Pick C disease is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation, and the early non-specific symptoms. The discovery of disease-specific biomarkers—cholestane-3β,5α,6β-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine [PPCS, initially referred to as lysosphingomyelin-509 (lysoSM-509)]—has led to development of non-invasive, blood-based diagnostics. Dissemination of these rapid, sensitive, and specific clinical assays has accelerated diagnosis. Moreover, the superior receiver operating characteristic of the TCG bile acid biomarker and its detection in dried blood spots has also facilitated development of a newborn screen for NPC, which is currently being piloted in New York state. The C-triol, TCG and PPCS biomarkers have also been proved useful for monitoring treatment response in peripheral tissues, but are uninformative with respect to treatment efficacy in the central nervous system (CNS). A major gap for the field is the lack of a validated, non-invasive biomarker to monitor the course of disease and CNS response to therapy. Review Thu, 09 Dec 2021 00:00:00 GMT XuntianJiang, Daniel S.Ory, Thu, 09 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100412 https://www.explorationpub.com/Journals/ent/Article/100413 The brain cholesterol content is determined by the balance between the pathways of in situ biosynthesis and cholesterol elimination via 24-hydroxylation catalyzed by cytochrome P450 46A1 (CYP46A1). Both pathways are tightly coupled and determine the rate of brain cholesterol turnover. Evidence is accumulating that modulation of CYP46A1 activity by gene therapy or pharmacologic means could be beneficial in the case of neurodegenerative and other brain diseases and affect brain processes other than cholesterol biosynthesis and elimination. This minireview summarizes these other processes, most common of which include abnormal protein accumulation, memory, and cognition, motor behavior, gene transcription, protein phosphorylation as well as autophagy and lysosomal processing. The unifying mechanisms, by which these processes could be affected by CYP46A targeting are also discussed. Review Fri, 17 Dec 2021 00:00:00 GMT Irina A.Pikuleva, Fri, 17 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100413 https://www.explorationpub.com/Journals/ent/Article/100414 Cholesterol serves as an essential lipid molecule in various membrane organelles of mammalian cells. The metabolites of cholesterol also play important functions. Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), also named as sterol O-acyltransferase 1, is a membrane-bound enzyme residing at the endoplasmic reticulum (ER). It converts cholesterol to cholesteryl esters (CEs) for storage, and is expressed in all cells. CEs cannot partition in membranes; they can only coalesce as cytosolic lipid droplets. Excess CEs are found in the vulnerable region of the brains of patients with late-onset Alzheimer’s disease (AD), and in cell and mouse models for AD. Reducing CE contents by genetic inactivation of ACAT1, or by pharmacological inhibition of ACAT is shown to reduce amyloidopathy and other hallmarks for AD. To account for the various beneficial actions of the ACAT1 blockade (A1B), a working hypothesis is proposed here: the increase in CE contents observed in the AD brain is caused by damages of cholesterol-rich lipid rafts that are known to occur in neurons affected by AD. These damages cause cholesterol to release from lipid rafts and move to the ER where it will be converted to CEs by ACAT1. In addition, the increase in CE contents may also be caused by overloading with cholesterol-rich substances, or through activation of ACAT1 gene expression by various pro-inflammatory agents. Both scenarios may occur in microglia of the chronically inflamed brain. A1B ameliorates AD by diverting the cholesterol pool destined for CE biosynthesis such that it can be utilized more efficiently to repair membrane damage in various organelles, and to exert regulatory actions more effectively to defend against AD. To test the validity of the A1B hypothesis in cell culture and in vivo, the current status of various anti-ACAT1 agents that could be further developed is briefly discussed. Review Thu, 30 Dec 2021 00:00:00 GMT Ta YuanChang, Catherine C. Y.Chang, Taylor C.Harned, Adrianna L.De La Torre, JunghoonLee, Thao N.Huynh, James G.Gow, Thu, 30 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100414 https://www.explorationpub.com/Journals/ent/Article/100415 The cholesterol is a vital component of cell membranes and myelin sheaths, and a precursor for essential molecules such as steroid hormones. In humans, cholesterol is partially obtained through the diet, while the majority is synthesized in the body, primarily in the liver. However, the limited exchange between the central nervous system and peripheral circulation, due to the presence of the blood-brain barrier, necessitates cholesterol in the brain to be exclusively acquired from local de novo synthesis. This cholesterol is reutilized efficiently, rendering a much slower overall turnover of the compound in the brain as compared with the periphery. Furthermore, brain cholesterol is regulated independently from peripheral cholesterol. Numerous enzymes, proteins, and other factors are involved in cholesterol synthesis and metabolism in the brain. Understanding the unique mechanisms and pathways involved in the maintenance of cholesterol homeostasis in the brain is critical, considering perturbations to these processes are implicated in numerous neurodegenerative diseases. This review focuses on the developing understanding of cholesterol metabolism in the brain, discussing the sites and processes involved in its synthesis and regulation, as well as the mechanisms involved in its distribution throughout, and elimination from, the brain. Review Thu, 06 Jan 2022 00:00:00 GMT LydiaQian, Amanda B.Chai, Ingrid C.Gelissen, Andrew J.Brown, Thu, 06 Jan 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100415 https://www.explorationpub.com/Journals/ent/Article/100416 Stroke causes acute neurological deficit which is an important cause of morbidity and mortality. Neurorehabilitation is an important dimension in the management of post-stroke deficits. Spasticity, pain, and neurological deficits are contributors to post-stroke disability. Dry needling (DN) is a technique commonly used in the management of myofascial pain. Recent evidence suggests its efficacy in the management of post-stroke disability. The descriptive review on the use of DN summarises the evidence for the management of post-stroke patients such as spasticity, balance, pain, functional outcome, tremor, and ultrasonographic evidence. The filiform needle is inserted into the target muscle until a local twitch response is obtained. The effects of DN are produced by the local stretch of the spastic muscle and afferent modulation of the reflex arc that decreases the excitability of the alpha motor neuron. The DN reduces muscle spasticity in post-stroke patients. The improved spasticity is translated to better functional outcomes and balance. The procedure is also shown to reduce pain including post-stroke shoulder pain. It is also shown to improve tremors in post-stroke patients. Ultrasonographic evidence of the beneficial effects of DN shows improved measures in the pennate angle and mean muscle thickness. Concurrent use of DN and electrical stimulation improve spasticity, the effect which may be seen for longer periods. DN is emerging as a useful and cost-effective technique in the management of post-stroke patients. The evidence for the use of DN in the management of post-stroke spasticity is high. However, more research is required to assess its efficacy in functional outcomes and other aspects of the stroke. Review Thu, 17 Feb 2022 00:00:00 GMT NirmalSurya, GuhanRamamurthy, Thu, 17 Feb 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100416 https://www.explorationpub.com/Journals/ent/Article/100417 Aim: Excitotoxicity results from unusually increased activation of excitatory amino acid receptors leading to neuronal death. Since glutamate is the main excitatory neurotransmitter in the central nervous system, it is also the most common excitotoxicity trigger. This uncontrolled neuronal response participates in various neurodegenerative diseases, such as ischemia, hypoglycemia, Huntington’s, Parkinson’s and Alzheimer’s disease. Thus, the investigation in the field expanded a lot in the past decade, leading to in vitro modelling adaptations. However, much performed work on glutamate-induced excitotoxicity is methodologically inconsistent in the literature. The field lacks reproducibility, which is one of the main fundaments of empirical science. In this regard, the literature was summarized and the main methodological features were critically evaluated, aiming to guide the researchers that are starting in the field. Methods: Published data since 1985 from PUBMED were collected and analyzed to observe which in vitro experimental conditions of excitotoxicity were reproducible. The suggested methods were based on the characteristics of excitotoxicity, such as abnormal intracellular calcium mediated signaling, mitochondria impairment, reactive oxygen species accumulation and cell death. Various conditions and comparative controls were used to design the standard investigation of excitotoxicity, such as culture medium content (presence of glutamate and aspartate), time interval of induction and the concentration of the inductor, based on the most reproducible published ones. Results: Our results and critical analysis point to some experimental conditions to consider, such as primary cultured neurons are more sensitive to glutamate and the response obtained is more robust than in other models; excitotoxicity mediated effects are better observed one hour following the stimulus; the culture medium should contain low levels of glutamate or aspartate or glycine. Online available phosphoproteomic data on excitotoxicity using the primary cortical neurons in vitro model supported the same conditions proposed by us. Conclusions: This manuscript will facilitate the design of any research for excitotoxic or neuroprotective compounds in physiological and pathophysiological conditions by standardizing and improving experimental conditions. Systematic Review Wed, 23 Feb 2022 00:00:00 GMT TalitaGlaser, Jean BezerraSilva, Guilherme A.Juvenal, Pedro NegrãoMaiolini, NataliaTurrini, Lyvia LintzmaierPetiz, Lucas BonfimMarques, Deidiane ElisaRibeiro, QingYe, YongTang, HenningUlrich, Wed, 23 Feb 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100417 https://www.explorationpub.com/Journals/ent/Article/100418 Subarachnoid hemorrhage (SAH) has deleterious outcomes for patients, and during the hospital stay, patients are susceptible to vasospasm and delayed cerebral ischemia. Coronavirus disease 2019 (COVID-19) has been shown to worsen hypertension through angiotensin-converting enzyme 2 (ACE2) activity, therefore, predisposing to aneurysm rupture. The classic renin-angiotensin pathway activation also predisposes to vasospasm and subsequent delayed cerebral ischemia. Matrix metalloproteinase 9 upregulation can lead to an inflammatory surge, which worsens outcomes for patients. SAH patients with COVID-19 are more susceptible to ventilator-associated pneumonia, reversible cerebral vasoconstriction syndrome, and respiratory distress. Emerging treatments are warranted to target key components of the anti-inflammatory cascade. The aim of this review is to explore how the COVID-19 virus and the intensive care unit (ICU) treatment of severe COVID can contribute to SAH. Graphical abstract. Broad effects of COVID-19 on inducing SAH. Created with BioRender.com. RBC: red blood cell; MMP-9: matrix metalloproteinase 9 Review Wed, 02 Mar 2022 00:00:00 GMT Eric J.Panther, BrandonLucke-Wold, Wed, 02 Mar 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100418 https://www.explorationpub.com/Journals/ent/Article/1004116 Aim: Post-exertional malaise (PEM) has been a challenging construct to measure, particularly with self-report instruments, which have the benefits of being less expensive and less invasive than cardiopulmonary exercise tests. Existing PEM questionnaires have often been used for diagnostic purposes and less frequently as outcome measures. Few self-report PEM measures address comprehensive PEM domains, including types of triggers, duration of symptoms, delayed symptom onset, number of symptoms, frequency and severity of symptoms, as well as whether pacing or other strategies reduce or eliminate PEM. Without characterizing these features, salient aspects of PEM would be overlooked. However, efforts to assess all these domains can be time-consuming and potentially burdensome. Methods: The current study offers investigators a brief but comprehensive instrument of critical PEM domains, called the DePaul Symptom Questionnaire (DSQ)-PEM-2, to assess PEM. Validation data were derived from a large sample of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Results: The DSQ-PEM-2 was developed using an existing dataset of individuals with ME, CFS, or both ME and CFS, allowing comprehensive coverage of key PEM domains. Conclusions: The DSQ-PEM-2 can be used either for diagnostic purposes or as an outcome measure. The instrument’s time frames for symptom manifestation can be adapted to suit a variety of research or clinical contexts. Future validation studies need to include a healthy control group. Original Article Wed, 15 Oct 2025 00:00:00 GMT Leonard A.Jason, Kelly J.Chee, Wed, 15 Oct 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004116 https://www.explorationpub.com/Journals/ent/Article/100419 Altered immunity may have destructive consequences for the integrated central nervous system. This immune response often affects progressive neurodegenerative diseases such as Parkinson’s disease and/or psychiatric disorders such as schizophrenia. In particular, schizophrenia pathogenesis may be mediated by multiple neuro-immune interaction pathways. Gut microbiota might affect the brain and/or immune function. Significant machineries of immunity are commonly affected by the commensal gut microbiota. Therefore, schizophrenia may be connected with the gut-immune system. In addition, the brain and immune systems cooperate on multiple levels. The brain could save several pieces of information about specific inflammation in a body. This immunological memory named “engrams”, also called memory traces, could restore the initial disease state, which may help to explain key features of schizophrenia. Based on this concept, therapeutic strategies for schizophrenia could be the modification of the gut microbiota. Probiotics and/or fecal microbiota transplantation are now emerging as the most promising treatments for the modification. More consideration of the roles of gut microbiota will conduct the further development of immune-based therapeutics for the prevention and/or treatments of psychiatric disorders. Perspective Mon, 25 Apr 2022 00:00:00 GMT HarukaSawamura, KurumiTaniguchi, YukaIkeda, AiTsuji, YasukoKitagishi, SatoruMatsuda, Mon, 25 Apr 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100419 https://www.explorationpub.com/Journals/ent/Article/100420 Several studies investigated the side effect of adjuvant cancer treatments, and different types of preventive techniques or treatments have been assessed. Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurological side effect. Exercise training has been widely studied as an adjuvant therapy to prevent CIPN and improve post-chemotherapy functional outcome and quality of life (QoL). This narrative review aims to summarize the data obtained from the latest studies about physical activity (PA) for the prevention and treatment of CIPN and associated QoL measures. Literature research was conducted to obtain studies including PA interventions for patients with CIPN. Ten studies met inclusion criteria and were therefore summarized and discussed, focusing on exercise type and functional outcome. It seems clear that, regardless of the type of exercise, PA plays a positive role in the treatment of CIPN, providing a significant symptom improvement. There has been no standardization of type, quantity, and intensity of PA administered to the subjects in the various studies probably due to a physiological difference between samples, grade of neuropathy, and difference among therapies. Review Thu, 28 Apr 2022 00:00:00 GMT DanieleDiotti, LucaPuce, LauraMori, CarloTrompetto, ElenaSaretti, CeciliaContenti, LucioMarinelli, Thu, 28 Apr 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100420 https://www.explorationpub.com/Journals/ent/Article/100421 Aim: Spasticity is one of the most common symptoms in post-stroke patients. Dry needling (DN) is a relatively new method for the management of muscle spasticity. A multimodal treatment may be more effective in spasticity management. The purpose of this study was to explore the short-term combined effects of DN and exercise therapy on wrist flexor spasticity, motor function, and motor neuron excitability in patients with chronic stroke. Methods: Ten patients with stroke and a mean age of 52 ± 4.9 years participated in this pretest-posttest pilot study. Patients received four sessions of DN and exercise therapy. Affected flexor carpi radialis and flexor carpi ulnaris muscles were needled each for 1 min. Patients underwent exercise therapy for about 30 min, once a week after DN. The outcome measures were the Modified Modified Ashworth Scale (MMAS), the maximal amplitude of H wave/maximal amplitude of M wave ratio (Hmax/Mmax Ratio), H-reflex latency, wrist extension active and passive range of motion (ROM), Action Research Arm Test (ARAT), and Fugl-Meyer Assessment (FMA). Assessments were performed at baseline, after four sessions of treatment, and three weeks after treatment. Results: After treatment, significant improvements in MMAS, wrist passive ROM, ARAT, and FMA were obtained (P ≤ 0.05). Conclusions: DN combined with exercise therapy improved muscle spasticity and motor function in patients with chronic stroke. Further investigations with a randomized controlled trial design with a comparator group of DN only are warranted (https://www.irct.ir/ identifier: IRCT20180611040061N1). Original Article Mon, 20 Jun 2022 00:00:00 GMT Seyedeh SaeidehBabazadeh-Zavieh, Noureddin NakhostinAnsari, NastaranGhotbi, SoofiaNaghdi, Seyed Mohammad JafarHaeri, MohammadrezaKhanmohammadi, KoroshMansoori, Mon, 20 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100421 https://www.explorationpub.com/Journals/ent/Article/100422 The glymphatic system, first described in 2012, is a brain-wide perivascular network that plays an important role in promoting interstitial metabolic waste removal from the brain. Glymphatic pathway function has been reported to be dramatically diminished in the aging brain. Furthermore, glymphatic system dysfunction has been linked to a spectrum of neurodegenerative diseases including Alzheimer’s disease (AD). This waste clearance pathway of the brain is most active during sleep and is largely disengaged during wakefulness. While norepinephrine (NE) is responsible for suppressing the glymphatic function, electroencephalographic slow-wave (delta) activity has a facilitating effect. An intriguing question is whether these regulators of glymphatic activity can be modulated by meditation-based approaches and whether such approaches have the ability to increase glymphatic function in the awake brain. The present article hypothesizes that meditation-based approaches, such as immersive sound meditation, may have the potential to enhance glymphatic pathway transport and solute clearance by reducing NE and increasing slow-wave activity. If confirmed, meditation could be an attractive approach to promoting healthy brain aging and to preventing neurodegenerative conditions like AD. Perspective Tue, 21 Jun 2022 00:00:00 GMT PeterWostyn, PietGoddaer, Tue, 21 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100422 https://www.explorationpub.com/Journals/ent/Article/100423 The glymphatic system, or glial-lymphatic system, is a waste clearance system composed of perivascular channels formed by astrocytes that mediate the clearance of proteins and metabolites from the brain. These channels facilitate the movement of cerebrospinal fluid throughout brain parenchyma and are critical for homeostasis. Disruption of the glymphatic system leads to an accumulation of these waste products as well as increased interstitial fluid in the brain. These phenomena are also seen during and after subarachnoid hemorrhages (SAH), contributing to the brain damage seen after rupture of a major blood vessel. Herein this review provides an overview of the glymphatic system, its disruption during SAH, and its function in recovery following SAH. The review also outlines drugs which target the glymphatic system and may have therapeutic applications following SAH. Review Tue, 21 Jun 2022 00:00:00 GMT StephanQuintin, ArnavBarpujari, YusufMehkri, JairoHernandez, BrandonLucke-Wold, Tue, 21 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100423 https://www.explorationpub.com/Journals/ent/Article/100424 Stroke is one of the most common causes of disability and exerts a high burden of direct and indirect costs. Stroke may cause spasticity, which limits patients’ abilities and affects their activities of daily living, decreasing their quality of life. Conventional treatments are based on physical therapy, anti-spasticity medication, and botulinum toxin type A (BTX-A). However, recently, non-pharmacological approaches have been used, such as dry needling (DN) of myofascial trigger points. BTX-A and DN are two treatments that aim to decrease spasticity in patients with stroke, but their mode of action, application, and costs differ. Thus, there is a need to determine the comparative economics of post-stroke spasticity treatments. For this purpose, a search for all types of cost-effectiveness studies (randomized controlled trials, matched controls, and cohorts) and models of epidemiological data was performed. Studies were selected if they included economic outcomes in stroke patients treated with BTX-A or DN. As a result, 7 studies of BTX-A and 2 of DN were selected. Similarities were found in the outcomes used to assess the effectiveness of both treatments in most studies, with modifications of the Ashworth Scale [Modified Ashworth Scale (MAS)/Modified Modified Ashworth Scale (MMAS)] and quality-adjusted life year (QALY) being the main indicators of effectiveness. However, both the duration of the studies and the evaluation of costs were highly heterogeneous, making comparison difficult. In conclusion, both BTX-A and DN are cost-effective to treat spasticity in patients with stroke, but there is a need for comparative studies to make direct comparisons of cost-effectiveness with the most frequently used outcomes such as the MMAS and QALYs. Review Thu, 30 Jun 2022 00:00:00 GMT DanielFernández, ClaraPujol, CarmenRuber, SandraCalvo, Mindy F.Levin, PabloHerrero, Eva MaríaGómez-Trullén, Thu, 30 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100424 https://www.explorationpub.com/Journals/ent/Article/100425 Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders (NDD) characterized by deficits in three domains: impairments in social interactions, language, and communication, and increased stereotyped restrictive/repetitive behaviors and interests. The exact etiology of ASD remains unknown. Genetics, gestational exposure to inflammation, and environmental stressors, which combine to affect mitochondrial dysfunction and metabolism, are implicated yet poorly understood contributors and incompletely delineated pathways toward the relative risk of ASD. Many studies have shown a clear male bias in the incidence of ASD and other NDD. In other words, being male is a significant yet poorly understood risk factor for the development of NDD. This review discusses the link between these factors by looking at the current body of evidence. Understanding the link between the multiplicity of hits—from genes to environmental stressors and possible sexual determinants, contributing to autism susceptibility is critical to developing targeted interventions to mitigate these risks. Review Thu, 11 Aug 2022 00:00:00 GMT SarahOtaru, David A.Lawrence, Thu, 11 Aug 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100425 https://www.explorationpub.com/Journals/ent/Article/100426 Delayed cerebral ischemia after subarachnoid hemorrhage is one of the most important causes of mortality and poor functional outcome in patients. Initially, the etiology and treatment of delayed cerebral ischemia focused primarily on cerebral vasospasm. However, recent studies have detected that depolarization, microcirculation, and autoregulation disorder, which spreads together with cerebral vasospasm, also play a role in the etiology. The main treatment strategies in the prevention and treatment of delayed cerebral ischemia are the regulation of blood pressure and the use of calcium channel blockers, especially nimodipine. The main step in the early diagnosis and treatment of the disease is to monitor the neurological clinical status. In addition to transcranial Doppler ultrasonography, computed tomography, or magnetic resonance imaging angiography, continuous electroencephalography and invasive brain multimodal examination may be required in the follow-up period of the disease. In addition to blood pressure regulation, optimization of cardiac output, endovascular interventions, angioplasty, and/or intra-arterial vasodilator infusion are other treatment methods. This review aimed to evaluate delayed cerebral ischemia, one of the most important complications of subarachnoid hemorrhage, in the light of current literature. Review Tue, 23 Aug 2022 00:00:00 GMT FettahEren, Aydin TalipYildogan, AysegulDemir, CihatOzguncu, Sueda EcemYilmaz, Tue, 23 Aug 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100426 https://www.explorationpub.com/Journals/ent/Article/100427 The global prevalence of intracranial aneurysms (IA) ranges from 5–10%, with a demographic variation. Large and giant aneurysms typically involve cavernous and paraclinoid segments of the internal carotid artery (ICA), and represent 5% of IA. Typically, these lesions involve segments of the ICA, especially the cavernous and paraclinoid segments. The remaining cases affect the vertebrobasilar region, middle cerebral artery (MCA), and anterior cerebral artery (ACA). From the morphological point of view, they are divided into saccular and fusiform. In cases of rupture, the subarachnoid hemorrhage (SAH) is the most common presentation followed by intracerebral hemorrhage (ICH), or both. Other manifestations can occur as occlusion of perforating vessels, embolic events, seizures, and mass effects. The management of unruptured intracranial aneurysms (UIA) is controversial, and the aim of treatment is to exclude the lesions and preserve neurological function. Endovascular techniques for the treatment of paraclinoid aneurysms, in particular, ICA reconstruction using flow-diverting stents, have become a valid option. However, surgery or endovascular treatment has a number of limitations and the choice of treatment is individual in each case. This type of lesion has an extremely poor natural history, and treatment is a challenge regardless of the technique used. The report described a clinical case of a 55-year-old female, with a personal history of hypertension, hyperthyroidism, and depressive syndrome. The patient started complaints of moderate-intensity right frontal headache, progressively worsening with two months of evolution. She also reported blurred vision and diplopia. Brain computed tomography (CT) documented a partially calcified sellar and parasellar lesion. Subsequently, magnetic resonance imaging (MRI)/MRI angiographies were performed and showed a saccular aneurysm of the right ICA, cavernous segment. The patient underwent a diagnostic and therapeutic angiography with stent placement. Clinical and imaging improvements were documented by angiography and MRI angiography with progressive reduction of the aneurysm during the period of follow-up. Case Report Tue, 30 Aug 2022 00:00:00 GMT GonçaloJanuário, Tue, 30 Aug 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100427 https://www.explorationpub.com/Journals/ent/Article/100428 Different stressors can elicit neuroinflammatory responses modulated by innate immunity receptors, such as the family of Toll-like receptors (TLRs). The TLR4, a pattern recognition receptor (PRR), is involved in many diseases, such as inflammatory and central nervous system (CNS) diseases. Stress exposure can regulate the expression of PRRs, including TLR4, in the brain of animals, especially in the hippocampus and prefrontal cortex. Moreover, TLR4 modulates behavior and neuroinflammatory responses in the brain. In addition, to TLR4, the endocannabinoid (eCB) system plays a role in stress response and immunity, acting as a regulatory, stress-buffer system. This system is involved in many TLRs-mediated immune responses, such as microglia activation. Therefore, pharmacological approaches targeting the eCB system could modulate neuroinflammatory responses to stress by interfering with the TLR4 pathway. Although the connection between TLR4, stress, and neuroinflammation is well documented, almost no pre-clinical studies investigate the possible direct relationship between TLR4, behavior, stress, and the eCB system. Studies exploring the relationship between stress, neuroinflammation, TLR4, and the eCB system were searched using Pubmed, Web of Science, and Embase databases. Based on this search, this review is focused on the involvement of TLR4 receptors and signaling in neuroinflammation and the behavioral consequences of stress exposure. Moreover, evidence of the eCB system modulating TLR4-mediated responses was brought to the attention, pointing out a possible regulatory role of these responses by eCBs in behavior changes related to mood disorders. Review Mon, 31 Oct 2022 00:00:00 GMT Fábio José CoelhoSouza-Junior, Laura ColeteCunha, Sabrina FrancescaLisboa, Mon, 31 Oct 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100428 https://www.explorationpub.com/Journals/ent/Article/100429 Myasthenia gravis (MG) is a rare auto-immune neuromuscular junction (NMJ) disorder which is caused by formation of autoantibodies and destruction of NMJ components. The MG diagnosis is based on the symptoms, autoantibodies detection and paraclinical tests. Given that MG patients have so many differential diagnosis and various medication responses, choosing an accurate diagnosis and the therapy plan in MG is challenging. According to the studies, there are the immunologic, genetic, microRNAs, gut microbiome, and other established or newly proposed biomarkers for diagnosis and prognosis of MG. More studies are needed to provide better collection of biomarkers in MG patients and evaluate their role in MG pathology. Review Tue, 01 Nov 2022 00:00:00 GMT FatemehAfrashteh, RayanRajabi, Tue, 01 Nov 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100429 https://www.explorationpub.com/Journals/ent/Article/100430 Neuropathic pain (NP), which is difficult to treat, remains a heavy burden for both individuals and society. The efficacy of current treatments is insufficient. The pathophysiology of NP is still not fully elucidated, and there is a need to explore new therapeutic targets to develop more effective treatment strategies. Recent studies showed that thrombospondin 4 (TSP4) protein expression is increased in the spinal cord following nervous system injury and that blocking or inhibiting this increase improves NP. In this review, it has been aimed to present the evidence for the role of TSP4 in the mechanisms of NP development and to evaluate the therapeutic potential of TSP4 blockade in the treatment of NP. Graphical abstract.The relationship between TSP4 protein level in the spinal cord and behavioral hypersensitivity in rodents. This illustration has been created to collectively reflect the results of experimental animal studies investigating the relationship between the TSP4 levels in the spinal cord and NP. For more detailed information on related studies, please see the “Evidence of the relationship between TSP4 and NP” section of the article and tables Review Tue, 01 Nov 2022 00:00:00 GMT NeslihanDüzenli, CenkCan, AytülÖnal, Tue, 01 Nov 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100430 https://www.explorationpub.com/Journals/ent/Article/100431 The patient was a 6-year-old child with spastic quadriplegic cerebral palsy (CP) categorized