Lactulose enhances neuroplasticity to improve cognitive function in early hepatic encephalopathy

Lactulose is known to improve cognitive function in patients with early hepatic encephalopa- thy; however, the underlying mechanism remains poorly understood. In the present study, we investigated the behavioral and neurochemical effects of lactulose in a rat model of early hepatic encephalopathy induced by carbon