with the gross motor function classification system (GMFCS) as a level IV and a Modified Modified Ashworth Scale (MMAS) of 2 for the bilateral hamstring and hip adductor muscles, and 3 for the bilateral gastrocnemius muscles. This patient’s limited range of motion significantly affected the caregiver’s ability to perform activities of daily living (ADLs). Dry needling (DN) is considered a standard treatment (TX) when treating adults with poor range of motion. This article aims to place intramuscular electrical stimulation (IMES), the delivery of an electrical current through a monofilament needle into targeted trigger points (TrPs) within the context of treating children with spastic CP. Following IMES TXs over 32 months that totaled 12 left hamstring TXs, 13 right hamstring TXs, 13 hip adductor TXs, 21 left gastrocnemius TXs, and 18 right gastrocnemius TXs, the patient demonstrated an increase in passive range of motion (PROM) of the hamstring, hip adductors, and gastrocnemius muscles. These gains equated to ease in ADLs. Both the Pediatric Evaluation of Disability Inventory (PEDI, PEDI-Caregiver Assistance Scale) and the Goal Attainment Scale (GAS) demonstrated decreased caregiver burden. The child’s GMFCS level and the MMAS did not change. Further data collection related to treating children with spasticity using IMES is indicated to validate this type of TX with this patient population. Case Report Wed, 16 Nov 2022 00:00:00 GMT TemrahOkonski, JanDommerholt, Wed, 16 Nov 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100431 https://www.explorationpub.com/Journals/ent/Article/100432 Catatonia is a neuropsychiatric syndrome characterized by a broad range of motor, behavioral and cognitive abnormalities. Catatonia and Parkinson’s disease (PD) may show partially overlapping symptomatology. For this reason, catatonia could be misdiagnosed and overlooked in patients with severe PD, leading to a delay in proper treatment with benzodiazepines or electroconvulsive therapy (ECT). Two cases of women with PD and catatonia who have been admitted and treated with ECT at the University Hospital of Pisa are described here. Both had a history of bipolar disorder and developed withdrawn catatonia, in the context of affective episodes, approximately one year after the diagnosis of PD. In both cases, ECT was needed and successfully led to the remission of catatonic symptoms, without cognitive worsening. Since ECT appears to effectively treat catatonia in patients with PD, clinicians should consider it as a therapeutic option. Case Report Wed, 28 Dec 2022 00:00:00 GMT CamillaElefante, Giulio E.Brancati, BeniaminoTripodi, SamueleTorrigiani, LorenzoLattanzi, PierpaoloMedda, GiulioPerugi, Wed, 28 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100432 https://www.explorationpub.com/Journals/ent/Article/100433 Small fiber neuropathy (SFN) is a relatively common, but largely understudied neurological syndrome which has affected the lives of many globally. The common symptoms of SFN include pain, dysesthesia, and autonomic dysfunction, which are caused by damage to small nerve fibers. Due to its heterogeneous nature, SFN causes a multitude of symptoms which makes the disease and its subtypes difficult to diagnose. Furthermore, as the pathophysiology of SFN remains largely enigmatic, no cause is found in around 50% of the cases and these are classified as idiopathic SFN (iSFN). The difficult task of diagnosing SFN, and the even more elusive feat of hunting for the underlying etiology, demands accurate, precise, preferably noninvasive, and affordable tools, or a combination of them. Accordingly, appropriate biomarkers for SFN are needed to stratify patients and develop cause-centered treatments in addition to symptomatic treatments. As peripheral axons grow and repair, identifying underlying causes of SFN and intervening early may spur axonal regeneration in young patients, which can greatly improve their symptoms and improve quality of life. This narrative review aims to objectively highlight functional, histological, and molecular biomarkers to aid clinicians in discerning the diagnostic tests they should use to diagnose, confirm and determine the etiology of SFN. The strengths and limitations of each potential biomarker will be discussed. Clearer diagnostic criteria, guidelines, and work-up for SFN are required for clinicians to better identify the disease in patients presenting with non-specific symptoms. Review Fri, 30 Dec 2022 00:00:00 GMT Amanda C. Y.Chan, KathleenOng, Jonathan J. Y.Ong, Vijay K.Sharma, Hiu YiWong, JoyVijayan, Fri, 30 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100433 https://www.explorationpub.com/Journals/ent/Article/100434 More than 600 different neurological diseases affect the human population. Some of these are genetic and can emerge even before birth, and some are caused by defects, infections, trauma, degeneration, inflammation, and cancer. However, they all share disabilities caused by damage to the nervous system. In the last decades, the burden of almost all neurological disorders has increased in terms of absolute incidence, prevalence, and mortality, largely due to the population’s growth and aging. This represents a dangerous trend and should become our priority for the future. But what new goals are we going to set and reach now, and how will we exploit thought-provoking technological skills for making these goals feasible? Machine learning can be at the root of the problem. Indeed, most recently, there has been a push towards medical data analysis by machine learning, and a great improvement in the training capabilities particularly of artificial deep neural networks (DNNs) inspired by the biological neural networks characterizing the human brain. This has generated competitive results for applications such as biomolecular target and protein structure prediction, structure-based rational drug design, and repurposing, all exerting a major impact on neuroscience and human well-being. By approaching early risks for diseases, non-invasive diagnosis, personalized treatment assessment, drug discovery, and automated science, the machine learning arena has thus the potential of becoming the new frontier for empowering neuroscience research and clinical practice in the years ahead. Perspective Tue, 21 Feb 2023 00:00:00 GMT CinziaVolonté, Tue, 21 Feb 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100434 https://www.explorationpub.com/Journals/ent/Article/100435 There is no approved drug capable of halting the progression of the most prevalent neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD). Current therapeutic strategies focus mainly on the inhibition of the formation of protein aggregates and their deposition in the central nervous system. However, after almost a hundred years, proper management of the disease is still lacking. The fact of not finding effective management tools in the various clinical trials already carried out suggests that new hypotheses and strategies should be explored. Although vast resources have been allocated to the investigation of protein aggregates and the pathophysiology is now better understood, clues to the actual etiology are lacking. It is well known that brain homeostasis is of paramount importance for the survival of neurons. Drugs that target the periphery are often not subject to evaluation for their potential effect on the central nervous system. While acute treatments may be irrelevant, pills used for chronic conditions can be detrimental to neurons, especially in terms of progressive damage leading to a long-term decline in neuronal survival. Due to the lack of advances in the search for a curative treatment for neurodegenerative diseases, and the lack of new hypotheses about their etiology, a novel hypothesis is here proposed. It consists of assuming that the effects of the drugs most commonly used by the elderly, such as antihypertensive, hypoglycemic, and hypocholesterolemic, could have a negative impact on neuronal survival. Review Tue, 28 Feb 2023 00:00:00 GMT RafaelFranco, JoanSerrano-Marín, Tue, 28 Feb 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100435 https://www.explorationpub.com/Journals/ent/Article/100436 Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting 1% of the population above sixty years. It is caused by an interaction between genetic and environmental risk factors. Loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) is pathologically characterizing the disease and responsible for the cardinal motor symptoms, most notably, bradykinesia, rest tremors, rigidity, and loss of postural reflexes. Non-motor signs such as olfactory deficits, cognitive impairment, sleep behavior disorders, and gastrointestinal disturbances are reflecting disturbances in the non-dopaminergic system. They precede dopaminergic neuronal degenerations by 5–10 years and are considered the main contributors to patients’ disability, particularly after the successful implementation of levodopa (L-dopa) treatment of motor symptoms. The present general review aimed to briefly update non-motor signs and their underlying pathophysiology in PD. Review Tue, 28 Feb 2023 00:00:00 GMT KhaledRadad, RudolfMoldzio, ChristopherKrewenka, BarbaraKranner, Wolf-DieterRausch, Tue, 28 Feb 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100436 https://www.explorationpub.com/Journals/ent/Article/100437 Acute ischemic stroke (AIS) is the leading cause of disability and one of the top causes of mortality worldwide. The current standard of care is reperfusion therapy including intravenous thrombolysis (IVT) and thrombectomy. However, these treatments have limitations as they have a limited therapeutic window. Hence, there is a vital need to develop neuroprotective agents to prevent brain injury, extend the reperfusion window, improve mortality, and reduce disability in AIS patients. Neuroprotective agents work by counteracting the detrimental biochemical and molecular events that result in irreversible ischemic damage. Numerous preclinical studies and clinical trials have been done on different agents. Thus far, all have been definitively unsuccessful in large trials. Currently, there are several challenges in translation from animal studies to human trials. It is important to understand the current evidence as well as past challenges in the development of neuroprotective strategies in AIS in order for a more strategic selection of agents to be studied, improve study designs and thus contribute to the development of effective neuroprotective agents. Newer agents have shown promise in neuroprotection, and human trials are ongoing. In this review, the mechanisms of action of different families of neuroprotective agents were discussed. The evidence for the efficacy of different drugs in each family of neuroprotective agents was also evaluated and the current research landscape in neuroprotection for AIS was summarized. The past challenges and limitations in clinical trials and proposed possible ways to address these issues were highlighted. Review Wed, 01 Mar 2023 00:00:00 GMT Grace YYChia, SelvieYeo, Jamie SYHo, EricJou, Leonard LLYeo, Benjamin YQTan, Wed, 01 Mar 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100437 https://www.explorationpub.com/Journals/ent/Article/100438 The enteric nervous system (ENS) is considered by some authors as the second human brain, given its fundamental role in the regulation process of the central nervous system (CNS). Recent data from scientific literature have shown the existence of close bidirectional communication between the gut microbiota and the CNS, influencing physiological and biochemical changes related to cognition, emotion, behavior, anxiety, depressive symptoms, and stress. Furthermore, the existence of mediators in the connection between intestinal microorganisms and the CNS is evident, which includes neural networks, signaling, immune, and endocrine responses. However, the mechanisms underlying the effects of gut microbiota on brain processes still need to be determined. Therefore, understanding the relationship between the gut and neurodegenerative diseases (NDs) is essential for developing effective prophylactic alternatives and disease-modifying drugs that can prevent or slow the progression of such diseases. Herein, this short review aimed to present the most recent data from the scientific literature associated with the physiological, biochemical, and cellular aspects involved in the interrelationship between the gut-brain axis and NDs, discussing the role of the intestinal microbiota, and its relationship with CNS disorders. Review Wed, 29 Mar 2023 00:00:00 GMT Januário T.Ernesto, Caio M.Damásio, Vanessa S.Gontijo, JucianoGasparotto, CláudioViegas Jr., Wed, 29 Mar 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100438 https://www.explorationpub.com/Journals/ent/Article/100439 Alzheimer’s disease (AD), which affects around twenty-seven million people globally, is an aging-related neurodegenerative condition characterized by the extracellular deposition of misfolded amyloid-β (Aβ) peptides and the intracellular production of neurofibrillary tangles (NFTs) AD results from the death of certain groups of neurons in the brain while appearing to have no impact on neighboring neurons. It is progressive and incurable. Therefore, the pathophysiology of afflicted populations and the development of intervention measures to stop neuronal cell death have been the main areas of attention for delineating therapeutic options. Proinflammatory cytokines are responsible for the stimulation of inflammatory responses and are mostly generated by activated macrophages in the brain. This review discusses how glial cells and innate and adaptive immune responses have a critical role in AD. It also provides information about microglial activation through the cluster of differentiation 40 (CD40) ligation and CD40L. CD40L ligation of microglial CD40 results in a large increase in tumor necrosis factor-α (TNF-α) production. Cultured cortical neuronal injury is caused when microglia are activated by CD40 ligation in the presence of interferon-γ (IFN-γ). This injury is significantly reduced by blocking the CD40 pathway or neutralising TNF-α. The management of AD would require integrating all available information about the innate and adaptive immune response affecting AD-related neuronal death. Review Mon, 03 Apr 2023 00:00:00 GMT AnkitaSingh, Tiratha RajSingh, Mon, 03 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100439 https://www.explorationpub.com/Journals/ent/Article/100442 Aim: To compare the efficacy of memantine with that of valproate as a prophylactic treatment for episodic migraine within three months. The efficacy, safety, and response rate were evaluated. Methods: Prospective, randomized, double-blind, controlled clinical trial randomized participants were divided into two groups. The memantine group received memantine 10 mg twice daily, and the valproate group received valproate 500 mg twice daily. Results: Thirty-three patients participated in the study; 27 completed the treatment protocol, 14 in the memantine group, and 13 in the valproate group. The mean number of migraine attacks per month in the memantine group was 5.31 [standard deviation (SD) ± 1.54] initially and 0.93 (SD ± 1.49) at the end of treatment, noting a decrease of 4.21 (SD ± 1.76; P < 0.001). In the valproate group, the mean number of migraine attacks per month was 5.35 (SD ± 1.11) initially and 0.77 (SD ± 1.16) at the end of treatment, with a difference of 4.5 (SD ± 1.39; P < 0.001). All 27 patients had excellent response rates. Adverse effects were infrequent and mild in severity. Conclusions: A clinical trial compared the efficacy of memantine with that of valproate (first-line drug) as a prophylactic treatment. A significant reduction in attacks was noted in both drugs. Memantine could be a new preventive treatment option for migraine (ClinicalTrials.gov identifier: NCT04698525). Original Article Fri, 28 Apr 2023 00:00:00 GMT DamarisVazquez-Guevara, AlejandroOrozco-Narvaez, Hector G.Hernandez-Rodriguez, FranciscoRivas-Ruvalcaba, Juan ManuelShiguetomi-Medina, IldefonsoRodriguez-Leyva, Fri, 28 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100442 https://www.explorationpub.com/Journals/ent/Article/100440 Late-onset Alzheimer’s disease (LOAD) is the most common form of Alzheimer’s disease (AD) and its risk increases exponentially with aging. The incidence of LOAD is reported to increase from 1 in every 1,000 people aged 37 to 65 in every 100 people aged 80 years and older. LOAD is extensively associated with aging and cognition decline. Several risk factors, including lifestyle choices, environmental factors, and medical ailments, affect cellular stress. The cellular stress can bring upon epigenetic alterations that affect cellular aging making the individual more susceptible to LOAD development. In due course the cellular stress resulting into epigenetic deregulation, oxidative burden, and genomic mutations leads to increased disease risk. Role of epigenetic and non-epigenetic mechanisms in accelerated cellular aging that are reported to increase the risk of LOAD development are summarized in this review. The underlying biological mechanism of cellular aging and the risk factors that could predispose cellular aging and LOAD development are also discussed in the upcoming sections. Review Thu, 27 Apr 2023 00:00:00 GMT KajalRawat, PrathibaGarlapally, Thu, 27 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100440 https://www.explorationpub.com/Journals/ent/Article/100441 Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by thunderclap headache and intracranial segmental vasoconstriction with or without signs of neurological deficit with a variable course that requires extensive study to prevent complications. The evidence shows RCVS is characterized by being multi-etiological; both the cause and the specific symptoms must be treated to reduce the chance of complications and recurrence. The timely identification of the RCVS and its etiology is the cornerstone of success in managing the disease. New data must be generated to have more efficient resources for the approach to this disease. Review Fri, 28 Apr 2023 00:00:00 GMT AndrésRicaurte-Fajardo, Laura RodríguezSuarez, Nathalia MeloGonzalez, Fri, 28 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100441 https://www.explorationpub.com/Journals/ent/Article/100443 Aim: Up to date many successful attempts to identify various types of lesions with machine learning (ML) were made, however, the recognition of Alzheimer’s disease (AD) from brain images and interpretation of the models is still a topic for the research. Here, using AD Imaging Initiative (ADNI) structural magnetic resonance imaging (MRI) brain images, the scope of this work was to find an optimal artificial neural network architecture for multiclass classification in AD, circumventing the dozens of images pre-processing steps and avoiding to increase the computational complexity. Methods: For this analysis, two supervised deep neural network (DNN) models were used, a three-dimensional 16-layer visual geometry-group (3D-VGG-16) standard convolutional network (CNN) and a three-dimensional residual network (ResNet3D) on the T1-weighted, 1.5 T ADNI MRI brain images that were divided into three groups: cognitively normal (CN), mild cognitive impairment (MCI), and AD. The minimal pre-processing procedure of the images was applied before training the two networks. Results: Results achieved suggest, that the network ResNet3D has a better performance in class prediction, which is higher than 90% in training set accuracy and arrives to 85% in validation set accuracy. ResNet3D also showed requiring less computational power than the 3D-VGG-16 network. The emphasis is also given to the fact that this result was achieved from raw images, applying minimal image preparation for the network. Conclusions: In this work, it has been shown that ResNet3D might have superiority over the other CNN models in the ability to classify high-complexity images. The prospective stands in doing a step further in creating an expert system based on residual DNNs for better brain image classification performance in AD detection. Original Article Fri, 30 Jun 2023 00:00:00 GMT KarolinaArmonaite, Marco LaVentura, LuigiLaura, Fri, 30 Jun 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100443 https://www.explorationpub.com/Journals/ent/Article/100444 Currently, the predominant targets for the treatment of Alzheimer’s disease (AD) are the main components of the two pathological structures: senile plaques (composed of amyloid beta peptide aggregates) or neurofibrillary tangles (constructed of tau protein polymers). However, the existence of adequate disease modifiers based on such targets is discussed. In this special issue, it has been suggested to search for new possible targets for AD therapy. This contribution tries to analyze non-neuronal tissues (periphery) to identify potential factors (target) involved in the development of AD. Review Fri, 30 Jun 2023 00:00:00 GMT JesúsAvila, MarPérez, MarinaAvila-Villanueva, IsmaelSanta-María, FélixHernández, Fri, 30 Jun 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100444 https://www.explorationpub.com/Journals/ent/Article/100445 Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder affecting motor neurons. The complex etiopathogenetic mechanism of ALS can lead to extensive alterations, including cortical changes, neuroinflammation, and changes in muscular structure. These ALS-derived alterations may contribute to fatigue, a symptom severely impacting patients’ quality of life that is commonly associated with muscular exercise. Intriguingly, muscular exercise can be at once a promoter of motor neuron degeneration in predisposed patients as well as an effective non-pharmacological treatment of ALS. To fully disclose its therapeutic potential, muscular exercise must be tailored to patients’ phenotypes, balancing potential benefits and risks that are unique to each ALS case. Biomarkers of muscular fatigue, with their potential for insight into inflammation and oxidation, can be used to ensure that the intensity of physical activity remains below the threshold level beyond which exercise might become harmful. In this review, the authors explore the concept of fatigue in ALS patients, focusing on fatigue generation, definition, detection, quantification, and treatment. The study discusses the most important fatigue biomarkers, putting them in relation to the mechanism of fatigue generation and with monitoring of muscular exercise as a possible treatment of fatigue. Review Fri, 30 Jun 2023 00:00:00 GMT FrancescaBianchi, LucreziaBecattini, LuciaChico, GiuliaRicci, GabrieleSiciliano, Fri, 30 Jun 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100445 https://www.explorationpub.com/Journals/ent/Article/100448 Parkinson’s disease (PD) is a prevalent neurodegenerative disease (NDD) affecting millions of individuals. The pathogenesis of PD centers around α-synuclein (α-Syn), a pivotal protein whose aggregation significantly impacts disease progression. Although existing treatments mainly focus on managing motor symptoms by targeting the dopaminergic system, they frequently overlook other non-motor symptoms. The intricate nature of PD pathogenesis contributes to challenges in disease analysis and has hindered the development of effective PD treatments. In recent years, various novel therapies utilizing immunotherapy methods have exhibited promise in preclinical animal models. In NDDs, immunotherapy aims to counteract the detrimental effects of protein accumulation by neutralizing toxic species and aiding their elimination. Numerous active therapy (AI) and passive immunotherapy (PI) strategies have been devised for PD and related synucleinopathies, many of which are currently undergoing clinical trials. Despite demonstrating remarkable success in animal models, immunotherapies encountered substantial setbacks during the late stages of clinical trials, with the exception of lecanemab, which targets amyloid-β (Aβ) in Alzheimer’s disease (AD) and has recently received approval from the Food and Drug Administration (FDA). The lack of translation from experimental investigations to successful clinical outcomes, particularly in terms of cognitive and functional evaluations, highlights the limitations of relying solely on animal studies to comprehend the effects of immunotherapeutic approaches. This comprehensive review focuses on α-Syn-based immunotherapies and delves into their underlying mechanisms of action. Furthermore, Furthermore, the article discusses recent advancements and future prospects concerning the potential of immunotherapeutic strategies for PD. The focus is on highlighting the latest research in this domain to illuminate the challenges and opportunities related to the development of efficacious immunotherapies for individuals with PD. Review Fri, 25 Aug 2023 00:00:00 GMT GabrielaHenriquez, MaheshNarayan, Fri, 25 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100448 https://www.explorationpub.com/Journals/ent/Article/100447 Amyotrophic lateral sclerosis (ALS) is the most prevalent type of motor neuron disease (MND) and is diagnosed with a delay from the first appearance of symptoms. Surrogate markers that may be used to detect pathological changes before a significant neuronal loss occurs and allow for early intervention with disease-modifying therapy techniques are desperately needed. Using water molecules that diffuse within the tissue and experience displacement on the micron scale, diffusion magnetic resonance imaging (MRI) is a promising technique that can be used to infer microstructural characteristics of the brain, such as microstructural integrity and complexity, axonal density, order, and myelination. Diffusion tensor imaging (DTI) is the primary diffusion MRI technique used to evaluate the pathogenesis of ALS. Neurite orientation dispersion and density imaging (NODDI), diffusion kurtosis imaging (DKI), and free water elimination DTI (FWE-DTI) are only a few of the approaches that have been developed to overcome the shortcomings of the diffusion tensor technique. This article provides a summary of these methods and their potential as surrogate markers for detecting the onset of ALS at an early stage. Review Fri, 25 Aug 2023 00:00:00 GMT YuyaSaito, Fri, 25 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100447 https://www.explorationpub.com/Journals/ent/Article/100446 The management of symptomatic chronic subdural hematoma (CSDH) is surgical evacuation and prognosis in most cases is good. Tension pneumocephalus is the presence of air under pressure in the intracranial cavity. A case of tension pneumocephalus developing as a complication of burr hole evacuation of CSDH is illustrated. In this case, tension pneumocephalus was managed by reopening the wound and saline irrigation with a subdural drain placement. Considering this case report and after a careful review of the literature, the physiopathology, diagnosis, and treatment of this complication are highlighted in the article. Case Report Thu, 24 Aug 2023 00:00:00 GMT Mohammed A.Azab, AhmedHazem, BrandonLucke-Wold, Thu, 24 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100446 https://www.explorationpub.com/Journals/ent/Article/100449 Parkinson’s disease (PD) is a common neurodegenerative disorder affecting aged population around the world. PD is characterized by neuronal Lewy bodies present in the substantia nigra of the midbrain and the loss of dopaminergic neurons with various motor and non-motor symptoms associated with the disease. The protein α-synuclein has been extensively studied for its contribution to PD pathology, as α-synuclein aggregates form the major component of Lewy bodies, a hallmark of PD. In this narrative review, the authors first focus on a brief explanation of α-synuclein aggregation and circumstances under which aggregation can occur, then present a hypothesis for PD pathogenesis in the peripheral nervous system (PNS) and how PD can spread to the central nervous system from the PNS via the transport of α-synuclein aggregates. This article presents arguments both for and against this hypothesis. It also presents various non-pharmacological rehabilitation approaches and management techniques for both motor and non-motor symptoms of PD and the related pathology. This review seeks to examine a possible hypothesis of PD pathogenesis and points to a new research direction focus on rehabilitation therapy for patients with PD. As various non-motor symptoms of PD appear to occur earlier than motor symptoms, more focus on the treatment of non-motor symptoms as well as a better understanding of the biochemical mechanisms behind those non-motor symptoms may lead to better long-term outcomes for patients with PD. Review Mon, 28 Aug 2023 00:00:00 GMT ZhaoyangLiu, JessicaLemus, Irina V.Smirnova, WenLiu, Mon, 28 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100449 https://www.explorationpub.com/Journals/ent/Article/100450 Aim: The sequential phosphorylation of mitogen-activated protein (MAP) kinases MEK-ERK is the most relevant cellular signaling pathway. This study quantified the parallel in vivo regulation of brain phosphorylation-MEK1/2 (p-MEK1/2) to p-ERK1/2 by mechanistically different cannabinoid 2 (CB2) receptor ligands, i.e., direct (and endogenous) agonists and inverse agonists. Methods: Groups of Swiss albino CD1 IGS male adult mice were treated (i.p.) with the CB2 agonist JWH133 (1 mg/kg and 3 mg/kg, 1 h, n = 8) or the CB2 inverse agonist/antagonist AM630 (0.3 mg/kg and 1 mg/kg, 1.5 h, n = 8–9), and 0.9% NaCl (2 mL/kg, 1 h, n = 4–10) as vehicle control. Transgenic male mice overexpressing cortical CB2 receptors [messenger RNA (mRNA) and protein] on a Swiss ICR congenic background (CB2xP) and the corresponding littermates age-matched wild-type (WT) controls were used. Protein forms (total MEK and ERK p-kinases) were resolved by electrophoresis [sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) minigels] followed by immunoblotting standard procedures. Results: The selective CB2 agonist JWH133 (1 mg/kg and 3 mg/kg, i.p., 1 h) modestly decreased MEK (17%, n = 8) and upregulated ERK (25%, n = 8) activities. The endogenous CB2 agonists (acting on promoted overexpressed receptors) decreased MEK (44%, n = 9) and upregulated ERK (67%, n = 10) activities. The inverse agonist/antagonist AM630 (0.3 mg/kg and 1 mg/kg, i.p., 1.5 h) increases MEK activity (27%, n = 8) without significantly altering that of ERK (5%, n = 9). Conclusions: Acute treatments of mice with mechanistically different CB2 receptor ligands (i.e., direct agonists, endogenous agonists, and inverse agonists) resulted in disruption of MEK (p-MEK/total-MEK ratio) to ERK (p-ERK/total-ERK ratio) signals in the brain cortex. This striking disruption of MEK to ERK parallel regulation in the cannabinoid CB2 receptor system in the brain could be relevant to the postulated role of CB2 receptors in various central nervous system (CNS) diseases. Original Article Wed, 25 Oct 2023 00:00:00 GMT GlòriaSalort, MaríaÁlvaro-Bartolomé, Jesús A.García-Sevilla, Wed, 25 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100450 https://www.explorationpub.com/Journals/ent/Article/100451 Aim: The present study aims to analyze the impact on cognitive recovery of an interdisciplinary treatment for acute and severe psychiatric patients. Methods: The present research is a naturalistic observational study of 130 adults (mean age of 47.68 years, 68% women). Clinical severity was assessed using Brief Psychiatry Rating Scale (BPRS), Montgomery-Asberg Depression Rating Scale (MADRS), and Hamilton Anxiety Rating Scale (HARS). Functional performance was evaluated using the Functioning Assessment Short Test (FAST), and cognitive impairment by applying the Montreal Cognitive Assessment (MoCA). Patients were clustered into four diagnostic groups (non-affective psychosis, bipolar, depressive, and personality disorders) and had individualized psychopharmacological treatment. They receive a transdiagnostic group program including several interventions that have shown evidence of beneficial effects over the different cognitive domains impaired in mental illness (attention, speed of processing, memory, working memory, reasoning, and problem-solving), as well as social cognition domains (emotion processing and social skills), in combination with psychoeducation and some strategies oriented to achieve healthy lifestyle routines (balanced diet, physical exercise, sleep hygiene, and smoking and alcohol cessation). Results: All clinical scales scores were improved after the end of treatment compared with those achieved at admission (BPRS, MADRS, and HARS scores below the cut-off point for establishing a case diagnosis). MoCA scores improved after the end of treatment concerning admission, both in the total score and in the differentiated cognitive domains, excluding orientation, which remained unchanged in the whole of the sample studied. No statistical significance was found in any comparisons between different diagnostic groups. No correlation between MoCA scores and BPRS, MADRS, or HARS scores at admission or discharge was found. Conclusions: These results show that the interdisciplinary therapeutic intervention can be effective for recovering cognitive impairment associated with mental disorders, irrespective of the diagnosis. Original Article Thu, 26 Oct 2023 00:00:00 GMT Ana IsabelDe Santiago-Díaz, TeresaPérez-Poo, ErikaPindado-Jiménez, GabrielaCortez-Astudillo, AranzazuZabala-Alonso, ElsaGómez-Ruiz, Thu, 26 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100451 https://www.explorationpub.com/Journals/ent/Article/100452 Post-translational modifications (PTMs) of alpha-synuclein (α-syn) can alter protein aggregation propensity to affect α-syn oligomer and fibril formation. The inflammatory response in Parkinson’s disease (PD) is mediated by microglia, astrocytes, T cells, B cells, macrophages, and neutrophils, which respond to α-syn aggregates in an attempt to clear synucleinopathy and restore brain homeostasis. This review focuses on the effects of PTMs on α-syn aggregation and cell-specific immune responses to α-syn aggregates in the context of PD. Review Thu, 26 Oct 2023 00:00:00 GMT ZainaKhan, Yoo JinJung, Thu, 26 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100452 https://www.explorationpub.com/Journals/ent/Article/100453 Aim: Parkinson’s disease (PD) is characterized by degeneration of midbrain dopamine neurons and synucleinopathy [aggregated alpha-synuclein protein (αSyn)]. The correlation between αSyn pathology and dopamine neuron degeneration remains to be fully established. Mouse models of PD are commonly used to increase knowledge of disease mechanisms. Lately, midbrain dopamine neurons have gained attention as more heterogeneous than previously recognized. With the aim to determine how the midbrain dopamine system in mice is affected in the presence of αSyn pathology, this brain system was studied in two transgenic mouse models of synucleinopathy. Methods: Brain sections from two previously described transgenic mouse lines verified for αSyn pathology through expression of the human αSyn gene (SNCA) under control of the Thy-1 promoter [Thy1-h[A30P]αSyn and Thy1-h[wt]αSyn (L61)], were analyzed using fluorescent in situ hybridization (FISH) and compared with matching sections from wild-type control mice. Probes directed towards mouse and human αSyn mRNA, and a battery of probes towards mRNAs representative of dopamine cell identity and heterogeneity, were implemented. Results: First, validation of αSyn-encoding mRNA was performed. Ample ectopic αSyn mRNA was observed throughout the brain of mice of each transgenic line. Next, midbrain dopamine neurons located in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were analyzed using a battery of general and subpopulation-specific dopamine cell markers. This included tyrosine hydroxylase (Th), vesicular monoamine transporter 2 (Vmat2), dopamine transporter (Dat), aldehyde dehydrogenase 1 family member A1 (Aldh1a1), G-protein-activated inward-rectifying potassium channel type 2 (Girk2), calbindin 1 (Calb1), Calb2, gastrin-releasing peptide (Grp), and vesicular glutamate transporter 2 (Vglut2) mRNAs. No difference between transgenic and control mice was observed for any analyzed marker in either the Thy1-h[A30P]αSyn or Thy1-h[wt]αSyn transgenic mouse line. Conclusions: This study demonstrates remarkable robustness of midbrain dopamine cell integrity in the presence of brain-wide ectopic human αSyn in two transgenic mouse models of neurodegenerative disease, motivating further study into mechanisms correlating synucleinopathy with dopamine neuron degeneration in rodent models relevant to PD. Original Article Mon, 30 Oct 2023 00:00:00 GMT BiancaVlcek, SylvieDumas, SaraEkmark-Lewén, EleonoraRubino, MartinIngelsson, ÅsaWallén-Mackenzie, Mon, 30 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100453 https://www.explorationpub.com/Journals/ent/Article/100498 Neurodegenerative diseases are a complex ensemble of ailments characterized by progressive neuronal deterioration and ultimate loss, resulting in drastic impairments of memory, cognition and other brain functions. These incapacitating conditions are challenging for the public health system worldwide, with unfortunately no real cure and lack of efficient drugs capable of delaying or reversing these diseases. In this context, the endocannabinoid system and exogenous cannabinoids represent an interesting field of research due to numerous studies highlighting the neuroprotective effect of cannabinoids from different sources, i.e., endogenous, phytocannabinoids, and synthetic cannabinoids. This review highlights the multilayered effects of cannabinoids and the endocannabinoid system to block the progression of neurodegeneration and minimize the deleterious effects of insults that affect the brain. We illustrate examples showing that the main effects of cannabinoids modulate different components of the brain response to these insults at the level of three major mechanisms involved in neurodegeneration: neuroinflammation, excitotoxicity, and oxidative stress. Review Mon, 10 Mar 2025 00:00:00 GMT AhmedHasbi, Susan R.George, Mon, 10 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100498 https://www.explorationpub.com/Journals/ent/Article/100454 Astrocytes not only support neuronal function with essential roles in synaptic neurotransmission, action potential propagation, metabolic support, or neuroplastic and developmental adaptations. They also respond to damage or dysfunction in surrounding neurons and oligodendrocytes by releasing neurotrophic factors and other molecules that increase the survival of the supported cells or contribute to mechanisms of structural and molecular restoration. The neuroprotective responsiveness of astrocytes is based on their ability to sense signals of degeneration, metabolic jeopardy, and structural damage, and on their aptitude to locally deliver specific molecules to remedy threats to the molecular and structural features of their cellular partners. To the extent that neuronal and other glial cell disturbances are known to occur in affective disorders, astrocyte responsiveness to those disturbances may help to better understand the roles astrocytes play in affective disorders. The astrocytic sensing apparatus supporting those responses involves receptors for neurotransmitters, purines, cell adhesion molecules, and growth factors. Astrocytes also share with the immune system the capacity to respond to cytokines released upon neuronal damage. In addition, in response to specific signals, astrocytes release unique factors such as clusterin or humanin that have been shown to exert potent neuroprotective effects. Astrocytes integrate the signals above to further deliver structural lipids, remove toxic metabolites, stabilize the osmotic environment, normalize neurotransmitters, provide antioxidant protection, facilitate synaptogenesis, and act as barriers to contain varied deleterious signals, some of which have been described in brain regions relevant to affective disorders and related animal models. Since various injurious signals that activate astrocytes have been implicated in different aspects of the etiopathology of affective disorders, particularly in relation to the diagnosis of depression, potentiating the corresponding astrocyte neuroprotective responses may provide additional opportunities to improve or complement available pharmacological and behavioral therapies for affective disorders. Review Tue, 31 Oct 2023 00:00:00 GMT José JavierMiguel-Hidalgo, Tue, 31 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100454 https://www.explorationpub.com/Journals/ent/Article/100455 Self-neuronal regeneration is often limited or nonexistent after neuronal cell damage, making new technologies necessary for treating neurological damage. Although the brain can partially compensate by increasing its plasticity, these compensatory mechanisms can never fully restore the pre-damage state. Analysis of the literature regarding stem cell therapy in case of neurological disorders. Stem cells have shown promise for treating various neurological disorders and disabilities due to their regenerative capacity. Transplanting or administration of different types of stem cells has yielded promising results in animal models and early clinical trials. However, concerns remain regarding their implementation. The type of stem cell used, the optimal method and route of administration, the number of stem cells administered, preconditioning, and the injection schedule all need to be determined. Additionally, the long-term safety of stem cell treatment and the recipient’s age requires further investigation. Despite these concerns, stem cell therapy holds tremendous promise for treating neurological disorders, and continued research and well-designed studies will be crucial for unlocking its full potential. Review Tue, 31 Oct 2023 00:00:00 GMT SaidHachimi-Idrissi, Tue, 31 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100455 https://www.explorationpub.com/Journals/ent/Article/100456 Vagus nerve stimulation (VNS) has gained prominence in the treatment of various clinical disorders such as migraine, depression, and tinnitus. Based on increased scientific knowledge of the VNS and insights into the vagus nerve (VN) function and anatomy/conduction, robust treatment approaches have been developed. There are both noninvasive and invasive VNS (iVNS) techniques. Currently, only iVNS techniques are approved by the US Food and Drug Administration (FDA). In contrast, transcutaneous VNS (tVNS) is a new treatment option that is receiving increasing attention. The tVNS application uses the cutaneous distribution of afferent VN fibers in the auricle, the auricular branch of the VN (ABVN), or in the neck, the cervical branch of the VN (CBVN). However, the tVNS technique has not yet been sufficiently researched in its application and mode of action to be used clinically on a large scale. Moreover, the stimulation parameters of the VN vary widely in different studies. Despite the growing number of research papers on this topic, more coherence in neurostimulation research and neuroanatomical basis is needed. The aim of this review is to highlight new clinical treatment options based on existing clinically applied treatment options. In this article, current clinical applications of tVNS are analyzed and important stimulation parameters are highlighted. Based on this data, useful new tVNS therapies are recommended. The focus will be placed on the study of inflammatory processes associated with cancer and on applications to cardiovascular events such as heart failure. Review Tue, 31 Oct 2023 00:00:00 GMT NiklasFrank, MichiakiNagai, Carola Y.Förster, Tue, 31 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100456 https://www.explorationpub.com/Journals/ent/Article/100457 Aim: Stroke is the second most common cause of mortality and disability worldwide with ischemic strokes being the predominant type. The advent of neuroprotectants brought hope of improved outcomes and quality of life, but current guidelines, despite numerous trials, have no strong recommendation advising their use. This meta-analysis aims to evaluate the degree of effect and safety of the neuroprotectants cytidine-5’-diphosphocholine (CDP-choline), cerebrolysin, edaravone, and MLC601, in the recovery of patients with cerebral infarcts. Methods: An extensive literature search, through the databases of PubMed, PMC, Cochrane, and Ovid, was done with the keywords “CDP-choline”, “cerebrolysin”, “MLC601”, and “edaravone” each combined with the term “acute ischemic stroke”. Eligible studies included randomized controlled trials of these neuroprotectants administered to patients with acute ischemic strokes. A total of 2,025 studies were found, and after the application of screening criteria, 24 studies were eligible for analysis. Results: The analysis showed that the functional outcome of patients with acute ischemic strokes improved significantly when receiving neuroprotectants versus placebo supported by an odds ratio = 0.29 (0.09–0.50) with a confidence interval of 95%. The P-values are 0.0022 for the one-tailed test, and 0.0030 for the two-tailed test which express the significant improvement of functional outcomes in patients with acute ischemic strokes taking neuroprotectants. Conclusions: This study thus supports the use of neuroprotectants in patients with acute ischemic strokes to improve long-term functional outcomes and ultimately quality of life. Meta-Analysis Wed, 01 Nov 2023 00:00:00 GMT Shafiq Dexter B.Abou Zaki, Johnny K.Lokin, Wed, 01 Nov 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100457 https://www.explorationpub.com/Journals/ent/Article/100458 Recent investigations have shed light on the potential of seaweed, an abundant source of bioactive compounds, to mitigate and combat neurodegenerative diseases. In this comprehensive review, the accumulating evidence supporting the neuroprotective properties of seaweed-derived compounds is evaluated and their putative mechanisms of action are elucidated. The background of this review encompasses the general understanding of neurodegenerative diseases as debilitating conditions characterized by the progressive loss of nerve cell function and viability in the central nervous system. Furthermore, the global prevalence of these diseases, encompassing Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, and the persistent absence of effective treatments are emphasized. To address this critical issue, an innovative avenue of research is explored by investigating the potential of seaweed and its diverse array of bioactive compounds. By examining the available literature, the evidence supporting the neuroprotective effects of seaweed-derived compounds is consolidated. These bioactive constituents exhibit promising properties in preventing and mitigating neurodegeneration. Mechanistically, their actions involve intricate pathways that contribute to neuronal survival, reduction of oxidative stress, inhibition of neuroinflammation, and modulation of protein aggregation processes. This review provides a comprehensive analysis of the mechanisms underlying the neuroprotective effects of seaweed compounds. In conclusion, this review highlights the potential of seaweed as a valuable source of neuroprotective compounds and underscores the advancements made in this burgeoning field. The identification and elucidation of the mechanisms through which seaweed compounds exert their neuroprotective effects hold promise for the development of novel therapeutic interventions. These findings transcend disciplinary boundaries, offering insight into the potential application of seaweed-derived compounds as a valuable resource for combating neurodegenerative diseases across scientific domains. Review Fri, 17 Nov 2023 00:00:00 GMT LeonelPereira, AnaValado, Fri, 17 Nov 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100458 https://www.explorationpub.com/Journals/ent/Article/100459 Not applicable. Commentary Wed, 29 Nov 2023 00:00:00 GMT CinziaVolonté, RafaelFranco, Wed, 29 Nov 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100459 https://www.explorationpub.com/Journals/ent/Article/100460 Aim: Amyotrophic lateral sclerosis (ALS) is a progressive disease of unknown etiology, characterized by degeneration of motoneurons and skeletal muscle strength decline that progressively evolves to respiratory failure and death. A key point in the therapeutic approach is to understand the pathological processes associated with disease evolution. In spite of intensive research on the molecular/cellular mechanisms involved in ALS initiation and progression disease etiology, unfortunately, poorly understood and there is no efficient specific/decisive treatment for ALS patients. The aims of the present study are to identify specific factors in the cerebrospinal fluid (CSF) of ALS patients and to test their potential relevance to the etiology of this disease. Methods: Peptides were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Motor activity of mice was tested by the Rota-rod test and peptide-induced inflammation was assessed by induction nitric oxide synthase activity in BV2 microglia cells. Results: Analysis of CSF samples of ALS patients (n = 15) detected two peptides, C-terminal fragments of transthyretin and osteopontin, which were absent in a control group (n = 15). In addition to being potential biomarker candidates, the relevancy of these peptides to the disease etiology was tested by assessing their effects on motor activity in mice and inflammation model in cell culture. Intranasal administration of the peptides reduced motor activity in the Rota-rod test and activated lipopolysaccharide-induced inflammation in BV2 microglia cells. Conclusions: These findings suggest that during ALS onset and progression two potentially neurotoxic peptides are formed, released, or penetrated the central nervous system thus inducing neuroinflammation and neurodegeneration. Original Article Tue, 12 Dec 2023 00:00:00 GMT UriWormser, AmnonSintov, MarcoVinceti, JessicaMandrioli, BertaBrodsky, ElenaProscura, YoramFinkelstein, Tue, 12 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100460 https://www.explorationpub.com/Journals/ent/Article/100461 Aim: Recently, brain network research is actively conducted through the application of graph theory. However, comparison between brain networks is subject to bias issues due to topological characteristics and heterogeneity across subjects. The minimum spanning tree (MST) is a method that is increasingly applied to overcome the thresholding problem. In this study, the aim is to use the MST analysis in comparing epilepsy patients and controls to find the differences between groups. Methods: The MST combines entities for epileptic magnetoencephalography (MEG) data. The MST was applied and compared to 21 left surgery (LT) and 21 right surgery (RT) patients with epilepsy and good postoperative prognosis and a healthy control (HC) group. MST metrics such as betweenness centrality, eccentricity, diameter, and leaf fraction, are computed and compared to describe the integration and efficiency of the network. The MST analysis is applied to each subject, and then the integrated MST is obtained using the distance concept. This approach can be advantageous when comparing the topological structure of patients to controls with the same number of nodes. Results: The HC group showed less topological change and more network efficiency than the epilepsy LT and RT groups. In addition, the posterior cingulate gyrus was found as a hub node only in the patient group in individual and integrated subject data analysis. Conclusions: This study suggests propose that the hippocampus borrows from the default network when one side fails, compensating for the weakened function. Original Article Wed, 13 Dec 2023 00:00:00 GMT SunhanShin, Chun KeeChung, JaeheeKim, Wed, 13 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100461 https://www.explorationpub.com/Journals/ent/Article/100462 The currently available pharmacological anti-dementia treatments provide only temporary and limited benefits. Not surprisingly, patients and professionals increasingly explore non-pharmacological interventions that may alleviate dementia symptoms. Among these interventions is hyperbaric oxygen therapy (HBOT). A brief review is presented on HBOT use in medicine, with its mode of action in dementia, specifically Alzheimer’s disease, as well as a case report of self-initiated HBOT in a 62-year-old man with a clinical diagnosis of probable Alzheimer’s disease. He had over 400 HBOT sessions [2–3 times weekly, with a duration of 30–50 min, in a multi-place hyperbaric chamber at 2 atmospheres absolute (ATA)] over 7 years and use of donepezil (10 mg daily) for the last 3 years when formally diagnosed by the National Health Service (NHS) Memory Service. The patient’s longitudinal neurocognitive and neuroradiological evidence over 7 years of follow-up remained stable (with no major cognitive decline and no behavioral changes) when compared to his initial presentation when diagnosed by the private health provider. His driving remains unimpaired, and he continues to be independent. This highlights the potential HBOT benefits including those on visuospatial ability and activities of daily living in people with Alzheimer’s disease. This case report argues for more extensive research into the clinical effects of HBOT in Alzheimer’s disease. Discussion of HBOT use is along with the latest advances in anti-amyloid immunotherapy for Alzheimer’s disease, as well as HBOT augmentation of current and novel dementia drug delivery via nanotechnology. Case Report Fri, 22 Dec 2023 00:00:00 GMT Elizabeta B.Mukaetova-Ladinska, JoannaSteptoe, MatthewCritchfield, Ha-JunYoon, MishaalSharif, QadeerArshad, Fri, 22 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100462 https://www.explorationpub.com/Journals/ent/Article/100463 Aim: The aim of this study is to review the effectiveness of dry needling in patients with multiple sclerosis (MS). Methods: PubMed, Physiotherapy Evidence Database (PEDro), Web of Science, Scopus, and Cochrane Library databases were searched from its inception until July 2023 and the reference lists of the articles obtained were manually searched. Studies examining the effectiveness of dry needling treatment alone or in combination with a different protocol in individuals diagnosed with MS, regardless of type, were included. The systematic review included quasi-experimental studies and case reports. Studies involving traditional Chinese medicine acupuncture applications, conference abstracts, and protocol records were excluded. Methodological quality assessments were carried out independently by two authors using tools developed by the Joanna Briggs Institute (JBI). Results: A total of 130 studies were found in the searches. Some studies were excluded due to duplication, protocol registration, conference abstract, and content outside the scope of the study and 7 studies were included in the review. In total, 33 individuals were included in this review, 22 of whom were women. Four studies specified the MS type of the patients, while the other studies did not specify MS type. Conclusions: Despite some limitations, this is, to our knowledge, the first review summarizing studies evaluating the effectiveness of dry needling in MS patients. The dry needling technique alone or in a combination of treatments was effective in improving pain, spasticity, range of motion, dexterity, mobility, limb function, and quality of life in MS patients. However, these results should be treated with caution due to the small number of included studies and the lack of randomized controlled trials. Although it is too early to talk about the positive effects of the dry needling technique in MS patients, the study results are promising. More randomized controlled trials should be conducted on this topic. Systematic Review Tue, 26 Dec 2023 00:00:00 GMT AliMutlu, Mehmet HanifiKaya, ÖznurBüyükturan, BuketBüyükturan, Tue, 26 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100463 https://www.explorationpub.com/Journals/ent/Article/100464 Aim: To evaluate the application of an acoustic neurostimulation program with binaural beats and isochronic tones isolated or in association, and its effects on sleep, depression, anxiety, and stress in healthy workers. Methods: A randomized, single-blind, parallel-group clinical trial, using acoustic neurostimulation with binaural beats, isochronic tones, or a combination of these in the 10 Hz range (alpha) performed with daily 20-minute sessions for 21 days. Changes in brainwave patterns were assessed by electroencephalogram (EEG). Psycho-emotional state was assessed with the Depression, Anxiety and Stress Scale 21 Items (DASS-21), and sleep quality with the Pittsburgh Sleep Quality Index (PSQI). In addition, salivary cortisol levels were evaluated as a biomarker of stress. Results: The data revealed distinct patterns of brainwave modulation via brainwave entrainment (BWE) techniques. Binaural beats and isochronic tones, alone and in combination, effectively increased alpha brainwaves in the temporoparietal region. However, when assessing theta brainwave frequencies in the same region, only binaural beats showed a significant effect. Furthermore, in the prefrontal cortex, an elevation in beta waves was exclusively observed with the use of binaural beats. These findings underscore the specificity of BWE techniques on different brainwave frequencies and regions. The study demonstrated marked improvements in several symptoms related to stress, depression, anxiety, assessed by psychometry with DASS-21 and related to sleep quality assessed by the PSQI. Conclusions: These results indicate that 10 Hz acoustic neurostimulation in the alpha range, whether through binaural beats, isochronic tones, or a combination of both, can significantly influence brainwave patterns and intensity. Notably, participants exhibited decrease in symptoms of stress, depression, and anxiety, coupled with improved sleep quality. These data suggest that alpha acoustic neurostimulation holds promise as an effective intervention for bolstering mood, mental health, and overall emotional well-being [Brazilian Clinical Trials Registry (ReBec, ensaiosclinicos.gov.br) identifier: RBR-10yj42dj]. Original Article Wed, 27 Dec 2023 00:00:00 GMT Sandro A.Kanzler, Francisco J.Cidral-Filho, BeatrizKuerten, Rui DanielPrediger, Wed, 27 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100464 https://www.explorationpub.com/Journals/ent/Article/100465 Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is associated with selective and progressive loss of motor neurons. As a consequence, the symptoms of ALS are muscle cramps and weakness, and it eventually leads to death. The general markers for early diagnosis can assist ALS patients in receiving early intervention and prolonging their survival. Recently, some novel approaches or previously suggested methods have validated the potential for early diagnosis of ALS. The purpose of this review is to summarize the status of current general markers discovery and development for early diagnosis of ALS, including genes, proteins neuroimaging, neurophysiology, neuroultrasound, and machine learning models. The main genetic markers evaluated are superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), transactivation-responsive DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes. Among proteins, neurofilament light chain is still the most established disease-specific adaptive change in ALS. The expression of chitinases, glial fibrillary acidic protein (GFAP), and inflammatory factors are changed in the early stage of ALS. Besides, more patient-friendly and accessible feature assays are explored by the development of neuroimaging, neurophysiology, and neuroultrasound techniques. The novel disease-specific changes exhibited the promising potential for early diagnosis of ALS. All of these general markers still have limitations in the early diagnosis, therefore there is an urgent need for the validation and development of new disease-specific features for ALS. Review Wed, 27 Dec 2023 00:00:00 GMT YizhouLu, LuHe, HuanyuMeng, ShengChen, QinmingZhou, Wed, 27 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100465 https://www.explorationpub.com/Journals/ent/Article/100466 Not applicable. Retraction Fri, 29 Dec 2023 00:00:00 GMT , Fri, 29 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100466 https://www.explorationpub.com/Journals/ent/Article/100467 Fibromyalgia syndrome (FMS) is characterised by the presence of distributed pain in different areas of the body accompanied by the alteration of some functions such as the activity of the neurovegetative system, the sleep quality, or the presence of fatigue. The present narrative review aims to evaluate some key studies regarding the effects of different therapeutic exercise (TE) modalities on clinical variables of interest in patients with FMS, as well as to discuss some of the possible mechanisms of action of TE in improving pain intensity in patients with FMS. All aerobic, strengthening, and body-mind exercises were shown to bring about changes in the improvement of clinical variables of interest in patients with FMS. In addition, with regard to the improvement of pain intensity, there are different arguments that could explain the hypoalgesic effect of TE (structured in physical, neurophysiological, and psychosocial mechanisms). In conclusion, TE is a clinical tool with great potential for patients with FMS as it may produce hypoalgesia through physical, neurophysiological, and psychosocial mechanisms. All these TE modalities have demonstrated in isolation a remarkable effectiveness in the overall improvement of patients with FMS. However, more research is needed in this field especially on the long-term effects and on the combination of the different training modalities. Review Wed, 21 Feb 2024 00:00:00 GMT CarlosForner-Álvarez, CarlosZanón-Chanzá, FerranCuenca-Martínez, NúriaSempere-Rubio, Wed, 21 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100467 https://www.explorationpub.com/Journals/ent/Article/100468 Depression is a known risk factor for dementia. Antidepressants are the most commonly used treatment for this condition, and are effective in at least half to two-thirds of cases. Extensive evidence from in vitro and animal models suggests that antidepressants have anti-inflammatory and neuroprotective properties. These effects have been shown to reduce the oxidative damage, amyloid aggregation, and expression of pro-inflammatory genes associated with animal models of neurodegenerative disorders. However, longitudinal research in humans has shown that antidepressants do not protect against dementia, and may even be associated with a risk of cognitive deterioration over time in older adults. The contrast between two sets of findings represents a paradox of significant clinical and public health significance, particularly when treating depression in late life. This review paper attempts to resolve this paradox by critically reviewing the medium- and long-term effects of antidepressants on peripheral immune-inflammatory responses, infection risk, gut microbiota, and neuroendocrine responses to stress, and how these effects may influence the risk of neurodegeneration. Briefly stated, it is possible that the peripheral actions of antidepressant medications may antagonize their beneficial effects against neuroinflammation. The implications of these findings are then explored with a particular focus on the development and testing of multimodal neuroprotective and anti-inflammatory treatments that could reduce the risk of Alzheimer’s and related dementias in patients suffering from depression. Review Fri, 23 Feb 2024 00:00:00 GMT Ravi PhilipRajkumar, Fri, 23 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100468 https://www.explorationpub.com/Journals/ent/Article/100469 Over the last two decades, immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG), previously thought to be a biomarker of multiple sclerosis (MS), have been shown to cause a distinct disease called MOG antibody-associated disease (MOGAD). MOGAD accounts for approximately one-third of all demyelinating syndromes in children and is the second most common central nervous system (CNS) demyelinating disease after MS. The diagnosis is made by detecting anti-MOG IgG antibodies against the natural MOG antigen, in the presence of compatible clinical and neuroradiological features. However, due to controversies in the methodologies for detecting anti-MOG antibodies and their diagnostic cutoff values, as well as the expanding clinical spectrum, accurate diagnosis may be challenging, at least in a subset of patients. Clinical presentations of MOGAD vary by age; the highest rates are seen in acute disseminated encephalomyelitis in younger children and optic neuritis, myelitis, or brainstem symptoms in older children. Although it was previously thought to be a milder demyelinating disorder and to have a monophasic course in the majority of patients, recent studies have shown that relapses occur in about half of the patients and sequelae develop in a significant proportion of them, especially in those with persistently high antibody titers, leukodystrophy-like magnetic resonance imaging (MRI) lesions, and spinal cord involvement. However, due to the monophasic course in about half of the patients, long-term treatment is not recommended after the first clinical episode but is recommended for patients who experience relapse. Accurate and early diagnosis of MOGAD is essential for proper management and better outcome. This review covers the challenges in the diagnosis of MOGAD in children. Review Tue, 27 Feb 2024 00:00:00 GMT ÜnsalYılmaz, Tue, 27 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100469 https://www.explorationpub.com/Journals/ent/Article/100470 Acute ischemic stroke (AIS) is the leading cause of disability worldwide, and recanalization therapy is significant in the hyperacute phase of AIS. However, reperfusion injury and hemorrhagic transformation after recanalization predict poor prognosis of AIS. How to minimize reperfusion injury and hemorrhagic transformation, which greatly improves the prognosis of vascular recanalization, is becoming a hot topic in AIS research and an urgent problem to be solved. A wealth of neuroprotective drug studies is now available, while some of the neuroprotectants have met with failure in human studies. It is discussed in this review about the progress in neuroprotective therapy for AIS based on understanding the pathophysiologic mechanisms of reperfusion injury and hemorrhagic transformation, as well as challenges in exploring new neuroprotectants. Review Tue, 27 Feb 2024 00:00:00 GMT YangYang, DandanGuo, YimingLiu, YiLi, Tue, 27 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100470 https://www.explorationpub.com/Journals/ent/Article/100471 Carbon nanotubes, an emerging class of carbon nanomaterials, possess tremendous potential for application in biotechnology and biomedicine particularly in neurological disorders. Carbon nanotubes owing to their fascinating properties have the potential to revolutionize medicine and technology, particularly in the realm of drug delivery, biosensing, bioimaging, and as therapeutic agents to tackle complex neurological disorders such as Alzheimer’s and Parkinson’s disease. In this review, a summary of the use of carbon nanotubes for neuropathological outcomes such as alleviating oxidative stress and amyloid formation, which are well-studied molecular outcomes associated with Alzheimer’s and Parkinson’s disease. In the end, challenges associated with the clinical testing of carbon nanotubes and possible ways to overcome them are highlighted. Review Tue, 27 Feb 2024 00:00:00 GMT Daisy L.Wilson, JyotiAhlawat, MaheshNarayan, Tue, 27 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100471 https://www.explorationpub.com/Journals/ent/Article/100472 Aim: A Zika virus outbreak that began in Brazil, developed into an international public health emergency that extended from February 2015 until November 2016. Zika-infected pregnant women gave birth to a cohort of infants with congenital Zika syndrome (CZS) originally defined by severe microcephaly, retinal scarring, joint deformities, and hypertonia. This study examines the nature, extent, and severity of all CZS clinicopathologic findings described to date, compiled and analyzed by system. It reviews studies monitoring disease progression and proposing classification schemes for CZS stages. The teratogenic cellular and molecular mechanisms implicated in CZS pathogenesis are also discussed. Methods: A systematic review was conducted by literature search through WorldCat.org and ProQuest Central databases to identify studies on case series from the 2015–2016 CZS outbreak. Results: Twenty-six reports were included describing radiologic, ophthalmologic, audiologic, orthopedic, and laboratory test results in CZS cases including stillborns between 2016 and 2023. CZS neuropathology included prenatal and postnatal microcephaly, cerebral calcifications, quadriparesis, epilepsy, ventriculomegaly, reduced cerebral parenchyma, malformation of cortical development, and sleep electroencephalogram disturbances. Visual deficits were due to retinal and optic nerve lesions. Conductive and sensorineural hearing deficits were stable. Hypertonia, hypotonia, and spasticity with foot, hip, knee, and shoulder deformities resulted in arthrogryposis and restricted joint mobility. There was enlargement of immune organs, increased leukocyte counts, and cytokine dysregulation. Oro-craniofacial deformities affected the midface and caused dental eruption delay. Additional studies proposed that these systemic teratogenic effects could be attributable to transplacental Zika virus infection of multiple fetal progenitor cell lineages. Conclusions: The CZS-associated impairments in brain, eye, musculoskeletal, and immunologic functions caused disabilities that varied from moderate to severe, and significantly increased age-specific mortality rates. Further research is warranted to assess progression, classify stages, elucidate the precise molecular mechanisms mediating Zika teratogenicity, develop suitable therapeutic strategies, and design supportive social policies. Systematic Review Wed, 28 Feb 2024 00:00:00 GMT DhaaraShah, DhairaviShah, OliviaMua, RanaZeine, Wed, 28 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100472 https://www.explorationpub.com/Journals/ent/Article/100473 Short-chain fatty acids (SCFAs) play a key role regulating immune and metabolic homeostasis. Consequently, dysregulation in SCFA levels is involved in the pathogenesis of autoimmune, inflammatory, metabolic, and neurodegenerative disorders. These metabolites are generated by gut microbiota, and their production is influenced mainly by diet. Here, an overview is provided of how SCFA production is associated with diet and with neurological disorders. The mechanisms by which SCFAs exert beneficial effects are analysed, along with how their production may be boosted by diet and how the use of specific dietary interventions might improve the outcome of neurological diseases. Perspective Tue, 19 Mar 2024 00:00:00 GMT CarolinaPrado, RodrigoPacheco, Tue, 19 Mar 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100473 https://www.explorationpub.com/Journals/ent/Article/100474 Behavioural environment and behavioural responses of an individual are known to affect multiple aspects of physiology including neuroendocrine and growth factor signalling, angiogenesis, stem cell dynamics, tissue homeostasis, and maintenance. Despite substantial evidence, the role of behaviour-physiology interface in human health and disease remains underappreciated. The hypothesis proposed here suggests that deficiencies of certain behaviours that have evolved to become essential or “vitactions” can potentially trigger multiple health problems. Altered growth factor expression because of vitaction deficiencies affects angiogenesis and vascular function, neuronal maintenance, transport of glucose and other nutrients to the brain, mitochondrial function, oxidative stress, inflammation, and protein aggregation dynamics all implicated in Alzheimer’s disease (AD). Exercise is already known to be effective in prevention of AD. The hypothesis suggests that it is the behavioural component of exercise over mechanical activity and calorie burning that has crucial effects on brain health through multiple signalling pathways. Similar to vitamin deficiencies, where supplying the deficient vitamin is the only effective solution, for vitaction deficiencies supplying the deficient behavioural stimuli through behaviourally enriched exercise can be the most effective remedy. Perspective Sun, 07 Apr 2024 00:00:00 GMT MilindWatve, AshwiniKeskar Sardeshmukh, Sun, 07 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100474 https://www.explorationpub.com/Journals/ent/Article/100475 Degeneration and dysfunction of neurons in the brain are hallmarks of neurodegenerative diseases. Over the past decades, significant efforts have been devoted to the development and validation of biomarkers for neurodegenerative diseases. The range and diversity of biomarkers for central nervous system (CNS) diseases has continued to expand, encompassing biofluid-based sources such as blood or cerebrospinal fluid (CSF), nucleic acids, tissues, and imaging. While imaging and tissue biopsy-based markers are continually being identified and their applications expanding, they do have limitations compared with RNA and protein biomarkers. This review comprehensively summarizes various biomarkers, including microRNA (miRNA), long noncoding RNA (lncRNA), circulating miRNA (cimiRNA), and proteins, in the context of CNS disorders. In addition, the review emphasizes the existing limitations and challenges associated with the use of biomarkers in both clinical practice and research on neurodegenerative diseases. In conclusion, this review provides an insightful overview of the identified biomarkers for neurodegenerative diseases, underscoring the crucial role of biomarker research in combating these debilitating conditions. The article also highlights future challenges related to the implementation of novel biomarkers in clinical practice and trials, thereby contributing to the ongoing efforts to advance the understanding and management of neurodegenerative diseases. Review Tue, 16 Apr 2024 00:00:00 GMT SathishSelvam, VelpandiAyyavoo, Tue, 16 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100475 https://www.explorationpub.com/Journals/ent/Article/100476 It is widely known that each tissue has unique mechanisms to respond to injury and maintain homeostasis effectively. Although peripheral nerves have limited regeneration capacity, they conduct a complicated regeneration process by orchestrating multiple cell complexes after injury. In addition to drawing attention to anterograde and retrograde transportation, the absence of a cell body in the damaged area also points to the significance of immune and glial cells in the environment. Cellular reorganization following injury in the dorsal root ganglion, which takes place in the cell bodies of sensory peripheral nerve fibers, has attracted much attention. Growing research has been focused on investigating the molecular and cellular interactions occurring in sensory neurons and glial cells within the dorsal root ganglia after injury. It is clearly becoming that the sensory neurons and glial cells in the dorsal root ganglion are derived from the same embryological origins. Therefore, this information attracts attention to the potential of these two cells to differentiate into each other in case of injury. The focus of these studies is to illuminate the genes and pathways responsible for an increase in the plasticity of the neurogenic cell line following nerve injury. This review explores and discusses the underlying mechanisms responsible for maintaining homeostasis in the dorsal root ganglion and regeneration of peripheral nerves and how neuronal plasticity functions in the regeneration of the injury. Mini Review Thu, 18 Apr 2024 00:00:00 GMT BurcuDelibaş, Abdalla Ahmed EldawElamin, SüleymanKaplan, Thu, 18 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100476 https://www.explorationpub.com/Journals/ent/Article/100477 Aim: Childhood stressors can increase adult stress perception and may accumulate over the lifespan to impact symptoms of multiple sclerosis (MS). Growing evidence links childhood stressors (e.g., abuse, neglect) to fatigue, pain, and psychiatric morbidity in adults with MS; yet literature in this area is lacking a comprehensive lifespan approach. The aim of this cross-sectional study was to examine contributions of childhood and adulthood stressor characteristics (i.e., count, severity), on three individual outcomes: fatigue, pain interference, and psychiatric morbidity in People with MS (PwMS). Methods: An online survey was distributed through the National MS Society. Hierarchical block regression modeling was used to sequentially assess baseline demographics, childhood stressors, and adult stressors per outcome. We hypothesized that child and adult stressors would significantly contribute to fatigue, pain interference, and psychiatric morbidity. Results: Overall, 713 PwMS informed at least one final analytic model. Both childhood and adult stressors significantly contributed to pain interference and psychiatric morbidity. Adult stressor severity independently correlated with psychiatric morbidity (P < 0.0001). Childhood stressors significantly contributed to fatigue (LR test P < 0.0001). Childhood stressor severity independently significantly correlated with both fatigue likelihood (P = 0.03) and magnitude (P < 0.001). Conclusions: This work supports a relationship between stressors across the lifespan and fatigue, pain, and psychiatric morbidity in PwMS. Stressor severity may have an important role which may not be captured in count-based trauma measurement tools. Clinicians and researchers should consider lifetime stress when addressing fatigue, pain, and psychiatric morbidity among PwMS. Original Article Mon, 22 Apr 2024 00:00:00 GMT Carri S.Polick, Tiffany J.Braley, RobertPloutz-Snyder, Cathleen M.Connell, AliWatson, Sarah A.Stoddard, Mon, 22 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100477 https://www.explorationpub.com/Journals/ent/Article/100478 Stroke, one of the leading causes of global morbidity and mortality, results from disrupted cerebral blood circulation, leads to cellular damage or death. Ischemic stroke, the predominant subtype, relies mainly on recombinant tissue plasminogen activator (rtPA) and endovascular thrombectomy for the treatment. Neurological impairments following ischemic stroke highlight the importance of understanding the interplay between neuroinflammation and neurogenesis in brain repair. Research reveals a complex relationship, where inflammation both promotes and hinders neurogenesis, impacting post-stroke outcomes. The subventricular zone (SVZ) of striatum and sub granular zone (SGZ) in hippocampus play pivotal roles in adult neurogenesis, with distinct characteristics and functions. SVZ neurogenesis involves neuroblast progenitors migrating to the olfactory bulb, while SGZ facilitates granule cell generation for hippocampal function. Understanding the intricate processes of neuroinflammation, neurogenesis, and angiogenesis is crucial for developing effective stroke therapeutics. Promising avenues include drug therapy, selective serotonin reuptake inhibitors, antibody therapy, angiogenesis stimulation, growth factor therapy, hormone therapy, miRNAs, extracellular vesicles, and neuroprotective agents. Stem cell therapy, exploring various cell types, holds potential for neuronal replacement and recovery. In conclusion, deciphering the roles of SVZ and SGZ in neurogenesis, unraveling the complexity of neuroinflammation’s impact on repair, and exploring diverse therapeutic approaches highlight the need for comprehensive investigations to enhance stroke outcomes. The multifaceted landscape of stroke therapeutics presents challenges, but ongoing research offers promising avenues for bridging the gap between preclinical findings and clinical treatments. Review Fri, 26 Apr 2024 00:00:00 GMT MydhiliRadhakrishnan, RoliKushwaha, B. SuprajaAcharya, ArvindKumar, SumanaChakravarty, Fri, 26 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100478 https://www.explorationpub.com/Journals/ent/Article/100479 Transmethylation in the context of psychiatry has historically referred to the enzymatic transfer of a methyl group from one biochemical to another, whose resulting function can change so dramatically that a biochemical like tryptamine, for example, is converted into the hallucinogen dimethyltryptamine. Central to endogenous methylation activity is the folate cycle, which generates the primary transferable methyl groups in mammalian biochemistry. The relevance of this cycle to mental health becomes clear when the cycle is dysregulated, often leading to a buildup of both homocysteine and S-adenosylhomocysteine (SAH), while accompanied by a transient reduction in the intended physiologic target, S-adenosylmethionine (SAM). This paper includes an in-depth review of the causes of folate cycle perturbations associated with psychotic symptoms, expounding on alternative downstream pathways which are activated and pointing toward potential etiologic agents of the associated psychosis, the methylated tertiary amines N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome, which appear in scientific reports concerning their association with hallucinogenic and/or neurotoxic outcomes. Electrotopological state (E-state) data has been generated for these compounds, illustrating a strong similarity with hallucinogens, particularly in terms of the E-state of the nitrogen in their tertiary amine moieties. In light of the role the folate cycle plays in transmethylation, neuroprotective strategies to prevent the transition to psychosis are suggested, including the advisory that folate supplementation can be harmful depending on the status of other relevant biochemicals. Review Thu, 16 May 2024 00:00:00 GMT Christine L.Miller, Thu, 16 May 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100479 https://www.explorationpub.com/Journals/ent/Article/100480 Epilepsy, a complex neurological disorder, is influenced by intricate interactions within cortical, hippocampal, or thalamocortical neuronal networks, presenting a genetically complex condition with non-Mendelian inheritance patterns. This complexity is underscored by the involvement of numerous “susceptibilities” or “modifier” genes, complicating the assessment of risk and therapy outcomes. A critical inquiry in epilepsy treatment involves understanding how genetic diversity impacts treatment strategies and efficacy. Pharmacogenomic advancements have elaborated the connection between genetic variants and antiseizure medication (ASM) safety and response, marking a shift towards precision medicine in epilepsy care. Notably, genetic screening for variants such as HLA-B*1502 and HLA-A*3101 has demonstrated significant efficacy in preventing severe hypersensitivity reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), particularly among specific ethnic populations. However, putting pharmacogenomic discoveries into clinical practice faces numerous challenges, including educational, legal, and economic barriers, emphasizing the need for broader acceptance and integration of pharmacogenomic data. This review synthesizes recent studies on pharmacogenomics in epilepsy, highlighting the current advances and prospects for personalizing epilepsy treatment through genetic insights, aiming to enhance ASM safety, reduce adverse effects, and improve treatment outcomes. Through a comprehensive examination of the genetic basis of epilepsy and its influence on pharmacotherapy, this review endeavors to contribute to the evolving landscape of precision medicine in epilepsy care, advocating for a more individualized and effective treatment approach. Review Wed, 29 May 2024 00:00:00 GMT AmnaShahid, KainatHameed, AbihaZainab, AhsanZafar, SameenAbbas, Wed, 29 May 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100480 https://www.explorationpub.com/Journals/ent/Article/100481 Background: The beneficial effects of gardening as a form of physical activity have garnered growing interest in recent years. This research aimed to evaluate the effect of gardening as a physical activity on promoting neuroplasticity and cognitive functioning in people. Methods: A systematic review was conducted on published articles between January 2010 to December 2022. The systematic search identified 3,470 records based on the PRISMA recommendations, 23 studies were eligible for inclusion in the review. Results: The study revealed the potential benefit of gardening physical activity on brain health. The evidence suggests that engaging in gardening physical activity not only boosts immunity and lowers inflammation but can also increase levels of growth neurotrophic factors like brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), which are essential for promoting neuroplasticity and improving cognitive function. These results should be interpreted cautiously given the small number of included studies and few randomized controlled trials. Discussion: The study results of gardening physical activity are promising. However, to adequately comprehend the underlying mechanism of the physical activity of gardening on brain health, more well-designed research is still necessary. Systematic Review Wed, 05 Jun 2024 00:00:00 GMT Antonio G.Lentoor, Wed, 05 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100481 https://www.explorationpub.com/Journals/ent/Article/100482 Aim: This article is based on our previous research, which was presented as a poster at the ECTRIMS Congress 2018 and published as a conference abstract (https://www.professionalabstracts.com/ectrims2018/iplanner/#/presentation/1698). Cognitive-motor interference (CMI) has been observed in both healthy controls (HC) and persons with multiple sclerosis (pwMS), but limited and contradictory data is making it difficult to assess the impact of motor and cognitive functioning levels on CMI. The aim of this study was to investigate CMI in pwMS and HC by means of a dual task postural paradigm, to compare them between groups and to analyse the influence of motor and cognitive functioning levels assessed with complementary instruments on observed CMI. Methods: The dual task posturography paradigm serves to quantify the impact of a cognitive (i.e., performing serial subtractions), a motor challenge (closing eyes), or both challenges combined (triple task) on body sway during standing in an upright position feet closed. The data analysed were acquired in one interventional and four observational studies and selected based on predefined criteria and by systematic quality control. A total of 113 pwMS and 42 HC were selected for analysis. Results: Comparable changes in motor and cognitive performance due to cognitive or combined cognitive-motor challenges were observed in both HC and pwMS. Combining both tasks did not result in further changes in motor performance but resulted in a decrease in cognitive performance. This reduction in cognitive performance with an additional motor challenge correlated with lower levels of cognitive and motor functioning in pwMS. Unexpectedly, an increase in body sway due to a cognitive or combined cognitive-motor challenges was primarily observed in pwMS and HC with better cognitive and motor functioning. Conclusions: The results suggest that dual-task effects are not disease-specific but rather reflect individually different adaptation strategies depending on the specific motor and cognitive functioning levels. Original Article Thu, 13 Jun 2024 00:00:00 GMT PatrikAlthoff, FriederikeRosenthal, Eva-MariaDorsch, DanielDrebinger, RadinaArsenova, AnnaChorschew, Sina C.Rosenkranz, JudithBellmann-Strobl, ChristophHeesen, FriedemannPaul, MartinWeygandt, TanjaSchmitz-Hübsch, Thu, 13 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100482 https://www.explorationpub.com/Journals/ent/Article/100483 Peripheral nerve injuries (PNIs) constitute a significant concern as they predominantly affect young and productive age groups of the population, causing social and economic pressure on patients. PNIs are a global problem that can result in disability because of the disruption of nerve function. PNI leads to a reduction in nerve conduction velocity, which worsens or impairs the mobility of the innervated area. Managing PNI remains a major clinical challenge. Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant first identified in 1957. It is an important antioxidant necessary for the organs to maintain their normal function and the body’s chemical processes. It scavenges free radicals and reduces oxidative stress. Studies showed that antioxidants such as CoQ10 a potent antioxidant, help the regeneration of PNIs. It has been observed to increase the myelination process in nerve fibres and promote nerve regeneration in rats after injury. Therefore, this review handles the current positive effects of CoQ10 on peripheral nerve regeneration following injury. Review Fri, 21 Jun 2024 00:00:00 GMT AhmedMead, BurcuDelibaş, Mehmet EminÖnger, SüleymanKaplan, Fri, 21 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100483 https://www.explorationpub.com/Journals/ent/Article/100484 A novel concept has been recently put forward in the mind/body interface (https://doi.org/10.37349/ent.2024.00074). The new concept has led to a new word: vitaction. Vitactions offer benefits to the brain and mind comparable to the advantages vitamins provide for the body’s overall health. The field of vitactions is as it was the vitamin field one century ago, i.e., without tools to make a complete classification. I propose to classify vitactions into five categories according to the behaviours necessary to maintain balanced brain functionality. A deficit of vitactions would contribute to the enormous prevalence in developed countries of diseases ranging from type 2 diabetes to neuropsychiatric diseases. The concept should help to identify which vitactions are deficient and to outline how they can be progressively implemented to improve the quality of life. The parallelism vitactions/vitamins also extends to overdosing; both hypervitaminosis and hypervitactinosis may be detrimental. This perspective article argues that vitactions should be considered at the practical and the scientific research levels, and that a balanced vitamin and vitaction supply is essential for a better life. In addition, reasons for proposing a synonym, “vitactin”, are given. Perspective Mon, 01 Jul 2024 00:00:00 GMT RafaelFranco, Mon, 01 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100484 https://www.explorationpub.com/Journals/ent/Article/100485 Parkinson’s disease (PD) is a neurodegenerative disorder characterized by both non-motor and motor symptoms, due to the loss of dopamine-producing neurons in the brain. Monoamine oxidase-B (MAO-B) inhibitors are essential in the treatment of PD, as they increase dopamine levels and could potentially slow down the progression of the disease. MAO-B inhibitors block the ability of the enzyme to degrade dopamine in the brain. MAO-B inhibitors work by inhibiting this enzyme, which raises dopamine levels and helps reduce motor symptoms, such as akinesia and stiffness in the muscles. In addition to their impact on dopamine levels, MAO-B inhibitors may possess neuroprotective properties. Research indicates that these inhibitors can shield neurons from the harmful byproducts of dopamine breakdown, such as dihydroxy acetaldehyde and hydrogen peroxide. This neuroprotective effect could potentially slow the progression of PD and protect against neuronal damage. MAO-B inhibitors are effective in treating both advanced and early stages of PD. They are recommended as initial treatments for individuals with early PD and can also be used as supplementary therapy in advanced PD to assist in managing motor complications. Additionally, MAO-B inhibitors have shown promise for the treatment of non-motor symptoms of PD, such as fatigue and sleep disturbances. MAO-B inhibitors are an important class of drugs for the treatment of PD, offering both symptomatic relief and potential disease-modifying effects. The goal of ongoing research and development of MAO-B inhibitors is to enhance their safety and selectivity profiles, which could lead to improved treatment approaches for PD and other neurodegenerative disorders. Review Mon, 15 Jul 2024 00:00:00 GMT Praveen KumarChandra Sekar, Sheena MariamThomas, RamakrishnanVeerabathiran, Mon, 15 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100485 https://www.explorationpub.com/Journals/ent/Article/100486 To quantitatively analyze the effects of acoustic neurostimulation on the symptoms of depression, anxiety, stress, and sleep quality in healthy workers. Eleven physiological and psychological variables (V1–V11) representing stress levels, sleep quality, and cortisol levels were acquired from a recent article (https://doi.org/10.37349/ent.2023.00064) that analyzed the effects of brainwave entrainment (BWE) techniques—binaural beats (BB), isochronic tones (IT), or a combination of the two (BB + IT). Principal component analysis (PCA) was used to create principal components to analyze the contribution of each variable to the efficacy. A thermodynamic cycle and equations based on a Venn diagram were used to understand the differences in treatment effectiveness in individual and combined auditory stimulations. PCA reduced the dimensionality of variables from eleven to three. PC1 represented auditory treatment efficacy, while neither PC2 nor PC3 did. All eleven variables had a negative correlation to PC1, with stress (V3) showing the most negative correlation and salivary cortisol level (V11) showing the least. Treatments using BB were more effective than treatments with IT or BB + IT. PCA successfully aided in the analysis of auditory treatment efficacies. All examined variables, especially the stress scale (V3), had a negative correlation in treatment efficacy, aligning with the results of the original paper. Analysis using the thermodynamic cycle and Venn diagram based on PCA provided an explanation why a combined treatment (BB + IT) was less effective than BB alone in the collective consideration of all eleven variables. This study demonstrates that the thermodynamic cycle and Venn diagram in conjunction with PCA are useful analytical tools for the quantitative analysis of multi-factor systems. Letter to the Editor Thu, 22 Aug 2024 00:00:00 GMT Radiance C.Bouldin, Julia R.Higdon, JonghoonKang, Thu, 22 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100486 https://www.explorationpub.com/Journals/ent/Article/100487 Neuroinflammation can be caused by disease, aging, infection, brain injury, toxicity, or stress. It is a contributory factor in the neuropathology of serious conditions that include multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and autoimmune encephalomyelitis (EAE). The neuroinflammatory response involves the activation of microglia, astrocytes, the endothelial cells of the blood-brain barrier, and peripherally-derived immune cells. The endocannabinoid system is composed of the natural cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), enzymes regulating their synthesis/catabolism, and the cannabinoid CB1 and CB2 receptors. It regulates multiple systems in the body including inflammation and endocannabinoid system dysregulation is involved in numerous inflammatory conditions. The Cannabis sativa plant produces over 100 phytocannabinoids, some of which interact with the endocannabinoid system. The major phytocannabinoids are delta-9-tetrahydrocannabinol (delta-9-THC), cannabidiol (CBD), and cannabigerol (CBG). Compelling evidence is emerging that many phytocannabinoids have anti-inflammatory and antioxidant properties. Phytocannabinoids including delta-9-THC, CBD, and CBG bind to a wide variety of targets in the endocannabinoid and/or other systems, which probably accounts for their diversity of effects in non-clinical and clinical studies. The benefits of certain phytocannabinoids have been proven by regulatory approval for medical use of CBD (Epidiolex®), chemically synthesized delta-9-THC (Marinol® and Syndros®) and 1:1 delta-9-THC/CBD (Sativex®). Furthermore, the widely recognized therapeutic properties of Cannabis have been a key driver in legalizing the medical use of Cannabis in 38 USA states. In this review, the potential of phytocannabinoids as effective treatments in neuroinflammatory disorders is discussed based on a critical evaluation of the non-clinical and clinical evidence. We focused on delta-9-THC, CBD, and CBG because they are the most abundant phytocannabinoids in Cannabis sativa and a substantial body of scientific data exists to describe their respective pharmacological mechanisms. Review Thu, 22 Aug 2024 00:00:00 GMT SharonSmith, TaurriSpurgeon, RuarriSpurgeon, DavidHeal, Thu, 22 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100487 https://www.explorationpub.com/Journals/ent/Article/100488 The central nervous system (CNS) is one of the most complex physiological systems, and treatment of CNS disorders represents an area of major medical need. One critical aspect of the CNS is its lack of regeneration, such that damage is often permanent. The damage often leads to neurodegeneration, and so strategies for neuroprotection could lead to major medical advances. The G protein-coupled receptor (GPCR) family is one of the major receptor classes, and they have been successfully targeted clinically. One class of GPCRs is those activated by bioactive lysophospholipids as ligands, especially sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Research has been increasingly demonstrating the important roles that S1P and LPA, and their receptors, play in physiology and disease. In this review, I describe the role of S1P and LPA receptors in neurodegeneration and potential roles in neuroprotection. Much of our understanding of the role of S1P receptors has been through pharmacological tools. One such tool, fingolimod (also known as FTY720), which is a S1P receptor agonist but a functional antagonist in the immune system, is clinically efficacious in multiple sclerosis by producing a lymphopenia to reduce autoimmune attacks; however, there is evidence that fingolimod is also neuroprotective. Furthermore, fingolimod is neuroprotective in many other neuropathologies, including stroke, Parkinson’s disease, Huntington’s disease, Rett syndrome, Alzheimer’s disease, and others that are discussed here. LPA receptors also appear to be involved, being upregulated in a variety of neuropathologies. Antagonists or mutations of LPA receptors, especially LPA1, are neuroprotective in a variety of conditions, including cortical development, traumatic brain injury, spinal cord injury, stroke and others discussed here. Finally, LPA receptors may interact with other receptors, including a functional interaction with plasticity related genes. Review Fri, 23 Aug 2024 00:00:00 GMT EricBirgbauer, Fri, 23 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100488 https://www.explorationpub.com/Journals/ent/Article/100489 Excitotoxicity represents a neuropathological process, describing the toxic actions of excitatory neurotransmitters, where the excessive or prolonged activation of glutamate receptors triggers a cascade of events leading to neuronal injury or death. Under conditions of reduced energy availability and increased oxidative stress neurons become particularly vulnerable to excitotoxicity and a large body of available evidence indicates that excitotoxicity represents a central mechanism in the pathogenesis of acute and degenerative diseases of the central nervous system. Astrocytes represent key elements in the regulation of glutamate homeostasis by their opposing functions of glutamate uptake and release, and microglial cells play an important role in the response to damage. Depending on the phenotype they assume when activated, microglial cells can trigger immune defense or neuroprotective processes. To perform their functions both glial cell populations monitor the extracellular space through a panel of receptors. Furthermore, a variety of signaling pathways also contribute to the modulation of the glutamatergic transmission, acting on specific cell receptors expressed by neurons, astrocytes, and microglia. In the last decades, evidence has been provided that receptors of almost all families can establish structural receptor-receptor interactions, leading to the formation of heteroreceptor complexes at the cell membrane of neurons and glial cells. The cooperativity that emerges in the actions of ligands of the monomers forming these assemblies provides the cell decoding apparatus with flexible dynamics in terms of recognition and signal transduction and allows an integration of the incoming signals already at the membrane level. Available data on possible modulatory roles played by heteroreceptor complexes in excitotoxic processes will be here reviewed and discussed. From the pharmacological standpoint, these findings may offer possibilities to explore novel therapeutic strategies targeting receptor complexes to address disorders of the central nervous system associated with dysregulation of glutamatergic signaling. Review Tue, 24 Sep 2024 00:00:00 GMT DiegoGuidolin, CinziaTortorella, ManuelaMarcoli, ChiaraCervetto, RaffaeleDe Caro, GuidoMaura, Luigi F.Agnati, Tue, 24 Sep 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100489 https://www.explorationpub.com/Journals/ent/Article/100490 Alzheimer’s disease continuum has been described as the progressive stages of the disease over a long period. This progression can be categorized into three main stages: preclinical, mild cognitive impairment (MCI), and dementia. It has been suggested that there is a bidirectional relationship between the preclinical stage and MCI, but not between dementia and the earlier stages. The stage of MCI should be further analyzed, especially in cases where there is a reversion from MCI to a normal cognitive condition. The mechanisms behind this reversion deserve further investigation to differentiate true reversion from compensatory mechanisms. Analyzing reversion in greater detail could help identify potential therapies aimed at preventing or delaying the onset of dementia. As indicated, the primary focus has been on research indicating that MCI can revert to normal cognition. This reversion can occur by addressing risk factors through lifestyle changes, although a novel mechanism involving a transient functional compensation process in response to cognitive impairment should be also taken into account. Perspective Fri, 27 Sep 2024 00:00:00 GMT MarinaAvila-Villanueva, JesúsAvila, Fri, 27 Sep 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100490 https://www.explorationpub.com/Journals/ent/Article/100492 Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, with an unknown etiology and a multifactorial pathophysiology characterized by protein misfolding, neuroinflammation, and neuronal loss. There are three well-discussed main hypotheses for the pathophysiology of AD, which are related to i) the accumulation of amyloid β (Aβ) protein aggregates in the extracellular space, ii) deposition of hyperphosphorylated tau fragments as neurofibrillary tangles, and iii) dysregulation of hemostasis of some neurotransmitters involved in the disease, such as acetylcholine (ACh) and glutamate. The association of all these factors is responsible for installing oxidative stress and neuroinflammation, which contribute to progressive neuronal death in specific brain regions. More recently, other remarkable pathological characteristics have been described, involving changes in all levels of cellular components, especially in the action and function of protein kinases. These enzymes are crucial for cellular regulation since they play a pivotal role in the phosphorylation of protein substrates by transferring a phosphate group from the ATP molecule to threonine, serine, or tyrosine residues. In more recent studies, some kinases have been especially reported by their role in inflammatory and oxidative processes associated to AD, such as cAMP-dependent protein kinase A (PKA), cyclin-dependent protein kinase 5 (CDK5), glycogen synthase kinase 3β (GSK-3β), and the microtubule affinity regulatory kinases (MARKs). Under homeostatic conditions, protein kinases act as cellular signals, directing physiological responses, but in AD pathogenesis, these enzymes have an exacerbated activity in the brain, justifying the need for a better comprehension of their function and role, and how new kinase inhibitors could lead to innovative drugs. In this context, this brief review aimed to compile the literature data related to the most recent efforts and strategies in Medicinal Chemistry in the discovery of new kinase inhibitors, opening new ways to AD therapeutics. Review Tue, 29 Oct 2024 00:00:00 GMT Isabela Marie FernandesSilva, Graziellados Reis Rosa Franco, Vanessa SilvaGontijo, ClaudioViegas Jr., Tue, 29 Oct 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100492 https://www.explorationpub.com/Journals/ent/Article/100491 Alzheimer’s disease (AD) is the leading cause of dementia worldwide. The disease is characterized by the abnormal accumulation of amyloid β (Aβ) protein creating neuritic plaques, hyperphosphorylated tau (p-tau) protein forming intracellular tangles, and neuronal degeneration. Pathological changes related to abnormal Aβ and p-tau accumulation may begin more than fifteen years before the clinical diagnosis of AD is made. The glymphatic system is the brain’s waste clearance pathway that prevents the accumulation of these abnormal proteins and macromolecules. Glymphatic clearance is negatively affected by physiological conditions such as sleep deprivation, and pathological conditions such as traumatic brain injury and hemorrhagic strokes. These physiological and pathological conditions are strong risk factors for AD. In conclusion, impaired glymphatic clearance is an important pathogenetic mechanism for AD. Mini Review Thu, 24 Oct 2024 00:00:00 GMT IyawnnaHazzard, MaryannBatiste, TianyuLuo, CyrusCheung, ForshingLui, Thu, 24 Oct 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100491 https://www.explorationpub.com/Journals/ent/Article/100493 Insulin-like growth factor-1 (IGF-1) elicits a variety of effects on the regulation of oxidative stress, a topic that remains shrouded in controversy. This intricate regulation plays a pivotal role in the aging process and its associated diseases. Notably, it centers around the challenge posed by endogenous antioxidant defenses, which often struggle to counteract free radicals-induced damage to various neural cell macromolecules. The interplay between IGF-1 and oxidative stress holds significant implications. Both factors are intertwined in the context of degenerative and inflammatory disruptions within the central nervous system (CNS), giving rise to dysfunctions in neurons and glial cells. These dysfunctions encompass detrimental outcomes such as excitotoxicity, neuronal attrition, and axonal impairment, all of which are closely related to behavioral irregularities. However, the complexities of IGF-1’s impact remain a topic of debate. Divergent research findings present IGF-1 as both an antioxidative agent and a catalyst to produce reactive oxygen species (ROS) in various neuropathologies. This diversity of outcomes has contributed to the ongoing controversy in the field. The present theoretical review undertakes a comprehensive vision, shedding light on the role of IGF-1 as a regulator within the mechanistic framework of oxidative stress responses. This regulatory role serves as the basis for the emergence of progressive neurodegenerative and neuroinflammatory conditions. Particularly compelling is the exploration of IGF-1 as a potential target for promising therapeutic interventions in this domain. However, the review also highlights significant limitations, including the considerations to work with this factor and the need for further research to clarify IGF-1’s role. Future perspectives should focus on refining our understanding of IGF-1’s mechanisms and exploring its therapeutic potential in more detail. Review Thu, 31 Oct 2024 00:00:00 GMT Macarena LorenaHerrera, Leandro GabrielChamparini, Alberto LeandroOliveros, Maria JoséBellini, Claudia BeatrizHereñú, Thu, 31 Oct 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100493 https://www.explorationpub.com/Journals/ent/Article/100494 This review focuses on the current advances in the field of therapeutic targets and treatments for stroke. Stroke is a major health problem worldwide, with significant impacts on morbidity and mortality, and a considerable burden on the medical and socio-economic systems. This review provides a comprehensive overview of the current state of knowledge on acute treatments and therapeutic targets. Current stroke treatments like recanalization therapies focus mainly on restoring blood flow to the brain, reducing cell death, and preventing further damage, but have limitations in terms of efficacy and long-term outcomes. Besides acute treatments (mobile stroke units, telerehabilitation) and acute therapeutic targets, the review focuses on longer-term therapeutic targets, such as neuroprotection and neuroregeneration. Neuroprotective strategies target the mechanisms underlying energy failure, cellular acidosis, mitochondrial dysfunction, endoplasmic reticulum stress, excitotoxicity, calcium channels dysregulation, oxidative stress, neuroinflammation, blood-brain barrier disruption, apoptosis, and ischemia-reperfusion injury. Neuroregenerative approaches include stem cell therapy, gene therapy, growth factors, and rehabilitation techniques that promote the rewiring of neuronal circuits in the brain. Non-pharmacological treatments like neurostimulation and bioengineering are also presented. Additionally, we highlight the challenges and future directions in translating these therapies into clinical practice. Overall, the treatment of ischemic stroke is a complex and multifaceted process that requires a combination of acute measures as well as longer-term strategies to promote brain repair and recovery. The treatment of ischemic stroke has made significant progress in recent years with the development of new treatments and ongoing research to improve outcomes for stroke patients. However, before these therapies can be successfully integrated into routine clinical practise, further research is needed to establish standardised protocols, overcome methodological limitations, and overcome clinical challenges. By further deepening our understanding of the pathophysiology of ischemic stroke and developing innovative treatments, we can improve outcomes and quality of life for stroke survivors. Review Wed, 20 Nov 2024 00:00:00 GMT LidijaRadenovic, Wed, 20 Nov 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100494 https://www.explorationpub.com/Journals/ent/Article/100496 Aim: This study aims to investigate the effects of administering coenzyme Q10 (CoQ10) after both short-term and long-term sciatic nerve damage. Methods: Six groups of adult male Wistar albino rats were used. Sciatic nerve injury was performed on the rats in the short-term injury (STI) and long-term injury (LTI) groups for 15 and 60 s. For 21 days, the rats in the CoQ10, STI + CoQ10, and LTI + CoQ10 groups were also administered CoQ10 orally at a dose of 10 mg/kg of body weight; the control (Cont) group received no treatment. The nerve samples were evaluated by electrophysiology, the sciatic functional index (SFI), stereological investigations, and light and electron microscopic methods. Results: The number of myelinated axons was higher in the LTI group according to the Cont and the sham groups. The numbers of axons in the LTI and LTI + CoQ10 groups were higher than that in the STI and STI + CoQ10 groups. Latency and amplitude levels were significantly changed following STI and LTI treatment and CoQ10 treatment significantly improved the results following the injuries. SFI results showed highly significant differences between the Cont and STI, Cont and LTI, Cont and STI + CoQ10, STI + CoQ10 and LTI + CoQ10, and Cont and LTI + CoQ10 groups. Microscopic examinations indicated that LTI produced a significant change in the nerve structure than STI. CoQ10 ameliorated the degree of injury. Conclusions: Treatment with CoQ10 following sciatic nerve damage was more successful in the LTI than the STI group, and it may, therefore, effectively improve peripheral nerve regeneration, especially following LTI. Original Article Sun, 26 Jan 2025 00:00:00 GMT Ahmed OmerMead, Berrin ZuhalAltunkaynak, SüleymanKaplan, Sun, 26 Jan 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100496 https://www.explorationpub.com/Journals/ent/Article/100495 Repeat expansion diseases (REDs) are genetic disorders caused by unusual expansions of DNA sequences within certain genes. They cause several neurodegenerative diseases including Huntington’s disease (HD), myotonic dystrophy (DM), spinal and bulbar muscular atrophy (SBMA), fragile X syndrome (FXS), and others. The pathogenic repeat expansions disrupt normal cellular processes by producing aberrant RNA repeat sequences, leading to toxic protein aggregation, RNA foci, and altered gene expression. Although they belong to the rare disease group, such diseases must be investigated to understand integral mechanisms and prevention. Current methods for alleviating these diseases involve—gene silencing therapies by antisense oligonucleotides (ASOs) and RNA interference (RNAi), CRISPR/Cas9 gene editing, small molecule therapies, etc. ASOs and RNAi reduce toxic protein production genes while CRISPR/Cas9 excise or alter expanded repeats. Small molecule therapies targeting RNA repeat-binding or proteostasis regulation are being developed to alleviate toxic protein accumulation, prevent RNA toxic foci formation, and promote the degradation of misfolded proteins. Additionally, gene replacement and regulatory element modification restore normal gene function. Some researchers tried to modulate toxic protein aggregation using heat shock proteins and chemical chaperones. This is a comprehensive review on the available research on RED treatment and their ongoing challenges, such as efficient delivery of therapies to the central nervous system, minimizing off-target effects in gene editing, sustaining therapeutic efficacy, and addressing toxicity and scalability in large-scale applications. Mini Review Wed, 25 Dec 2024 00:00:00 GMT AfsanaBhuiyan, Wed, 25 Dec 2024 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100495 https://www.explorationpub.com/Journals/ent/Article/100497 Aim: This study investigates the association between ApoE genotype, plasma cholesteryl ester (CE) levels, and Alzheimer’s disease (AD) status, with a focus on CE(20:4) and CE(22:5) levels as potential indicators of lipid metabolism alterations in AD patients. Methods: Publicly available metabolomics data (DOI: 10.3233/JAD-215448) from 94 AD patients and 62 controls aged 55 and older were re-analyzed. CE levels were examined using non-parametric tests due to the non-normal overall data distribution. Comparisons were stratified by ApoE genotypes (ε3/ε3 and ε3/ε4). Results: Significant increases in CE(20:4) and CE(22:5) levels were observed in AD patients with the ApoE ε3/ε4 genotype compared to controls (p-values 0.0387 and 0.0348, respectively). No significant differences were found for other CEs or among ε3/ε3 carriers (except for sex). Overlap between CE levels in AD and control groups limits their potential as diagnostic biomarkers but underscores their role in lipid dysregulation in AD pathophysiology. Conclusions: Elevated CE(20:4) and CE(22:5) levels in ε3/ε4 AD patients highlight lipid metabolism alterations associated with ApoE genotype. While not providing standalone biomarkers, these findings offer insights into AD-related lipid dysregulation and warrant further investigation in high-risk ε4/ε4 carriers and therapeutic targeting of lipid metabolism. Original Article Tue, 25 Feb 2025 00:00:00 GMT EleonoraStefanini, JoanSerrano-Marín, AlbertoIglesias, Miguel G.Fernández, JuanSánchez-Navés, Hanan A.Alkozi, DavidBernal-Casas, RafaelFranco, Tue, 25 Feb 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100497 https://www.explorationpub.com/Journals/ent/Article/100499 Aim: Growing evidence suggests that Attention Deficit Hyperactivity Disorder (ADHD) may not be a single entity with a universal remedy, but rather a group of conditions resulting from interactive bio-psycho-social factors and requiring specifically targeted interventions. ADHD research, including neurophysiology, faces inconsistent findings due to heterogeneity. This variety might indicate different physiopathogenic mechanisms. This study aimed to identify dysfunctional mechanisms behind ADHD symptoms and test if targeting these dysfunctions can improve clinical outcomes. Methods: 230 children with ADHD diagnosis studied with hypothesis-related variables from electroencephalogram (EEG) visual inspection and quantitative z-scored power, coherence and ratios, and from event-related brain potentials (ERPs) z-sored P50, N100, N200, P300 latencies amplitudes and ratios. Parametric and non-parametric classifications were conducted on neurophysiological findings to identify clusters and design neuropsychologically-based recommended treatments (NBRTx). Treatment response evaluated thrgbrough ADHD scores comparing NBRTx with guidelines recommended treatment (GBRTx). Treatment selected by agreement between each child’s physician and the parents, both parties thoroughly informed. Results: Six clusters of neurophysiological findings were identified, each characterized by a combination of EEG/ERP abnormalities hypothetically related to distinct dysfunctional mechanisms. Cluster (C) findings, hypothetical dysfunction, and treatment recommendations: C1: Longer P300 latencies, hypodopaminergia: methylphenidate. C2: Centrotemporal spiles, hyperexcitable network: carbamazepine. C3: Bisynchronous spike-waves complexes, thalamocortical involvement: valproic. C4: Altered psychosis-related variables: risperidone. C5: Altered migraine-related variables: valproic. C6: Abnormal maturational interhemispheric rate: tailored psychotherapy. At 3 months, ADHD scores decreased with methylphenidate (MPH) only in C1. In other clusters children under NBRTx had good responses, those under GBRTx did not, and were switched to NBRTx with significant improvement at 6 months. Conclusions: Six different neurophysiological mechanisms responding to targeted interventions were identified by neurophysiological signatures. A personalized medicine approach guided by physiopathogenic mechanisms may be necessary when facing multifactorial, heterogeneous disorders such as ADHD. Original Article Mon, 31 Mar 2025 00:00:00 GMT MontserratGerez-Malo, ArmandoTello, Maria JimenaMartin-Salas, LauroCastanedo, ArturoMendizábal, OscarMeneses Luna, LeslieQuintanar, CarlosAcosta, Mon, 31 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/100499 https://www.explorationpub.com/Journals/ent/Article/1004100 Similar to other psychiatric disorders, drug addiction is linked to changes in neuronal activity within the mesolimbic system, which consists of dopamine (DA) neurons of the ventral tegmental area projecting to the ventral part of the striatum, the nucleus accumbens (NAc). All drugs of abuse indeed artificially increase DA concentration in the NAc, which hijacks the reward system and triggers lasting behavioral alterations, including compulsive drug-seeking and drug-taking behavior despite negative consequences and a high rate of relapse after abstinence. DA chiefly signals through DA receptor (DAR) type 1 (D1R) and type 2 (D2R), which are G protein-coupled receptor (GPCR) that are positively and negatively coupled to adenyl cyclase, respectively. Multiple evidence indicates that the potent modulatory roles of DA on other neurotransmitters and neuromodulator systems implicate the direct physical interactions (i.e., heteromerization) of DAR with other receptors. DAR heteromerization, which is increased in several preclinical models of psychiatric disorders, leads to a reciprocal and fine-tuned modulation of DAR and partner receptors, therefore suggesting that targeting DAR heteromerization may contribute to the development of clinically relevant strategies. Herein, we provide an overview of current methodologies used for detecting receptor heteromers both in heterologous systems and in situ in the brain and discuss their respective advantages and limitations. We also argue that D1R and D2R have been shown to form heteromers with multiple partner receptors in heterologous systems but only few studies were able to a provide proof of their existence in the brain or establish their biological roles. This review will emphasize on studies describing the modulation and functions of DAR heteromerization in the brain in preclinical models of psychiatric disorders, with a particular focus on addiction, a field in which those heteromerization processes have been the most extensively studied. Review Tue, 01 Apr 2025 00:00:00 GMT AdèleVilette, AnnaPetitbon, Marie-CharlotteAllichon, PierreTrifilieff, PeterVanhoutte, Tue, 01 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004100 https://www.explorationpub.com/Journals/ent/Article/1004101 Stroke is the third leading cause of death and disability in industrialized countries. The estimated costs of stroke to the healthcare system are $85 billion in the United States and $40 billion in the European Union. Despite the extensive research over the past decades, only therapies aimed at restoring blood flow to the affected area have been successful. However, the high risk of causing intracranial hemorrhage limits the application of this type of therapy to a small number of patients. Several studies have shown that, in addition to its well-known regulatory function in erythropoiesis, erythropoietin (EPO) is a potent neuroprotective agent against ischemic stroke. However, the use of EPO to treat stroke requires long-term protocols, high doses, and multiple administrations, which may cause thromboembolic complications due to increased hematocrit and blood viscosity, making EPO treatment unsuitable. To mitigate these adverse effects, various EPO analogues with neuroprotective properties but lacking erythropoietic activity have been investigated. This review aims to provide an overview of the protective mechanisms of EPO and its derivatives in the treatment of stroke. Review Thu, 24 Apr 2025 00:00:00 GMT RamónRama, Joan RamonTorrella, Thu, 24 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004101 https://www.explorationpub.com/Journals/ent/Article/1004102 Chronic upper limb pain is rather common among people in general and is characterized by a complex diagnosis due to the wide variety of factors that are involved in its development. In terms of treatment, pharmacology and manual therapy have classically been the most used options. However, based on current evidence, recommendations are more inclined to apply multimodal treatments, mainly with exercise therapy and pain education, based on the patient-centered care model. This case report details the evaluation and treatment of a 23-year-old woman with chronic upper limb pain using a multimodal physical therapy with a biobehavioral approach. The intervention lasted 12 weeks with a total of 9 sessions, in which manual therapy, therapeutic exercise, pain neuroscience education, motion representation methods, and sensory retraining were applied. The treatment resulted in a substantial improvement in the patient’s health condition. This case report indicates that a multimodal physical therapy treatment based on a biobehavioral approach may offer benefits in reducing pain symptoms and enhancing somatosensory, motor-functional, and affective-cognitive abilities in patients with chronic upper limb pain, as observed in the described case. Accordingly, this treatment can be a therapeutic option for patients with chronic upper limb pain. Case Report Sun, 27 Apr 2025 00:00:00 GMT Fernando-BalbinoBlanco-Fernández, CarlosForner-Álvarez, CeliaVidal-Quevedo, FerranCuenca-Martínez, MónicaGrande-Alonso, Sun, 27 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004102 https://www.explorationpub.com/Journals/ent/Article/1004103 The diagnosis of attention deficit hyperactivity disorder (ADHD) poses several diagnostic problems, as is widely acknowledged. The name points to two symptoms only, which are unspecific and embedded in many more neuropsychological symptoms. The additional deficits, such as problems with orientation, memory, cognition, emotion, autonomic nervous regulation, and motor dysfunctions, can be more important for patients in their daily lives than attention and hyperactivity. The general term “neurodevelopmental disorder (6A0)” in the International Classification of Diseases (ICD-11) is more appropriate and should be used instead. A further question is, when a dysfunction, such as inattention, becomes a clinical sign. As outlined in the International Classification of Functioning, Disability and Health (ICF), the context and the associated impairment decide on the clinical relevance of dysfunctions. Accordingly, the diagnosis of neurodevelopmental disorders must start with the description of context requirements, then assess capacity restrictions, and finally relate these to neuropsychological deficits. Subdimensions of neurodevelopmental disorders, as listed in ICD-11, are of no additional benefit, as they are comorbid merging syndromes. Perspective Tue, 06 May 2025 00:00:00 GMT MichaelLinden, Tue, 06 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004103 https://www.explorationpub.com/Journals/ent/Article/1004104 Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation. Review Wed, 07 May 2025 00:00:00 GMT NingyunHu, LiangChen, GuokuHu, RongMa, Wed, 07 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004104 https://www.explorationpub.com/Journals/ent/Article/1004105 Neuroinflammation is a hallmark of various neurodegenerative and neuropsychiatric disorders, driven by complex interactions between neurotransmitter receptors and immune signaling pathways. Among these, heteroreceptor complexes—functional assemblies formed by the physical interaction of different G protein-coupled or ionotropic receptor subtypes within the same membrane microdomain—play a crucial role in modulating synaptic activity, neuroimmune responses, and inflammatory cascades. For example, the A2A-D2 receptor complex modulates dopaminergic signaling in the striatum and has been implicated in Parkinson’s disease pathology. These receptor-receptor interactions influence key signaling pathways involving dopamine, serotonin, glutamate, adenosine, and cannabinoid systems, thereby contributing to the pathophysiology of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, schizophrenia, and depression. Dysregulation of heteroreceptor complexes disrupts neuronal homeostasis, exacerbates neuroinflammatory responses, and influences microglial and astrocytic activation. Understanding the molecular mechanisms governing these interactions, including allosteric modulation and biased agonism, offers novel therapeutic avenues for targeting neuroinflammation. Pharmacological strategies, such as selective allosteric modulators, biased agonists, and receptor-specific ligands, aim to restore heteroreceptor function and mitigate neuroinflammatory damage. Emerging clinical trials—such as those evaluating A2A receptor antagonists like istradefylline for Parkinson’s disease and 5-HT2A antagonists for schizophrenia—have shown promising neuroprotective and anti-inflammatory effects, although larger-scale, long-term studies are needed to confirm efficacy. This review highlights the pivotal role of heteroreceptor complexes in neuroinflammation, discusses their therapeutic potential, and underscores the need for further research into their functional dynamics to develop effective interventions for neurodegenerative and neuropsychiatric diseases. Review Tue, 13 May 2025 00:00:00 GMT Neelakanta SarvashivaKiran, SenthilkumarRajagopal, Tue, 13 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004105 https://www.explorationpub.com/Journals/ent/Article/1004107 Polyunsaturated fatty acids (PUFAs) are critical for human health, serving as key components of cellular membranes and regulators of various physiological functions. Since the body can endogenously synthesize only a small amount of these fatty acids from precursors, adequate dietary intake is essential. This article discusses the vital role of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), in fetal brain development, with maternal omega-3 intake during pregnancy linked to improved neurodevelopment and long-term cognitive outcomes. However, variability in study findings highlights the need for further research to clarify DHA’s mechanisms of action. This article explores recent findings indicating that insufficient omega-3 levels during pregnancy disrupt key neurodevelopmental processes, particularly microglial function, potentially elevating the risk of cognitive impairments and neurodevelopmental disorders, highlighting the need for further research to confirm these effects and elucidate underlying mechanisms and long-term consequences. Ensuring adequate maternal omega-3 intake is vital for supporting healthy brain development and reducing these risks. Additionally, DHA and eicosapentaenoic acid (EPA) show promise in treating pediatric depression by modulating the gut-brain axis, reducing neuroinflammation, and restoring autonomic nervous system function—mechanisms implicated in depression. While omega-3 supplementation holds potential as an adjunctive treatment for pediatric major depressive disorder (MDD), further research is necessary to refine dosing strategies and explore underlying mechanisms, ultimately advancing neuropsychiatric care. Review Wed, 28 May 2025 00:00:00 GMT Raghd MGhazal, Moawiah MNaffaa, Wed, 28 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004107 https://www.explorationpub.com/Journals/ent/Article/1004109 Aim: Our previous research (Abstract, J Vessels Circ. 2021;2) suggested an increased risk of thrombotic events, including ischemic strokes, in patients with COVID-19. This study aims to determine the mortality rate and its predictors in patients with stroke and concurrent COVID-19 infection. Methods: A retrospective analysis was conducted on stroke patients admitted to three Iranian referral hospitals within a 3-month period during the COVID-19 pandemic (COV-pos and COV-neg groups). The mortality rate was compared to a similar period one year before the pandemic (non-COV group). The Cox proportional hazards model was used to assess the independent and interactive effects of various variables on mortality. Results: Among 124 stroke admissions, 59 (47.6%) had confirmed COVID-19 infection. The COV-pos group had a significantly higher initial NIHSS score (P = 0.001) compared to other groups. Mortality rates were 49.2%, 24.2%, and 17.3% in the COV-pos, COV-neg, and non-COV groups, respectively (P < 0.001). Posterior cerebral artery (PCA) stroke (HR = 65.099), internal carotid artery (ICA) stroke (HR = 19.102), and a history of diabetes mellitus (HR = 3.824) were identified as the most significant predictors of mortality in patients with stroke and COVID-19 infection. Conclusions: Stroke patients with COVID-19 infection exhibited a significantly higher mortality rate compared to patients without COVID-19. The type of stroke involving the PCA or ICA and a history of diabetes emerged as the strongest predictors of mortality in the studied population. Original Article Mon, 23 Jun 2025 00:00:00 GMT MostafaAlmasi-Dooghaee, SeyedehnargesTabatabaee, FatemehMoghadas, TaraKhoeini, Mona RamezaniGhamsari, TayebehLotfi, MatinehHeidari, ZakiehShafiei, RoyaYazdani, ZahraMirzaasgari, Seyed MohammadTabatabaei, MehdiMoghaddasi, Abdol-HosseinVahabie, Mon, 23 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004109 https://www.explorationpub.com/Journals/ent/Article/1004108 Aim: Aging and early Alzheimer’s disease (AD) affect pattern separation (PS) based mnemonic discrimination in humans. PS function involves the dentate gyrus (DG), a brain region producing new neurons during adulthood. Aging and AD presumably affect PS and DG function through different mechanisms, although it has never been clearly shown within the same study. Passive immunotherapy targeting β-amyloid peptides (Aβ) was used to determine the relative contribution of abnormal levels of Aβ to early PS deficits in two mouse models of aging and amyloid pathology, and potential involvement of adult neurogenesis. Methods: Female Tg2576 mice were tested in a spatial PS task from the age of three months to determine the age of onset of PS deficits. A cohort of five-month-old female Tg2576 mice and a cohort of 20-month-old male C57BL/6J mice were treated with passive immunization for four weeks, and then tested for PS performance. ELISA assays were used to quantify Aβ levels in CA3/DG regions of these mouse models. DG recruitment during PS testing was assessed with an Egr-1 ex vivo imagery. The contribution of adult-born neurons to a potential rescue of PS performances was evaluated using bromodeoxyuridine and doublecortin co-immunostainings. Results: Spatial PS deficits appeared first in four-month-old female Tg2576 mice, an early pre-plaque stage of Alzheimer pathology. Aβ immunotherapy restored PS performance in Tg2576 mice, but not in aged male C57BL/6J mice. PS impairments were associated with an overactivation of the DG in both models and a potentially abnormal level of immature adult-born neurons in Tg2576 mice. Conclusions: Alleviation of PS deficits following Aβ immunotherapy in Tg2576 mice is associated with reduced DG activation and improved adult-born neurons maturation. The absence of beneficial effects in aged mice suggests that PS deficits in aging and AD may be related to different underlying mechanisms. Original Article Tue, 17 Jun 2025 00:00:00 GMT KarinHerbeaux, ChristopherBorcuk, CarolineMursch, VéroniqueKemmel, OlivierBousiges, Anne-LaurenceBoutillier, ChantalMathis, CélineHéraud, Tue, 17 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004108 https://www.explorationpub.com/Journals/ent/Article/1004110 Neurodevelopmental disorders form a considerable group in the DSM-5, the diagnostic mental disorders manual employed in numerous regions. Some disorders are identified with biomedical tests while those from unknown sources are verified with behavioural scales. They are ubiquitous in youths, significantly impacting their behaviours and lives. They begin in early development and persist mostly throughout their lifespan with chronogeneity, i.e., changes over time. They often form comorbidities, adding to the complexity by creating “new” phenotypes at the intersection. The article aims to provide clinically critical views of ADHD and the added burden of alexithymia comorbidities with profound effects on developmental language disorder (DLD) and autism. The noted problem is the DSM-5’s mental health categorical measure of disease identification of the disorders’ symptoms, but the neglect of comorbidity. The article’s guiding theory is the adoption of the dimensional approach in addressing the target disorders, and the Vygotskian social interactional and linguistic-cognitive learning theory in proposing dimensional treatments. The ADHD including alexithymia in these disorders exhibit commonalities: 1. all are dimensional conditions rather than categorical ones requiring dimensional approaches as these include the entire continuum; 2. all show accompanying developmental language and learning limitations, and 3. all have histories of literacy acquisition problems that impact their academic trajectory while sabotaging their executive functions (EFs) development and undermining the affected individuals and the clinicians’ treatment efforts. The suggested interventions target multiple ages based on the Vygotskian social-interactional learning theory acknowledging cognitive development as language and knowledge transmitted via psychosocial interactions facilitating the internalization of education that actively forges learners’ character, psychology, and behaviours. They are meant to address their conditions’ dimensionality, remediate cognitive linguistic lags, alleviate symptoms, and substitute ineffective learning and thinking habits with more functional ones. Issues to be addressed in developing a clinical plan complete the review. Review Mon, 23 Jun 2025 00:00:00 GMT YvetteHus, OsnatSegal, Mon, 23 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004110 https://www.explorationpub.com/Journals/ent/Article/1004111 MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a pivotal role in post-transcriptional gene regulation, influencing various biological processes such as cell division, proliferation, and apoptosis. Recent research has illuminated the significant involvement of miRNAs in neurological disorders, which encompass a wide range of conditions affecting both the central and peripheral nervous systems. These disorders, including neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as psychiatric conditions such as depression and schizophrenia, impose a substantial burden on global health. Dysregulated miRNAs contribute to disease pathogenesis by modulating neuronal differentiation and related signaling cascades. This review explores the biogenesis of miRNAs and their dysregulation in neurological disorders, highlighting specific miRNAs that serve as potential biomarkers and therapeutic targets. For instance, decreased levels of miR-125b-5p and miR-26b-5p in cerebrospinal fluid have been associated with Alzheimer’s disease progression. In Parkinson’s disease, distinct profiles of dysregulated miRNAs have been identified, including miR-7-5p and miR-153-3p, which target α-synuclein. Furthermore, studies have demonstrated the potential of miRNA-based therapies to modulate disease processes and improve clinical outcomes. This review critically evaluates current therapeutic strategies for miRNA delivery in neurological disorders, focusing on advanced platforms such as nanocarriers, exosomes, viral vectors, and ligand-mediated systems designed to overcome the blood-brain barrier. We also explore the future of miRNA research in the context of precision medicine, highlighting the importance of targeted delivery, safety optimization, and integration of patient-specific molecular profiles. A comprehensive understanding of miRNA-regulated networks will be essential for developing innovative diagnostics and personalized treatments for neurodegenerative and neuroinflammatory diseases. Review Tue, 15 Jul 2025 00:00:00 GMT SouravPal, SubhajitMandal, Tue, 15 Jul 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004111 https://www.explorationpub.com/Journals/ent/Article/1004112 Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder affecting an estimated 0.4% to 2.5% of community populations. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and marked metabolic heterogeneity underscore its complex pathophysiology. The hypothalamic peptides hypocretin-1 and -2 (also known as orexin-A and orexin-B), synthesized by neurons in the lateral hypothalamus, regulate sleep-wake cycles, arousal, autonomic function, and energy homeostasis. This integrative review aimed to synthesize current evidence on hypothalamic orexinergic dysfunction in ME/CFS and assess its potential as a biomarker framework for stratification in precision medicine. The review followed Whittemore and Knafl’s five-stage methodology. Comprehensive searches were conducted across PubMed, Scopus, Web of Science, and OpenAlex up to April 2025, supplemented by manual screening of reference lists. Data extraction and synthesis were performed using constant comparison techniques to integrate quantitative outcomes with theoretical insights. Twenty-seven studies met the inclusion criteria, consistently reporting reduced orexin-A levels in individuals with ME/CFS and variable orexin-B responses indicative of biomarker potential. Neuroendocrine findings, including alterations in cortisol and adrenocorticotropic hormone levels, along with inflammatory profiles, confirmed the involvement of neuroimmune interactions. Multi-omics analyses further delineated distinct patient subtypes characterized by unique molecular signatures. Hypothalamic orexinergic dysfunction emerges as a central feature of ME/CFS, with orexin-B representing a promising candidate biomarker. The integration of orexin profiling with multi-omics data and machine learning strategies provides a viable pathway towards precision-medicine interventions for this heterogeneous condition. Review Thu, 14 Aug 2025 00:00:00 GMT NoéLópez-Amador, Thu, 14 Aug 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004112 https://www.explorationpub.com/Journals/ent/Article/1004113 Aim: Epilepsy is associated with cognitive and neuropsychiatric impairments, affecting attention, memory, executive functions, and emotional well-being. While these impairments are well-documented in general epilepsy populations, limited research focuses on economically active young adults who face unique cognitive demands in competitive academic and professional environments. The objective of this research was to evaluate the cognitive and neuropsychiatric outcomes in economically active young adults with epilepsy compared to matched controls. Methods: An observational, analytical, case-control study was conducted at a secondary medical center in Mexico. Participants included 25 patients with well-controlled epilepsy and 25 matched controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Addenbrooke’s Cognitive Examination III (ACE-III). Anxiety and depression were evaluated using the Beck Anxiety Inventory and Patient Health Questionnaire-9 (PHQ-9). Statistical analysis included Student’s T-test and Chi-square for cognitive scores and Wilcoxon rank-sum tests for non-parametric data. Results: Cognitive impairments were significantly more frequent in patients with epilepsy than in controls, particularly in attention (p = 0.041), episodic memory (p = 0.048), clock drawing (p = 0.004), and cube copying (p < 0.001). Verbal (p = 0.011) and semantic fluency (p = 0.027) were also affected. No significant differences were observed in anxiety (p = 0.221) or depression (p = 0.800) between groups. Conclusions: Economically active young adults with well-controlled epilepsy showed significant cognitive impairments, particularly in attention, memory, visuospatial, and executive functions, independent of anxiety and depression levels. This study underscores the need for comprehensive cognitive and neuropsychiatric evaluations in epilepsy treatment, regardless of seizure control. It advocates for targeted cognitive rehabilitation and a holistic approach to epilepsy care beyond seizure frequency control. Original Article Thu, 21 Aug 2025 00:00:00 GMT Rodolfo ManuelRomán-Guzmán, RaúlMedina-Rioja, IldefonsoRodríguez-Leyva, CristinaMonzón-Tapia, Luis MarioMéndez-Casillas, José LuisRodríguez-Castro, Luis DanielMarquez-Farias, DavidMartínez-González, Hector G.Hernández-Rodríguez, Denisse GraceMartínez-Roque, Mario OhtlitonaliHernández-Bautista, SahianFlores-Guerrero, MarisolGallegos-Guerrero, Christian AndreMartín-Solís, Ilse SofíaDávalos-Higareda, Thu, 21 Aug 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004113 https://www.explorationpub.com/Journals/ent/Article/1004114 Aim: Pain and overuse syndromes are common problems among musicians. The prevalence of musculoskeletal complaints in professional musicians ranges from 62% to 93%. Excessive muscle tension, rigidity, weakness, and stiffness in various anatomical regions such as the arm, neck, and lower back are common complaints. This study investigates the prevalence and severity of musculoskeletal symptoms, such as the amount and distribution of pain in the cranio-cervical-mandibular complex, the presence of bruxism and temporomandibular noises in conservatory clarinet students. Methods: A 36-item questionnaire regarding the presence of musculoskeletal symptoms was sent to all clarinet students at Italian conservatories. Results: From the analysis of the responses of 100 students, the occurrence of pain was not related to experience and was higher during non-musical activities (70%) than during performance (38%) (P = 0.001). Female players reported higher levels of pain using a 0–10 numeric rating scale: 4 during performance, 5 during non-musical activities, while males scored 3 in both conditions. A slight positive correlation emerged between pain and years of study (P = 0.03). The most painful regions were those of the posterior neck (29–45%) and the masseter muscle (28–31%). Temporomandibular noises were prevalent in female students (female 43%, male 22%, P = 0.005) and were often associated with bruxism (P = 0.015). Conclusions: Clarinet students should be informed about the symptoms they may experience, but also about the prevention of these symptoms and the techniques to improve clarinet performance. Original Article Thu, 28 Aug 2025 00:00:00 GMT LudovicaBadino, EmmaGarzoglio, TizianaCanfori, MaurizioBalestrino, LucillaVestito, CarloTrompetto, LucioMarinelli, Thu, 28 Aug 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004114 https://www.explorationpub.com/Journals/ent/Article/1004115 Exercise may be one of the most potent tools for protecting the brain—but only through active participation can its benefits be realized. This perspective provides a brief overview of current research avenues and key insights into the role of physical activity and exercise in preventing and mitigating chronic and neurodegenerative diseases and promoting optimal health across the population. The perspective opens with a summary of key findings on how exercise supports brain health and cognitive well-being. It then draws on rodent model studies which shed light on the molecular mechanisms behind these benefits. The paper addresses challenges in translating this research into effective, real-world exercise programs and introduces a new framework aimed at fostering global, inclusive initiatives. This transformative approach is designed to reach individuals across all ages, backgrounds, and health statuses. A central theme throughout is the critical role of psychological factors in exercise adherence—highlighting the need to tackle these barriers if scientific advances are to translate into meaningful benefits for diverse populations. Perspective Wed, 17 Sep 2025 00:00:00 GMT Elizabeth A.Franz, Wed, 17 Sep 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004115 https://www.explorationpub.com/Journals/ent/Article/1004118 Tau phosphorylated at threonine 217 (p-tau217) has moved from research novelty to clinical reality, but its greatest value lies in dynamic monitoring, not static stratification. The pace of adoption of the plasma measurement of p-tau217 now demands clear guidance on optimal use. Two complementary evidence strands inform this perspective. First, a multi-cohort evaluation of a commercial assay shows high concordance with amyloid and tau reference standards and supports a pragmatic three-zone interpretation, rule-out, indeterminate, and rule-in, that can streamline diagnostic pathways while preserving accuracy. Second, longitudinal analyses in amyloid-positive individuals reveal that the most informative property of p-tau217 is dynamic: steeper rises occur in those who decline faster, whereas baseline values substantially overlap across outcome groups. These findings show that plasma p-tau217 levels can be a complementary tool for triage, enrichment, and longitudinal monitoring, but not as a time-stable baseline stratifier for defining trial cohorts or assessing therapeutic efficacy. Stratification should instead anchor to independent, stable measures such as tau burden measured by positron emission tomography (PET), structural magnetic resonance imaging (MRI), and cognitive history, reducing misclassification and avoiding circular validation. Comparable scrutiny should be applied to other p-tau biomarkers and to composite measures, such as the p-tau217/Aβ1–42 ratio, to rigorously define their risk-benefit profile, guide therapeutic evaluation, and maximize translational impact. Perspective Thu, 16 Oct 2025 00:00:00 GMT RafaelFranco, Thu, 16 Oct 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004118 https://www.explorationpub.com/Journals/ent/Article/1004117 Healthcare professionals, especially those in rehabilitation, are increasingly vulnerable to occupational burnout, particularly in the post-pandemic landscape. This review synthesizes existing literature on the prevalence of burnout, possible contributing factors, resilience mechanisms, and interventions tailored to physiotherapists and related disciplines. A narrative review was carried out by combing through databases including PubMed, Scopus, and Web of Science for literature published between 2020 and 2025. The studies focused on burnout, mental health, and resilience among rehabilitation professionals were included in the review. Burnout remains prevalent, with emotional exhaustion and reduced personal growth commonly reported. Risk factors include lack of support, excessive workload, and exposure to workplace bullying. Protective mechanisms entail individual resilience behaviors, social support, and institutional strategies such as regulated supervision and workload management. Addressing burnout in rehabilitation settings requires a dual approach—strengthening individual factors and directing systemic organizational reforms. Embedding resilience education into the training core curriculum and workplace code of conduct may boost mental well-being. Mini Review Thu, 16 Oct 2025 00:00:00 GMT AyeshaInam, MuhammadAhmed, Thu, 16 Oct 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004117 https://www.explorationpub.com/Journals/ent/Article/1004119 Parkinson’s disease (PD) is a devastating neurodegenerative condition characterized primarily by the degeneration of the dopaminergic neurons in the substantia nigra, causing motor dysfunction and many non-motor symptoms. Available pharmacological treatments and therapies provide symptomatic relief but do not halt the progression of PD. Gene therapy has been recognized as a valuable therapeutic frontier, providing the possibility of disease modification by targeting the underlying molecular and cellular mechanisms of PD. The parts of the methodology used for gene therapy entail the delivery of genetic material into particular regions of the brain with the aid of viral vectors to improve the synthesis of dopamine, maintain the integrity of neurons, or control pathological pathways. Recent clinical trials have shown promising efficacy and safety profiles for many gene therapy methods, consisting of those targeting enzymes in the biosynthesis of dopamine [e.g., L-amino acid decarboxylase (AADC)], synuclein alpha pathology, and neurotrophic factors [e.g., growth-derived neurotrophic factor (GDNF)]. However, in spite of these developments, there are limitations in vector delivery and prolonged expression of genes, as well as patient-specific responses. This review highlights the present landscape of gene therapy in PD, discussing the latest successes, ongoing clinical trials, and future perspectives that could shape therapeutic paradigms for PD. Review Fri, 31 Oct 2025 00:00:00 GMT Abraham OlufemiAsuku, Gbonjubola OyinlolaOgungbangbe, Grace AyobamiFajemidagba, Fri, 31 Oct 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004119 https://www.explorationpub.com/Journals/ent/Article/1004120 Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, and accumulation of amyloid-beta plaques and tau tangles. Emerging research emphasizes the gut-brain axis as a key modulator of AD pathogenesis, with gut microbiota influencing neuroimmune, neurochemical, and metabolic pathways. This review examines the therapeutic and preventive potential of probiotics, live beneficial microorganisms, in modulating the gut-brain axis to mitigate AD progression. Modifying gut microbiota presents a novel, potentially modifiable approach to influence AD pathophysiology and improve cognitive outcomes, offering insights for adjunctive clinical strategies. A systematic literature search was conducted across PubMed, Scopus, Web of Science, Google Scholar, and Cochrane Library for studies published up to July 2025. Studies were classified by design, sample size, follow-up duration, cognitive and biomarker outcomes, and risk of bias, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to ensure transparency and reproducibility. Preclinical studies indicate that probiotics can regulate gut microbiota, reduce oxidative stress, suppress neuroinflammation, and enhance synaptic plasticity, improving cognition in animal models. Clinical trials suggest potential benefits in humans, including improved memory scores and reduced inflammatory biomarkers, though limited sample sizes, trial duration, and strain variability constrain conclusions. Overall, probiotics demonstrate promise as an adjunctive intervention in AD. Further long-term, strain-specific, and large-scale clinical studies are needed to confirm efficacy, establish causality, and optimize therapeutic strategies. Review Tue, 04 Nov 2025 00:00:00 GMT Adnan AkhtarShaikh, Harsahaj SinghWilkhoo, AshwiniPillai, SairaThomas, BharatSingh, NivedithaNair, Tue, 04 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004120 https://www.explorationpub.com/Journals/ent/Article/1004121 The investigations pertaining to the effectiveness of natural products in novel drug development for the prevention of a myriad of neurodegenerative diseases are offering encouraging prospects in novel drug development. This review endeavors to offer a comprehensive insight into the neuroprotective effects of baicalein (BE) and baicalin (BI), bioactive flavonoids found in Scutellaria baicalensis, primarily from the perspective of Alzheimer’s disease (AD). It systematically encompasses the scientifically pertinent investigations on BE’s prospective benefits in AD models, highlighting its mechanistic approaches and impending therapeutic applications in the amelioration of AD. The multifaceted pharmacological interventions offered by these bioactives, including antioxidant, anti-inflammatory, and immunomodulation effects, reinforce the scientific evidence supporting them as promising candidates for anti-AD agents and for preventing and managing other allied neurodegenerative disorders. These findings suggest that BE and BI, along with other nutraceuticals, may offer a valuable therapeutic strategy for improving symptoms and slowing disease progression in neurodegenerative disorders. Thus, the review intends to offer comprehensive illustrations warranting further investigation to corroborate the safety and efficacy of these bioactives in clinical settings. The researchers are progressively entrusting nature’s own compounds for the treatment of neurodegeneration. Conclusively, this manuscript could aptly serve as an insight to embark upon the remarkable pharmacological actions of these bioactives, which might be harnessed to prevent and manage AD. Nevertheless, the findings so far are promising; still, further investigations are incumbent to establish their safety and efficacy in humans, as BE and BI may offer novel modalities to circumvent this devastating disease. Review Wed, 12 Nov 2025 00:00:00 GMT PrernaSarup, JaiMalik, SoniaPahuja, Wed, 12 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004121 https://www.explorationpub.com/Journals/ent/Article/1004122 Aim: Systemic inflammation is a key factor in cognitive decline and neurodegenerative diseases. Polyphenols, such as curcumin, resveratrol, and salidroside, exhibit neuroprotective effects, but their low bioavailability raises questions about their mechanism of action. The gut-brain axis, mediated by microbiome modulation, may play a critical role in their cognitive benefits. This study investigated whether polyphenols (curcumin, resveratrol, and salidroside) improve cognitive function in mice with lipopolysaccharide (LPS)-induced gut inflammation by modulating the gut microbiome and reducing neuroinflammation. Methods: C57BL/6 mice were divided into five groups: control, LPS, and LPS + polyphenol treatments (curcumin, resveratrol, or salidroside). LPS was administered intraperitoneally to induce inflammation, while polyphenols were given orally for three weeks. Cognitive performance was assessed using the Morris water maze. Gut microbiome composition (16S rRNA sequencing), mitochondrial DNA (mtDNA) damage, and gene expression in brain regions were analyzed. Results: LPS impaired spatial memory, but resveratrol and salidroside significantly mitigated these deficits. Polyphenols restored beneficial bacteria (e.g., Alloprevotella, Eubacterium) and suppressed pathogenic taxa (e.g., Peptostreptococcales). They also reduced pro-inflammatory markers in the cortex and hippocampus. Curcumin showed weaker effects. No significant mtDNA damage was detected. Conclusions: Polyphenols, particularly resveratrol and salidroside, improve cognition during systemic inflammation by remodeling the gut microbiome and attenuating neuroinflammation. These findings highlight the gut-brain axis as a therapeutic target for inflammation-driven cognitive disorders. Original Article Tue, 18 Nov 2025 00:00:00 GMT Ekaterina P.Krutskikh, Polina I.Babenkova, Veronika V.Nesterova, Arina D.Tsvetkova, Inna Yu.Burakova, Artem P.Gureev, Tue, 18 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004122 https://www.explorationpub.com/Journals/ent/Article/1004123 The glymphatic system (GS) consists of a paravascular fluid-exchange network that regulates cerebrospinal and interstitial fluid dynamics, clears metabolic waste, and modulates neuroinflammation. Aquaporin-4 (AQP-4), expressed in astrocytic end-feet, is central to GS function and blood-brain barrier integrity, but in cerebral ischemia (CI), GS disruption and AQP-4 mislocalization drive cytotoxic edema, inflammation, and vascular dysfunction, worsening outcomes. This review aimed to examine the role of the GS in CI, focusing on pathophysiology and potential therapeutic targets. A PubMed-based literature review was conducted, selecting 51 studies from 115 screened that addressed GS, AQP-4, and ischemic stroke. Evidence suggests that modulating GS flow, through strategies such as enhancing arterial pulsations or regulating AQP-4, may reduce edema and neuroinflammation, although selectively targeting AQP-4 without impairing waste clearance remains a key challenge. The GS represents a promising therapeutic target in ischemic stroke, and a deeper understanding of its physiology may guide the development of neuroprotective interventions; future research should refine pharmacological strategies to optimize glymphatic function and improve recovery in CI patients. Review Fri, 21 Nov 2025 00:00:00 GMT RenataMurguiondo-Pérez, EmilioMoreno-González, Iván IgnacioMejía, Exsal ManuelAlbores-Méndez, Héctor FaustinoNoyola Villalobos, YolandaCruz Martínez, AntonioIbarra, Fri, 21 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004123 https://www.explorationpub.com/Journals/ent/Article/1004124 The increasing prevalence of neurodegenerative diseases (NDs), such as Alzheimer’s, Parkinson’s, Huntington’s, multiple sclerosis, and amyotrophic lateral sclerosis, represents a serious global public health issue. Consequently, the search for compounds with neuroprotective potential has intensified. In this context, resveratrol (RSV), a stilbene polyphenol found mainly in red grapes, exhibits important pharmacological properties, such as antioxidant and anti-inflammatory, and has been widely investigated in neuroscience due to its potential in the prevention and treatment of NDs. This narrative review was conducted using the PubMed® database, with the keywords “resveratrol”, “molecular mechanisms”, “mechanisms of action”, “neuroinflammation”, “oxidative stress”, “autophagy”, “gene regulation”, and “clinical studies”. This study discusses the molecular mechanisms of RSV on NDs, focusing on signaling pathways involved in neuroinflammation, oxidative stress, gene regulation, autophagy, and cell death. Intracellular pathways such as NF-κB, JAK/STAT, MAPK/ERK, PI3K/Akt, and Nrf2/Keap1 are associated with immune modulation mediated by RSV, leading to a decrease in oxidative stress, induction of autophagy, and inhibition of apoptosis. RSV has pharmacokinetic limitations, such as low bioavailability and stability, although RSV can cross the blood-brain barrier. Thus, researches involving nonencapsulated formulations aim to enhance their delivery to the central nervous system. Current in vitro and in vivo studies are promising, although further clinical trials are needed, as few have been conducted and available data remain preliminary. In conclusion, RSV presents multiple benefits to neurological health and shows therapeutic potential in NDs; however, additional clinical studies and translational research are essential to validate and optimize its application. Review Fri, 21 Nov 2025 00:00:00 GMT Mac Dionys Rodrigues daCosta, Izabell Maria MartinsTeixeira, Bruna RibeiroDuque, Natasha Maria LimaPinheiro, Cauan FariasAnanias, Mateus OliveiraFernandes, Larissa Holanda eSilva, Hugo Leonardo PereiraFilho, Glautemberg de AlmeidaViana, Emanuel PaulaMagalhães, Ramon Róseo Paula Pessoa Bezerra deMenezes, Alice Maria CostaMartins, Tiago LimaSampaio, Fri, 21 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004124 https://www.explorationpub.com/Journals/ent/Article/1004126 Non-traumatic arterial dissection exhibits a propensity for the Asian population and predominantly affects the posterior circulation. Regrettably, during the initial fortnight prior to diagnosis, approximately one in thirty cervicocephalic artery dissections (CAD) are misdiagnosed. Overlooked CAD, more prevalent in the younger demographic, can result in severe complications such as ischemic stroke, subarachnoid hemorrhage, and possibly death. Comprehensive investigations are necessary to prevent overlooking such a diagnosis. Digital subtraction angiography (DSA) is universally acknowledged as the most efficacious technique for assessing luminal morphology and hemodynamics, but may miss the vessel wall characteristics, an important component for diagnosing dissection. Magnetic resonance angiography (MRA), conversely, is less invasive and can assess vessel wall properties. A high-resolution MRA with vascular wall imaging can efficiently identify conditions such as intimal flaps, double-lumen signs, intramural hematomas, mural thrombi, and pseudoaneurysms, aiding in the evaluation of suspected CAD. MRA with vascular wall imaging and DSA complement each other in the identification and characterization of cerebral artery dissections, both contributing to treatment. In cases of undefined stroke etiology, particularly among the young demographic, utilizing both tests (when one yields no significant findings) may assist in detecting overlooked instances of CAD. The prompt identification and treatment of CAD are essential, particularly for surgical intervention and to avert recurrence in predisposed patients. Identifying the etiology of a stroke or transient ischemic attack is important for providing precise therapy and preventing recurrence. Perspective Mon, 08 Dec 2025 00:00:00 GMT DebabrataChakraborty, Mon, 08 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004126 https://www.explorationpub.com/Journals/ent/Article/1004125 Background: This study aims to assess oral alpha lipoic acid’s (ALA’s) safety and effectiveness in managing diabetic neuropathy. Methods: A thorough search of the literature was conducted using PubMed, Google Scholar, and Embase databases, and the study was performed as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Based on inclusion and exclusion criteria, nine randomized controlled trials (RCTs) comprising 1,345 subjects were selected. The results showed that ALA has shown significant reduction in glycated hemoglobin (HbA1C) [inverse variance (IV): –0.66, (–0.81 → –0.51) at 95% CI, p < 0.00001, I2 = 92%], neuropathy impairment score (NIS) [IV: –1.19, (–2.28 → –0.09) at 95% CI, p = 0.03, I2 = 58%], along with improving the neuropathy symptoms and change (NSC) number [IV: –0.18, (–0.35 → –0.01) at 95% CI, p = 0.04, I2 = 0%], NSC severity score [IV: –0.65, (–0.83 → –0.48) at 95% CI, p < 0.00001, I2 = 89%], total severity score (TSS) [IV: –0.43, (–0.59 → –0.27) at 95% CI, p < 0.00001, I2 = 98%], neurological disability score (NDS) [IV: –0.72, (–1.03 → –0.40) at 95% CI, p < 0.00001, I2 = 98%], vibration perception threshold (VPT) [IV: –0.35, (–0.50 → –0.19) at 95% CI, p < 0.0001, I2 = 96%] and global satisfaction [Mantel-Haenszel (M-H) odds ratio (OR): 3.51, (1.06 → 11.61) at 95% CI, p = 0.04, I2 = 72%] when compared to the control or placebo group. However, ALA has not shown significant changes in motor nerve conduction velocity (MNCV) score [IV: 0.26, (–0.44 → 0.96) at 95% CI, p = 0.47, I2 = 49%] and NIS-low limb (NIS-LL) [IV: –0.58, (–1.35 → 0.19) at 95% CI, p = 0.14, I2 = 0%] when compared to the placebo group. Discussion: Based on the available moderate to high-quality evidence, we can conclude that oral administration of ALA at doses of 600–1,800 mg may be beneficial in improving/alleviating the symptoms resulting from diabetic neuropathy. Systematic Review Fri, 05 Dec 2025 00:00:00 GMT SusmitaDas, Gollapalle LakshminarayanashastryViswanatha, KrishnadasNandakumar, AnoopKishore, ShylajaHanumanthappa, Fri, 05 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004125 https://www.explorationpub.com/Journals/ent/Article/1004127 Background: Ischemic stroke is a leading cause of disability, with calcium (Ca2+) dysregulation contributing to neuronal injury and impaired recovery. While early clinical trials targeting calcium signaling showed limited success, growing preclinical evidence supports the potential of calcium modulation for long-term neuroprotection. This systematic review evaluates the long-term effects of calcium modulation in animal models of ischemic stroke. Methods: A comprehensive search across PubMed, Scopus, Web of Science, and the Cochrane Library up to June 2025 identified studies investigating calcium-targeted interventions (e.g., calcium channel blockers, chelators, antioxidants) with ≥ 30 days of follow-up. Risk of bias was assessed using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I). Results: Nine studies met the inclusion criteria. Interventions like L-type calcium channel blockers, magnesium sulfate, and ischemic preconditioning consistently reduced infarct volume (e.g., 22.4 ± 0.5% with preconditioning vs. 51.6 ± 2.1% with knockout) and improved neurobehavioral outcomes [e.g., epigallocatechin gallate (EGCG)-treated rats scored 2.17 ± 0.05 vs. 3.63 ± 0.06 in controls]. Molecular pathways involved included phosphoinositide 3-kinase (PI3K)/AKT, stromal interaction molecule 1 (STIM1)/ORAI1, and calcium-sensor proteins such as NCKX2. Discussion: Calcium modulation holds strong promise for neuroprotection in ischemic stroke models. Although clinical gaps remain, these findings support the development of calcium-targeted therapies for stroke recovery, especially when combined with multimodal strategies. Systematic Review Thu, 11 Dec 2025 00:00:00 GMT Poppy KristinaSasmita, Raden MohamadJavier, Steven AvianoShenelo, AndraDanika, Andreas DexterGeson, Bernadus BernardinoBramantyo, Thu, 11 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004127 https://www.explorationpub.com/Journals/ent/Article/1004128 Aim: Alzheimer’s disease (AD) devastates learning and memory, the defining faculties of the human species. Extracellular amyloid beta (Aβ) deposits and intracellular hyperphosphorylated tau are hallmarks of AD pathology. The exact cause of the disease remains unknown, but a lot of data support AD to be a multifactorial disease. Given the central roles of oxidative stress and neuroinflammation in AD pathogenesis, apocynin, a potent antioxidant and anti-inflammatory agent, was selected for investigation. Apocynin is an aromatic ketone, a naturally occurring methoxy-substituted catechol known to possess numerous biological activities, namely anti-oxidant, anti-inflammatory, etc. The present study assessed apocynin’s potential against an Aβ1–42-induced sporadic AD rat model. Methods: In the present study, Wistar rats were subjected to intrahippocampal administration of 200 µmol/L of Aβ1–42 peptide in right hemisphere. Further were treated with apocynin 50, 150, and 300 mg/kg per orally for 28 days. The study examined the neurobehavioral aspects using the Barnes Maze test (BMT). Hippocampus was examined for the antioxidant (SOD, GSH, catalase, and LPO), inflammatory (TNF-α) parameters, RAGE, caspase-3, PGC-1α expression, and IHC analysis for Aβ load, adult hippocampal neurogenesis markers (BDNF, Ki67, DCX, NeuN), at the end of 28 days. Results: Apocynin administration demonstrated significant improvement in cognitive functions, diminished oxidative stress and inflammatory response triggered by Aβ administration. Apocynin additionally instigated adult hippocampal neurogenesis and triggered mitochondrial biogenesis. Conclusions: These primary results strongly advocate apocynin’s nootropic, neurotrophic and neuroprotective potential in an Aβ induced neurotoxicity in rats. Original Article Thu, 11 Dec 2025 00:00:00 GMT SnehaBagle, SurajMuke, VaibhaviPeshattiwar, AakrutiKaikini, VikasDighe, SadhanaSathaye, Thu, 11 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004128 https://www.explorationpub.com/Journals/ent/Article/1004129 Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, in which gut microbiota alterations have emerged as a potential pathogenic factor, causing disruption of the brain-gut-microbiota (BGM) axis. Recent evidence supports the role of BGM axis disruption in enhancing neuroinflammation, alpha-synuclein (α-syn) aggregation, and dopaminergic neurodegeneration. Emerging therapeutic strategies targeting dysbiosis, such as probiotics and fecal microbiota transplantation (FMT), have become a new focus of investigation for PD treatment. Proposed mechanisms include modulation of immune responses, enhancement of intestinal barrier integrity, production of neuroactive metabolites such as short-chain fatty acids, and reduction of oxidative stress. This narrative review summarizes current evidence on probiotics as a therapeutic strategy in PD. By analyzing data from randomized controlled trials and preclinical studies, we highlight the beneficial effects of probiotics in improving motor and non-motor symptoms of PD, including constipation, depression, and anxiety. Strains such as Lactobacillus plantarum PS128 and Bifidobacterium animalis Probio-M8 show particular promise. Although probiotics have demonstrated a favorable safety profile and potential as an adjunctive therapy for PD, future research should focus on standardized protocols, biomarker identification, and exploration of combined microbiota-targeted strategies. Review Mon, 15 Dec 2025 00:00:00 GMT SalomónPáez-García, DanielHernández-Triana, FelipeEsparza-Salazar, George E.Barreto, Maria CruzRodriguez-Oroz, Miguel GermánBorda, Mon, 15 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004129 https://www.explorationpub.com/Journals/ent/Article/1004130 Apparent increases in autism and other forms of neurodivergence are often interpreted as a rise in incidence. Yet demographic expansion, diagnostic broadening, and growing cultural awareness all contribute to higher prevalence estimates. At the same time, contemporary sensory and digital environments have become increasingly overstimulating, characterized by persistent noise, visual saturation, hyperconnectivity, and unpredictable social rhythms. These conditions heighten sensory and cognitive load for many individuals, making neurodivergent traits more visible and increasing the urgency of diagnosis. Drawing on cognitive ecology, sensory neuroscience, and neuroaffirmative scholarship, this perspective proposes that neurodivergence can be understood as an adaptive response to environments that exceed nervous-system thresholds. Autistic regulatory behaviors—including withdrawal, shutdown, sensory avoidance, and monotropism-driven focus—may serve as mechanisms for maintaining coherence in overstimulating contexts. Interpreting neurodivergence as an ecological signal offers new pathways for public health, accessibility design, and social policy. It reframes autistic embodiment not as internal dysfunction but as meaningful information about the livability of contemporary environments. Perspective Fri, 19 Dec 2025 00:00:00 GMT LurCarreras, Fri, 19 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004130 https://www.explorationpub.com/Journals/ent/Article/1004148 Background: Atrial fibrillation (AF) substantially increases the risk of ischemic stroke (IS), underscoring the need for effective anticoagulation strategies. Direct oral anticoagulants (DOACs) have largely supplanted vitamin K antagonists (VKAs) due to their favorable safety profile and ease of use. Factor XI (FXI) inhibitors, which target the intrinsic coagulation pathway, are emerging as potential alternatives that may offer reduced bleeding risk. This systematic review evaluates the efficacy and safety of FXI inhibitors compared with DOACs for stroke prevention in AF. Methods: A total of 20 studies fulfilled the inclusion criteria, comprising 11 randomized controlled trials (RCTs), five systematic reviews or meta-analyses, and four narrative, cohort, or modeling studies. Eligible investigations compared FXI inhibitors with DOACs in patients diagnosed with AF. The primary outcomes assessed were stroke or systemic embolism, major bleeding, and all-cause mortality. Methodological quality was evaluated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, the revised Cochrane Risk of Bias 2 (RoB 2) tool for RCTs, and the Newcastle-Ottawa Scale (NOS). Results: FXI inhibitors were associated with a significant reduction in major bleeding [relative risk (RR) 0.31; 95% confidence interval (CI) 0.21–0.46] and clinically relevant non-major bleeding (RR 0.66; 95% CI 0.47–0.93) compared with DOACs. Conversely, FXI inhibitors demonstrated an increased risk of stroke or systemic embolism (RR 3.17; 95% CI 2.18–4.62), as observed in the OCEANIC-AF trial [hazard ratio (HR) 3.79; 95% CI 2.46–5.83]. No significant difference was noted in all-cause mortality (RR 0.85; 95% CI 0.67–1.08). Limited evidence suggests that FXI inhibitors may also reduce bleeding-related hospitalizations. Discussion: FXI inhibitors provide a favorable bleeding profile but are less effective than DOACs for stroke prevention in patients with AF. Further long-term RCTs are warranted to delineate their role, particularly in populations at high risk of bleeding. Systematic Review Tue, 21 Apr 2026 00:00:00 GMT RaziehParizad, JunialiHatwal, HalehBodagh, AkashBatta, BishavMohan, Tue, 21 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004148 https://www.explorationpub.com/Journals/ent/Article/1004131 The oral microbiome has been increasingly implicated in the development and progression of neurological disorders. This narrative review synthesizes contemporary literature on alterations of oral microbial communities in Alzheimer’s disease, Parkinson’s disease, and migraine and evaluates their potential contribution to neuroinflammation and neurodegeneration. We first outline the core oral taxa that maintain microbial homeostasis and summarize evidence that patients with these neurological conditions exhibit dysbiosis characterized by reduced diversity and enrichment of periodontal pathogens. Proposed mechanisms include hematogenous or neural translocation of oral bacteria and their virulence factors, amplification of systemic inflammation, disruption of the blood-brain barrier, altered production of neuroactive metabolites, and bidirectional signaling along the ‘oral-gut-brain’ axis. On this mechanistic basis, microbiome-targeted strategies, particularly probiotics and fecal microbiota transplantation, have been explored as adjunctive approaches to restore microbial balance and potentially improve neurological outcomes, although available clinical data remain preliminary and heterogeneous. Current evidence is further limited by small samples, methodological variability in microbiome profiling, and a paucity of longitudinal and interventional studies, which hampers causal inference. Future research should adopt standardized sampling and multi-omic approaches and prioritize well-designed clinical trials to determine whether modulation of the oral microbiome can be translated into preventive or therapeutic strategies for neurological diseases. Review Mon, 22 Dec 2025 00:00:00 GMT ZhengruiLi, YangSu, Ji'anLiu, JingLi, Mon, 22 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004131 https://www.explorationpub.com/Journals/ent/Article/1004136 Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic Lateral Sclerosis, are characterized by multifactorial pathologies that extend beyond neuronal loss to include neuroinflammation, oxidative stress, mitochondrial dysfunction, and glial dysregulation. Despite extensive research, disease-modifying therapies remain elusive, hindered by late diagnosis, limited availability of specific biomarkers, and the persistent dominance of reductionist, single-target strategies. This comprehensive and informative review provides a critical synthesis of integrated neuroprotective strategies, with particular focus on glial mechanisms and biomarker-guided interventions. Therapeutic emphasis is placed on coordinated mechanisms targeting both neurons and non-neuronal cells, such as astrocytes, microglia, and oligodendrocytes. Emerging strategies are reported to include modulation of synaptic plasticity and neurotransmission, delivery of neurotrophic factors, activation of intrinsic cytoprotective pathways (e.g., Nrf2 signaling), restoration of proteostasis, and induction of regeneration via cellular reprogramming. Glial cells are discussed as therapeutic targets involved in inflammation, metabolism, myelination, and neuronal survival. Advances in predictive, preventive, personalized, and participatory (P4) medicine, supported by genomics, multi-omics, imaging, and real-world data, are presented as accelerating biomarker discovery and enabling earlier and more precise stage-specific interventions. Future success in combating neurodegeneration will depend on integrated approaches that combine protective, supportive, and regenerative strategies, appropriate for disease stage and patient profile. By reframing neuroprotection as a systemic, multicellular endeavor, this review highlights the potential to not only extend life expectancy, but also preserve meaningful quality of life in individuals affected by neurodegenerative diseases. Review Sun, 04 Jan 2026 00:00:00 GMT CinziaVolonté, GuokuHu, Christopher A.Shaw, ClaudioViegas, Joyce Alvesdos Santos, Sandra H.Vaz, Ana M.Sebastião, Vladimir J.Balcar, P. DavidMozley, FedericoVerde, VincenzoSilani, Fernanda TibollaViero, YongTang, HenningUlrich, RafaelFranco, Sun, 04 Jan 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004136 https://www.explorationpub.com/Journals/ent/Article/1004132 Aim: Parkinson’s disease (PD) and Alzheimer’s disease (AD) represent critical neurological disorders that have emerged as significant health concerns in the 21st century. The pharmacological interventions currently employed to manage these diseases demonstrate limited efficacy and some adverse side effects. Historically, natural products have been used to develop therapeutic agents targeting neurodegenerative disorders. This study aimed to apply in silico techniques to investigate the pharmacological mechanisms of capsaicin as a possible alternative treatment or coadjutant phytotherapy for PD and AD. Methods: We obtained target genes for capsaicin, PD, and AD from the HERB database, the Swiss Target Prediction database, the Comparative Toxicogenomics Database, and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and matched them. Subsequently, we constructed a protein-protein interaction network and performed enrichment analysis of the common targets. Then, the interactions of capsaicin with the proteins with the highest degree were tested using molecular docking. The stability of the complexes was verified using molecular dynamics techniques. Results: A total of 25 targets were found in common from the databases for capsaicin, AD, and PD. The enrichment analysis revealed that proteins from these targets influenced integrin activity in the IGF1-IGF1R complex, cholinesterase activity, and dopamine neurotransmitter receptor activity, all of which are coupled via protein Gi/Go, among other cellular processes. From the protein-protein interaction network, we identified the hub proteins IL6, GSK3B, CASP, BCL2, ESR1, SIRT1, NGF, IGF1, and HMOX1. Furthermore, molecular docking studies between hub proteins and capsaicin showed strong binding affinity. Finally, molecular dynamics simulations support a stable interaction between capsaicin and SIRT1, ESR1, HMOX1, and NGF. Conclusions: This work contributes to understanding the neuroprotective activity of capsaicin in PD and AD. However, these bioinformatic predictions require further experimental validation. Original Article Fri, 26 Dec 2025 00:00:00 GMT Luis AntonioRamirez-Contreras, Luis MiguelAnaya-Esparza, SalvadorHernández-Estrada, Luis AlfonsoHernández-Villaseñor, Jorge ManuelSilva-Jara, LeonardoHernández-Hernández, GabrielaCamargo-Hernández, Andrés Frausto deAlba, Fri, 26 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004132 https://www.explorationpub.com/Journals/ent/Article/1004133 Age-related neurological disorders such as ALS (Lou Gehrig’s disease), Parkinson’s disease, and Alzheimer’s disease have few truly effective treatment options. At best, these may slow the inexorable disease progression without providing a cure. Part of the problem with therapeutic approaches may arise due to the stage at which these diseases are detected, particularly the sporadic forms. In most cases, early signs and symptoms may be insidious, thus hiding the significant damage done to the areas of the nervous system impacted prior to any firm clinical diagnosis. This situation appears to necessitate the development of earlier detection methods for “biomarkers” that might allow for much earlier phase disease state treatments that might serve to significantly slow or even halt disease progression. Currently, most biomarkers in use serve primarily as aids to disease diagnosis, at which point there are no successful treatment options. In contrast, a search for more effective early treatment options would need to identify characteristic and specific molecular signatures of disease onset and progression using methods that are simple, such as blood-based analytical assays, relatively cheap, and crucially minimally invasive. Perspective Fri, 26 Dec 2025 00:00:00 GMT Christopher A.Shaw, CeilidhBeck, LealMarakoff, Fri, 26 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004133 https://www.explorationpub.com/Journals/ent/Article/1004134 Aim: This study examined differences in attentional control and awareness of interference among children with attention-deficit/hyperactivity disorder (ADHD), children with subthreshold ADHD (children showing some but not all symptoms required for diagnosis), and children with typical development. Specifically, we investigated how visual and auditory distractions affect behavioral performance and eye movements, to clarify the degree and nature of attentional control impairments associated with subthreshold versus clinically diagnosed ADHD. Methods: One hundred and two children (mean age = 7.23 years, SD = 1.23; 34 per group) participated in three eye-tracking tasks involving a bouncing ball under no, visual, and auditory interference. Behavioral accuracy (number of correctly counted bounces), fixation duration on the target, gaze reorientation latency, and distractor awareness were analyzed using mixed-design analyses of variance (ANOVAs) and chi-square tests. Results: Significant group differences were found in counting accuracy, F(2, 99) = 16.42, p = 0.00069, η2p = 0.245, with typically developing children performing best, followed by those with subthreshold and full ADHD. Eye-tracking indices showed a similar gradient: fixation duration decreased with symptom severity, F(4, 198) = 7.65, p = 0.00094, η2p = 0.134, while gaze reorientation latency increased, F(2, 99) = 12.18, p = 0.00093, η2p = 0.197 (typical development ≈ 480 ms; subthreshold ≈ 621 ms; ADHD ≈ 721 ms). Awareness of distractors also varied significantly across groups, χ2(2, n = 102) = 38.12, p < 0.001, Cramer’s V = 0.61, with detection rates of approximately 80% (typical development), 50% (subthreshold), and 25% (ADHD). Conclusions: Both children with ADHD and children with subthreshold ADHD show measurable deficits in attentional control and awareness of interference, particularly under visual and auditory distraction. Children with subthreshold ADHD exhibited an intermediate profile, supporting a continuum rather than a categorical distinction in cognitive control impairments. These findings highlight the importance of early identification and interventions targeting attentional regulation and metacognitive monitoring across the ADHD spectrum. Original Article Tue, 30 Dec 2025 00:00:00 GMT Rosa AngelaFabio, GiuliaPicciotto, SvetlanaTsoy, RebeccaVazzana, MasoumehHosseinpour Fatmehsari, PinaFilippello, Tue, 30 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004134 https://www.explorationpub.com/Journals/ent/Article/1004135 Aim: Neurodegenerative diseases, such as Alzheimer’s, are strongly associated with amyloid-β aggregation. This study aimed to explore bioactive metabolites from endophytic bacteria as potential anti-aggregation agents with relevance to neuroprotection, focusing on isolate D11 obtained from a geothermal fern at Gedong Songo hot springs. Methods: Isolate D11 was characterized by Gram staining and 16S rRNA sequencing. Growth curve analysis was conducted to determine metabolite production phases. Phytochemical screening, bovine serum albumin (BSA) aggregation inhibition assays, liquid chromatography mass spectroscopy (LCMS) profiling, and molecular docking against amyloid-β were employed to evaluate bioactivity and metabolite composition. Results: D11 was identified as a Gram-negative rod with 97.94% similarity to Stutzerimonas stutzeri. Metabolite production peaked during the stationary and death phases. Phytochemical tests revealed alkaloids and tannins in aqueous fractions. BSA aggregation inhibition assays demonstrated potent inhibitory activity, with IC50 values (2.40–3.29 µg/mL) significantly lower than quercetin. LCMS profiling identified diverse metabolites, dominated by flavonoid glycosides such as kaempferol-7-O-deoxyhexosyl-3-O-acetylhexoside, along with alkaloids, peptides, and diterpenoids. Molecular docking confirmed strong binding affinities of flavonoid glycosides to amyloid β (–7.6 kcal/mol), outperforming quercetin (–6.0 kcal/mol). Conclusions: These findings suggest that isolate D11 Stutzerimonas produces bioactive metabolites with anti-aggregation activity and potential relevance to neuroprotection. However, since Stutzerimonas-derived metabolites remain poorly explored and the docking results are tentative, further in-depth characterization and in vivo validation are required to confirm their therapeutic relevance, and further validation using amyloid-β or α-synuclein models is required to confirm therapeutic implications. Original Article Tue, 30 Dec 2025 00:00:00 GMT Agustina Lulustyaningati NurulAminin, RosianaSitompul, Bayu FajriansyahAl-khairi, MukhammadAsy’ari, Muhammad AjmalShah, Tue, 30 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004135 https://www.explorationpub.com/Journals/ent/Article/1004137 Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke cause progressive and often irreversible neuronal loss, leading to major functional disability. Conventional pharmacological therapies primarily offer symptomatic relief and fail to promote neuro-restoration. Stem cell-derived exosomes have recently gained attention as acellular, regenerative biologics capable of modulating inflammation, enhancing synaptic repair, and facilitating neural recovery. These nanoscale vesicles carry bioactive molecules, including microRNAs (miRNAs) and growth factors, that replicate many of the paracrine benefits of stem cells without the associated risks of tumorigenicity or immune rejection. The objective of this review is to critically evaluate recent evidence on the neuroprotective, immunomodulatory, and translational mechanisms of stem cell-derived exosomes in major neurodegenerative and cerebrovascular disorders, highlighting their clinical relevance and therapeutic potential. Preclinical studies suggest that exosome administration may restore mitochondrial function, reduce oxidative stress, and support neuronal survival, with associated improvements in cognitive and motor outcomes in experimental models of AD, PD, and stroke. Exosomal miRNAs such as miR-21, miR-124, and miR-133b mediate neuroprotective effects through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, while miR-146a promotes immunomodulation by suppressing pro-inflammatory cytokines and facilitating microglial repair phenotypes. Early-phase clinical studies primarily demonstrate feasibility and short-term safety, with exploratory signals of neurological improvement that require confirmation in adequately powered trials. Despite challenges in standardization and regulation, exosome-based therapy represents a scalable, safe, and clinically translatable strategy for neuro-regeneration, with significant promise for future management of brain network disorders. Review Tue, 27 Jan 2026 00:00:00 GMT Afra WasamaIslam, Zohra KamranRao, Harsahaj SinghWilkhoo, BharatSingh, SuhaibHussain, Saumya RajeshKadam, Tue, 27 Jan 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004137 https://www.explorationpub.com/Journals/ent/Article/1004138 Background: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the central nervous system, the cause of which remains unknown. Environmental, genetic, and immunological factors are considered risk factors. MS has no cure; therefore, therapy focuses on reducing the number of outbreaks, controlling symptoms, and therapies aimed at modifying the course of the disease. Innovative strategies that promote remyelination and repair of damaged brain tissue are under investigation. This review aims to compile and systematize the available knowledge on the multifactorial nature of MS, highlighting the main risk factors. It also discusses the mechanisms underlying the pathogenesis of the disease, current therapies, and prospects, presenting a comprehensive overview of the effect of various drugs on remyelination and repair of central nervous system damage. Methods: A comprehensive literature search, guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards, was conducted across PubMed, Cochrane Library, Web of Science, and ClinicalTrials.gov to identify relevant clinical trials. Of the studies retrieved, 13 were selected for this review. These trials specifically explored integrated therapeutic approaches, combining pharmacological and non-pharmacological interventions, for managing MS. Results: The results reflect the multifactorial nature of MS and the existence of several promising therapies to combat inflammation and demyelination, as well as to promote remyelination. Reducing inflammation remains the main target, but new approaches such as clemastine, liothyronine, interleukin (IL)-2, N-acetylglucosamine, and intracranial transplantation of fetal human neural precursor cells have shown promising results. Discussion: Currently, the therapies available for MS target the peripheral immune system. Therefore, more studies are needed on treatment therapies that combine immunomodulation of the peripheral and central nervous systems to reduce the neurological disability of patients. It is also concluded that the therapies were safe and were well tolerated, given the occurrence of a small number of adverse events. Systematic Review Tue, 10 Feb 2026 00:00:00 GMT CarolinaMachado, AnaValado, Tue, 10 Feb 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004138 https://www.explorationpub.com/Journals/ent/Article/1004139 Aim: Attention is a core cognitive function that supports higher-order processes such as reasoning, problem solving, and intelligence. In children with attention deficit hyperactivity disorder (ADHD), particularly the hyperactive subtype, impairments in attentional control may interfere with the development and expression of cognitive abilities. This study examined the relationship between visuospatial attention and both verbal and nonverbal intelligence in children with ADHD-hyperactive type (ADHD-H). Methods: A sample of 65 children with ADHD-H and 73 typically developing controls (aged 8–10 years) completed three tasks: the Benton Visual Form Discrimination Test (VFDT), assessing complex visuospatial attention; the Raven’s Colored Progressive Matrices (RCPMs), measuring nonverbal fluid intelligence; and the Verbal Abstraction Test (Comprehension and Verbal Absurdities subtests), assessing verbal reasoning. Independent-samples t-tests and mixed-design ANOVAs were conducted to compare group performance and examine within-task variability. Results: Children with ADHD-H performed significantly worse than controls on both the VFDT and the RCPMs total scores. Qualitative analysis revealed a marked decline in performance across VFDT item sets, more frequent peripheral errors in later trials. Group differences in RCPMs emerged in gestalt and analogy subcomponents but not in perceptual similarity items. Conversely, verbal abstraction scores did not differ significantly between groups. Conclusions: Findings suggest that attentional deficits, rather than global intellectual impairment, primarily account for lower nonverbal reasoning performance in children with ADHD-H. Verbal reasoning abilities appear relatively preserved. These results underscore the need for differential diagnostic assessment and targeted interventions to strengthen visuospatial attention and cognitive control in ADHD-H. Original Article Wed, 11 Mar 2026 00:00:00 GMT DanielaSmirni, PietroSmirni, MicheleRoccella, Wed, 11 Mar 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004139 https://www.explorationpub.com/Journals/ent/Article/1004140 Background: Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder in older adults, and growing evidence suggests that alterations in the gut-brain axis may contribute to its pathophysiology. Probiotics have been proposed as a potential adjunctive strategy to modulate gut microbiota and related systemic pathways; however, clinical evidence in AD remains limited and heterogeneous. This systematic review evaluated current evidence on the effects of probiotic supplementation on cognitive outcomes and health-related biomarkers in patients with AD. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, PubMed, Web of Science, and Scopus were systematically searched for double-blind randomized controlled trials published within the last 10 years (up to November 30, 2025). Studies assessing probiotic supplementation in clinically diagnosed AD patients were included. Methodological quality and risk of bias were evaluated using the Physiotherapy Evidence Database (PEDro) scale, the McMaster assessment tool, and the Cochrane Risk of Bias 2.0 tool. Results: Of 253 records identified, five randomized controlled trials met the inclusion criteria, comprising 328 participants. The studies evaluated different probiotic formulations, mainly involving Lactobacillus and Bifidobacterium species, administered over short-term interventions (12 weeks). Some trials reported statistically significant improvements in selected cognitive outcomes, inflammatory and oxidative stress markers, metabolic parameters, brain-derived neurotrophic factor levels, anxiety, and instrumental activities of daily living. However, results were heterogeneous and several outcomes were non-significant. No serious adverse events related to probiotic supplementation were reported. Discussion: Probiotic supplementation may be associated with strain-specific and short-term effects on selected cognitive and biological outcomes in patients with AD. Nevertheless, limited trial numbers, small sample sizes, and substantial heterogeneity preclude definitive conclusions. Further well-designed randomized controlled trials with standardized probiotic formulations and longer follow-up periods are required. Systematic Review Mon, 16 Mar 2026 00:00:00 GMT DiegoFernández-Lázaro, Ana M.Celorrio San Miguel, Ana M.Fernández Araque, BeatrizValverde Olmedo, GemaSantamaría, JuanMielgo-Ayuso, Mon, 16 Mar 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004140 https://www.explorationpub.com/Journals/ent/Article/1004141 Background: This systematic review critically evaluates whether machine learning (ML) identifies biologically meaningful sex-related brain architecture or merely exploits methodological artifacts and allometric scaling. While ML models achieve high classification accuracies, it remains unclear if these reflect stable, mechanistically informative dimorphism or are driven by confounds such as total intracranial volume (TIV) and site-specific noise. We examine how imaging modalities, algorithms, and population strata influence both classification outcomes and biological interpretability. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched Web of Science, PubMed, and Scopus through January 2024. Included studies [healthy humans, 3T magnetic resonance imaging (MRI), ML-based sex classification] were assessed for risk of bias, focusing on data leakage, validation strategies, and confound management. Results: Thirty-five studies (n > 110,000) were included. While reported accuracies reached 98.06% for T1-weighted MRI, 96.0% for diffusion MRI (dMRI), and 94.72% for functional MRI (fMRI), performance was highly dependent on population characterization and age. Deep learning consistently outperformed traditional ML (TML) but showed high sensitivity to methodological artifacts. Notably, studies failing to correct for TIV reported potentially inflated accuracies, suggesting that many models identify physical scale rather than intrinsic neuroanatomical dimorphism. Discussion: High classification accuracies are often bolstered by methodological confounds and a lack of cross-site validation. There is a significant discrepancy between ML-driven predictive power and biological inference validity. Current pipelines do not yet allow for robust, generalizable inference about brain sex. To move beyond statistical separation toward mechanistic understanding, the field must prioritize TIV-corrected benchmarks and diverse non-WEIRD (Western, Educated, Industrialized, Rich, Democratic) datasets. We conclude that while ML is a powerful pattern detector, its results must be interpreted with caution regarding biological dimorphism. Systematic Review Mon, 23 Mar 2026 00:00:00 GMT Abdul HalimSapuan, IqbalJamaludin, Zafri AzranAbdul Majid, Mohd IzzuddinMohd Tamrin, Mohd ZulfaezalChe Azemin, SherzodTuraev, Mon, 23 Mar 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004141 https://www.explorationpub.com/Journals/ent/Article/1004142 Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) is an ultra-rare, progressive neurological disorder, with more than 60 individuals described in the medical literature. It is caused by de novo mutations in the interferon regulatory factor 2 binding protein-like (IRF2BPL) gene, leading to early-onset symptoms including seizures, developmental delays, intellectual disability, and other severe neurological impairments, typically beginning in infancy or early childhood. This review aims to consolidate and refine current knowledge on NEDAMSS, focusing on the molecular functions of IRF2BPL, the spectrum of clinical features, and underlying disease mechanisms. A comprehensive understanding of NEDAMSS is essential for guiding the development of targeted interventions and therapeutic strategies to improve patient outcomes. By integrating current findings, we focus both on the progress made and the gaps that remain in research, providing a foundation for future studies to advance diagnosis, treatment, and overall patient care. We reviewed the published literature through studies available up to 2025 to synthesize current knowledge on clinical features, genetics, and proposed disease mechanisms. Reported phenotypes show substantial heterogeneity, and current genotype-phenotype correlations remain limited by small cohorts and inconsistent reporting. Key next steps include standardized phenotyping, natural history studies, and biomarker development to enable trial-ready outcome measures and accelerate targeted therapy development. Review Thu, 02 Apr 2026 00:00:00 GMT Mauricio JavierSanchez-Castellanos, Albert FrankMagnusen, Manoj KumarPandey, Thu, 02 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004142 https://www.explorationpub.com/Journals/ent/Article/1004143 Phycocyanobilin (PCB), the covalently bound chromophore of the cyanobacterial protein C-phycocyanin (CPC), is recognized as a bioactive molecule with neuroprotective and anti-inflammatory properties. PCB and CPC, frequently coexisting in Spirulina extracts or experimental formulations, have demonstrated beneficial effects in preclinical models of multiple sclerosis, ischemic stroke, and Alzheimer’s disease. Reported mechanisms include attenuation of oxidative stress, reduction of neuroinflammation, and preservation of mitochondrial function, thereby contributing to a reparative microenvironment within the central nervous system. PCB can be obtained through two complementary approaches: Extraction from cyanobacterial biomass, where it remains covalently bound to CPC, and heterologous biosynthesis in Escherichia coli (E. coli), which enables production of free PCB as a high-purity, scalable linear tetrapyrrole suitable for translational applications. This mini-review summarizes current evidence on the neuroprotective actions of PCB and CPC, highlights their molecular targets, and discusses biotechnological advances that support their potential role in remyelination. By bridging natural pigment pharmacology with recombinant production strategies, PCB is positioned as a multitarget candidate of growing interest for the development of future neuroprotective and neurorepair therapies. Mini Review Fri, 03 Apr 2026 00:00:00 GMT SheylaDelgado-Lora, YunierRodríguez-Álvarez, GisellePentón-Rol, Fri, 03 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004143 https://www.explorationpub.com/Journals/ent/Article/1004145 Background: Acquired brain injury (ABI) often causes long-lasting impairments in written language and handwriting that limit autonomy and daily functioning. Despite their relevance, these deficits have received limited research attention compared with spoken language disorders. The present work aims to systematically review interventions designed to improve reading, writing, and handwriting abilities in individuals with ABI. Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, PubMed, American Psychological Association (APA) PsycINFO, Cochrane Library, Web of Science, and Google Scholar were searched from inception to 1 November 2025. Eligible studies were randomized or non-randomized clinical trials (non-RCTs) involving adults or adolescents with ABI and documented written language impairments. Risk of bias was assessed using the Risk of Bias 2 tool (RCTs) and Risk of Bias in Non-randomized Studies—of Interventions tool (non-RCTs). Results: Twelve studies met inclusion criteria (2 RCTs, 10 non-RCTs), all conducted in post-stroke populations, highlighting the absence of evidence from other ABI aetiologies. Three main intervention categories emerged: (1) Behavioral treatments, which consistently improved trained spelling and functional writing, with some advantages for errorless learning in maintaining gains. (2) Technology-assisted approaches, including assistive software, digital spelling aids, and handwriting-focused programs, which showed feasibility, high usability, and improvements in accuracy, legibility, and motor fluency. (3) Neuromodulation, with one RCT showing that dual-site transcranial direct current stimulation can modestly enhance behavioral writing therapy. Most non-RCTs showed serious or critical risk of bias, and sample sizes were small, limiting generalizability. Discussion: Current evidence—although preliminary and restricted to post-stroke ABI—indicates that behavioral, technological, and neuromodulatory interventions can improve aspects of written language and handwriting after ABI. However, the available literature is characterized by small samples, substantial methodological variability, and a paucity of standardized and ecologically valid outcome measures. High-quality, adequately powered trials with standardized, functional outcomes are urgently needed, particularly in non-stroke ABI populations. Systematic Review Fri, 10 Apr 2026 00:00:00 GMT FrancescaLazzari, EmiliaTricarico, GiulioVerrienti, Fri, 10 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004145 https://www.explorationpub.com/Journals/ent/Article/1004144 Background: Fully immersive virtual reality (IVR) is an emerging technology approach for cognitive training in individuals with mild cognitive impairment (MCI) and dementia. While interest in fully IVR continues to grow, it remains unclear the extent of effectiveness and the key components that contribute to successful implementation. This study aimed to explore the effectiveness of fully IVR cognitive training for individuals with MCI or dementia from previous research literature. Methods: A scoping review was conducted using a systematic search strategy based on the population, concept, and context framework. Results: Out of the 816 records identified, 123 full texts were screened, and eight studies were included in the review. The included studies all involved participants completing a cognitive training intervention using fully IVR headsets, with cognitive outcomes measured before and after the intervention. The most consistent improvements across the included studies were executive function, memory, and visuospatial abilities. Only two studies explicitly referenced a theoretical model. Discussion: Fully IVR cognitive training demonstrates promise for improving specific cognitive domains in individuals living with MCI or dementia. However, inconsistencies in outcomes and limited theoretical grounding highlight the need for further exploration. Broader considerations are discussed in the discussion section. Systematic Review Fri, 10 Apr 2026 00:00:00 GMT Emmanuel A.C.Obine, RachelKing, AntoninaPereira, Benjamin T.Sharpe, Fri, 10 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004144 https://www.explorationpub.com/Journals/ent/Article/1004146 The relationship between the gut microbiota and the central nervous system has gained attention as a biological axis that may influence the development of several neurological disorders. Recent evidence integrating genomic, neurobiological, and microbiota research shows how bacterial composition, host genetic variability, and the mechanisms of the microbiota-gut-brain axis interact in conditions such as autism spectrum disorder, epilepsy, and schizophrenia. These interactions function through neural, metabolic, and immunological related pathways involving intestinal and blood-brain barrier permeability. Genome-wide association studies (GWAS) and Mendelian randomization analyses highlight shared immunogenetic pathways that may shape both microbial profiles and neurological susceptibility. Consistent patterns of dysbiosis and alterations in neuroactive metabolites have also been reported, linking microbiota changes to neuroinflammation and disrupted neuronal signaling. This review synthesizes the current evidence supporting the integration of the microbiota-gut-brain axis and its underlying communication pathways. It also outlines the present therapeutic strategies for neurological disorders such as autism spectrum disorder, epilepsy, and schizophrenia, highlighting their potential to modulate neurological function. Additionally, it discusses the existing limitations in the field and offers insights into future research directions within this rapidly evolving area. Review Mon, 13 Apr 2026 00:00:00 GMT Ericka C.Loza López, GabrielaCano-Herrera, Maria F.Bautista Gonzalez, AmairaniMéndez Vionet, Ximena A.Van Tienhoven, EmmanuelSimental Aldaba, Enrique de Jesús GuzmánArgüelles, Renata MurguiondoPérez, Patricia Carolina MassieuPérez, Diego De LeónVela, Layra MenaGarcía, Itzel Valeria AlpizarAndrade, Felipe EsparzaSalazar, Mon, 13 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004146 https://www.explorationpub.com/Journals/ent/Article/1004147 Background: Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory disease that affects the central nervous system. Although the true etiology of MS remains unknown, recent research suggests that it arises from a combination of genetic vulnerability and environmental factors. The human leukocyte antigen (HLA) region is a highly polymorphic locus on chromosome 6 encoding antigen-presenting molecules central to adaptive immunity. MS exhibits significant genetic and geographic heterogeneity, reflecting complex interactions between HLA polymorphisms and environmental influences. Risk and protective alleles differ across populations, reinforcing the importance of studying such variations to better understand the disease’s pathogenesis and guide therapeutic strategies. Methods: This systematic review followed the “Preferred Reporting Items for Systematic reviews and Meta-Analyses” (PRISMA) guidelines, and a bibliographic search was conducted in the Medline (PubMed) and Web of Science databases using the keywords “Multiple Sclerosis”, “Genetic Polymorphisms”, “SNPs”, and “Human Leukocyte Antigen”. Results: Twenty-one studies were included, comprising a total of over 50,000 participants across diverse populations. The reviewed studies demonstrate that the alleles DRB1*15:01, DQB1*06:02, DRB1*03:01, DRB1*04:01, DRB1*15:03, DPB1*03:01, as well as the haplotypes DRB1*15:01~DQB1*06:02 and DRB1*15:01~DQA1*01:02~DQB1*06:02, show high expression and are strongly associated with MS susceptibility. In contrast, the alleles A*02:01 and DRB1*01:01 have shown a protective role. Discussion: The evidence confirms a central role of HLA class II alleles and conserved extended haplotypes, particularly DRB1*15:01-containing haplotypes, in MS susceptibility, while highlighting protective alleles and marked variability across ancestral backgrounds. These findings underscore the importance of high-resolution HLA typing, standardized haplotype definitions and inclusion of diverse populations to refine MS risk estimates. Systematic Review Wed, 15 Apr 2026 00:00:00 GMT LeonorPinheiro, AnaValado, Wed, 15 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004147 https://www.explorationpub.com/Journals/ent/Article/1004149 Neurodegenerative disorders represent a major and growing global health challenge, characterized by progressive neuronal loss, multifactorial pathophysiology, and limited disease-modifying pharmacological options. Increasing attention has therefore been directed toward non-pharmacological and integrative interventions as complementary strategies for neuroprotection and symptom management. These approaches target key mechanisms implicated in neurodegeneration, including oxidative stress, neuroinflammation, mitochondrial dysfunction, synaptic impairment, and dysregulated neuroplasticity. This narrative integrative review synthesizes current preclinical and clinical evidence on non-pharmacological interventions with demonstrated or emerging neuroprotective potential across major neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and related conditions. The review focuses on four principal domains: physical activity and exercise, nutritional and dietary strategies, mind–body and psychosocial interventions, and sensory or neuromodulatory therapies. Collectively, these interventions influence convergent neurobiological pathways, including neurotrophic signaling, immune modulation, autonomic regulation, and gut–brain communication. Studies indicate that structured physical exercise enhances neurotrophic factor expression and mitochondrial resilience; dietary patterns rich in antioxidants and anti-inflammatory components mitigate oxidative damage and neuroinflammation; mind–body practices modulate stress-related neuroendocrine pathways and promote functional connectivity; and sensory or neuromodulatory interventions engage limbic and cortical networks relevant to cognition, mood, and motor control. Importantly, multimodal and integrative approaches appear to exert synergistic effects, aligning with the complex and systemic nature of neurodegenerative processes. Despite promising findings, challenges related to methodological heterogeneity, biomarker validation, and translational implementation persist. Future research should prioritize standardized protocols, objective neuroprotective endpoints, and personalized intervention frameworks supported by digital health technologies. Overall, non-pharmacological and integrative therapies represent a valuable, increasingly evidence-based component of comprehensive neuroprotective strategies, with significant potential to enhance quality of life and complement pharmacological treatments in the care of neurodegenerative diseases. Review Wed, 29 Apr 2026 00:00:00 GMT SaraDiogo Gonçalves, RaquelGarcia Diogo, NatashaMiranda, AnaCaramelo, VerónicaEsteves, Wed, 29 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004149 https://www.explorationpub.com/Journals/ent/Article/1004150 Growing evidence has directly linked the gastrointestinal tract, gut microbiota, and central nervous system, forming the gut-brain axis, a process that has been described as a key mechanism in regulating neurological processes. However, the presence of alterations in the composition of microorganisms in the digestive tract and dysbiosis has been linked to the activation of microglia, increased oxidative stress, alterations in the production of neurotransmitters, and exacerbation of neuroinflammation. These mechanisms have been associated with multiple pathologies and neurological conditions, and regulating them is key to the control of these diseases. In this context, various bacterial species play a neuroprotective role by promoting the integrity of the intestinal barrier, stimulating the synthesis of beneficial metabolites such as short-chain fatty acids (SCFAs), neurotransmitters, and modulating the inflammatory response. In addition, the characterization of these microbial profiles provides a broad perspective on understanding how changes in the microbiota contribute to the progression of neurological diseases. On the other hand, these new updates open up the possibility of designing personalised targeted therapeutic interventions that can regulate the gut microbiota and promote a neuroprotective and neuroregenerative environment. Another key point is that greater emphasis is placed on the need for more controlled clinical studies to validate efficacy and safety in humans, as well as knowledge of the mechanisms of action that make them possible. Finally, the modulation of the gut microbiota using probiotics, prebiotics, and postbiotics represents an innovative and effective opportunity to intervene in neuroimmune processes such as microglial activation, regulation of synaptic pruning, and neuroinflammatory pathways—processes implicated in various neurological diseases. In this context, this review integrates and analyzes the available evidence, highlighting potential interventions as treatments for these pathologies, as well as current limitations, to provide an updated framework to guide future research. Review Wed, 29 Apr 2026 00:00:00 GMT FernandoLeal-Martínez, Irene AlejandraBerumen Coronado, Wed, 29 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004150 https://www.explorationpub.com/Journals/ent/Article/1004151 Short-chain fatty acids (SCFAs) are microbial-derived metabolites produced primarily through the fermentation of dietary fibre by the intestinal microbiota. Current evidence indicates that they play a key role in modulating nociception and pain processing across immune, metabolic, and neural pathways. The prevailing view that SCFAs suppress pain has been challenged by emerging evidence demonstrating that these same metabolites can also drive hyperalgesia. This apparent “SCFA paradox” persists because most studies have examined individual metabolites in isolation rather than considering them within their broader biological context. Here, we propose an integrative framework in which SCFAs function within a competitive receptor triad, and pain outcomes are dictated by the balance among three signalling axes: a pro-inflammatory immune axis driven by acetate acting through G protein-coupled receptor 43 (GPR43), a pro-resolutive metabolic axis mediated by butyrate via histone deacetylase (HDAC) inhibition and activation of GPR109A, and a direct neural sensing axis triggered by propionate through olfactory receptor 78 (OLFR78). Chronic pain, therefore, does not arise simply from the presence or absence of SCFAs, but from the pathological dominance of one of these axes shaped by specific dysbiosis profiles. This framework moves beyond correlation by providing a mechanistic basis for precision interventions designed to rebalance SCFA signalling, offering novel therapeutic opportunities for neuropathic and inflammatory pain conditions. Perspective Wed, 13 May 2026 00:00:00 GMT LuisRodríguez-Cortés, RodrigoPacheco, Wed, 13 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004151 https://www.explorationpub.com/Journals/ent/Article/1004153 By individual examination, the present review provides an overview of the potential involvement of various human microbiomes, including the gut, oral, skin, and nasal, in the pathophysiology of neurodegenerative diseases. Research has demonstrated that gut microbiome dysbiosis is linked to the pathogenesis of neurodegenerative conditions, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, through mechanisms involving microbial metabolites, neuroinflammation, amyloid aggregation, and altered neurotransmission. Emerging evidence suggests that the oral, skin, and nasal microbiomes may also influence neurodegenerative diseases through mechanisms such as microbial translocation, immune modulation, metabolite production, and interactions with the gut-brain axis. Although the potential of microbiome-based interventions for neurodegenerative diseases has been highlighted, several gaps remain, such as variability between human and animal models, a lack of standardized multi-omics approaches, and a limited understanding of individual microbial roles. Future studies should focus on clarifying the mechanisms by which dysbiosis in human host microbiomes impacts the pathophysiology of neurodegenerative diseases, identifying reliable biomarkers, and developing safe and effective microbiome-based therapies. Review Thu, 14 May 2026 00:00:00 GMT AlejandroBorrego-Ruiz, Juan J.Borrego, Thu, 14 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004153 https://www.explorationpub.com/Journals/ent/Article/1004152 Explanations and treatment of fibromyalgia syndrome (FMS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are controversial, and outcomes are poor. This paper describes sensation-suppression theory, a theory modelled on self-organizing control systems that are capable of adaptation in response to inputs and used in applications of artificial intelligence. The theory shows how the need to suppress inflammatory and other causes of pain or fatigue due to challenging circumstances sensitizes the neurological processing of pain and fatigue, thereby creating the amplified sensations and abnormal cognitions of central sensitivity syndromes. These syndromes are caused by errors in an evolutionarily early behavior-control mechanism of animals that comes into conflict with the later cognitive behavior-control mechanism of humans. Unlike the cognitive and current biological theories, the sensation-suppression theory explains both the personality and biological risk factors for central sensitivity syndromes and why onset is sometimes gradual and sometimes sudden. A specific form of autonomic dysregulation that could act as a new empirical test of the theory is suggested. Recovery is achieved by reversing the biological homeostatic dysregulation through a specific form of pacing where the person changes from one short, non-stressful activity to another, and where activity is calibrated to the level of illness and the patient’s current biological state. Recovery is hampered or prevented by systemic inflammation and lifestyle obligations. The theory provides a sympathetic narrative for the cause and treatment of FMS and ME/CFS and promotes a recovery lifestyle that prioritizes the needs of the patient. Prevention requires hearing what the body is saying. Perspective Wed, 13 May 2026 00:00:00 GMT Michael E.Hyland, Wed, 13 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004152 https://www.explorationpub.com/Journals/ent/Article/1004154 The NEUROD2 gene encodes a transcription factor essential for neuronal differentiation and cortical development. Pathogenic variants cause a rare autosomal dominant neurodevelopmental disorder with variable expressivity, typically presenting in early infancy with developmental delay, epilepsy, and behavioral abnormalities. We report a newborn girl carrying a de novo heterozygous missense variant NM_006160.4:c.790G>A, p.(Ala264Thr), located outside the canonical basic helix-loop-helix (bHLH) domain. Soon after birth, she presented respiratory depression, hypotonia, feeding difficulties, and electrographic seizures. Magnetic resonance imaging (MRI) showed subcortical white matter hyperintensity, and the electroencephalogram (EEG) revealed abnormal background activity. During follow-up, epilepsy was controlled, but neurodevelopmental delay with autistic features emerged. This case represents the earliest reported clinical onset associated with NEUROD2 variants and expands the phenotypic and mutational spectrum. It highlights that variants outside known hotspots can cause severe disease and supports including NEUROD2 in the differential diagnosis of neonatal neurological impairment. Case Report Tue, 19 May 2026 00:00:00 GMT LiciaLugli, IsottaGuidotti, CeciliaRossi, NatasciaBertoncelli, MartinaButtera, ValeriaCapone, EmmaBertucci, MarisaPugliese, AlbertoBerardi, Tue, 19 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004154 https://www.explorationpub.com/Journals/ent/Article/1004155 Norepinephrine (NE), a central catecholamine neurotransmitter synthesized primarily in the locus coeruleus (LC), plays a critical role in regulating arousal, attention, emotional processing, and stress responsiveness. While contemporary personality neuroscience has established the role of NE in acute psychological states, its contribution to stable personality traits remains underexplored. This review synthesizes neurobiological, psychological, genetic, and psychopharmacological evidence to propose a NE-personality continuum that links tonic and phasic dynamics of the LC-NE system to enduring individual differences in alertness, anxiety, and adaptability. Alertness is associated with optimal noradrenergic tone and efficient phasic signaling, which enhances the signal-to-noise ratio and attentional focus. Anxiety arises from chronic hyperactivation or dysregulated NE release, particularly involving excessive α1- and β-adrenergic receptor activity and impaired modulation from the prefrontal cortex. Adaptability denotes a harmonious interaction between the limbic system and prefrontal cortex, which facilitates cognitive flexibility and emotional regulation in response to changing environmental demands. The connection between NE activity and personality traits follows an inverted U-shaped pattern. Low tone leads to apathy and less engagement, moderate tone helps with resilience and optimal functioning, and high tone leads to hypervigilance and rigidity. This model combines findings from fundamental neuroscience and clinical research to provide a physiologically based framework for understanding how long-term variations in noradrenergic regulation affect personality traits, as described in established trait theories. The findings underline the feasibility of adding noradrenergic biomarkers and pharmaceutical therapies into clinical practice, as well as the importance of longitudinal and multimodal research to determine trait-level causality. This is especially important for understanding how to use these elements to improve treatment plans for personality disorders. Review Mon, 25 May 2026 00:00:00 GMT TaslimUddin, OtondrillaHossain Bhuiyan, Maisha MalihaMisha, SushmitaSharma, FariaSharmin, SadiaTasnim, SalahaAktar, RakheeSarker, Rhea SarkarNipun, Kanak YadabGhosh, Most. TamannaHaque, Anika TabassumAziz, Tayaba TanjinIslam, JannatulFerdous, Fatma HosnyAhmed, Mon, 25 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004155 https://www.explorationpub.com/Journals/ent/Article/1004156 Aim: To assess the effect of a synbiotic supplement composed of Enterococcus faecium and agave inulin on cognitive function in older adults with mild cognitive impairment (MCI). Methods: In a triple-blind randomized crossover trial, nineteen adults aged 64–85 years with MCI received either the synbiotic or an isocaloric vehicle for eight weeks, followed by a three-week washout and treatment crossover. Cognitive outcomes were assessed at baseline, after the first intervention, and after crossover using the Modified Mini-Mental State Examination (MMSE), Rey-Osterrieth Complex Figure Test (RCFT; copy and memory), and Abbreviated Instrument for Expectations of Self-Efficacy for Daily Activities in Older Adults (AERAC) self-efficacy scale. Paired and unpaired Student’s t-tests were used for statistical comparisons (p < 0.05). Results: The synbiotic group showed significant improvement relative to baseline across all domains: MMSE (p = 0.05), AERAC (p = 0.005), RCFT-copy (p = 0.03), and RCFT-memory (p = 0.03). Post-treatment comparisons between groups also favored the synbiotic, with significant differences in MMSE (p = 0.001), AERAC (p = 0.001), RCFT-copy (p = 0.0095), and RCFT-memory (p = 0.001). After crossover, cognitive gains were sustained and reproduced. MMSE scores reached 17.89 ± 1.45 in the synbiotic-first group versus 18.20 ± 0.63 in the control-first group (p < 0.001). RCFT-copy remained high (29.83 ± 4.18 vs. 29.52 ± 5.60, p = 0.0157), while RCFT-memory scores converged (17.56 ± 6.73 vs. 17.20 ± 3.29, p = 0.0005). AERAC scores continued to improve during crossover (82.60 ± 10.49 vs. 85.46 ± 8.28, p < 0.001). No adverse effects occurred. Conclusions: Synbiotic supplementation significantly improved global cognition, visuoconstructive ability, memory, and functional self-efficacy in older adults with MCI. Benefits persisted beyond the initial intervention and were replicated when the control group received the synbiotic, supporting its potential as a safe and effective strategy to mitigate age-related cognitive decline. Original Article Mon, 25 May 2026 00:00:00 GMT NataliaRojas-Sánchez, AdelaEscandón-Cesarman, EmilioMoreno-González, Oscar MarioDelgado-Casillas, Andrea P.Ibarra García, IvanIgnacio-Mejía, Exsal ManuelAlbores-Mendez, Marco AntonioVargas-Hernandez, Martha PatriciaHernandez-Valdez, PaulinaRomaña-Espiritu, Silvia G.Sanchez-Ávila, María E.Sanchez-Hernandez, AntonioIbarra, Mon, 25 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/ent/Article/1004156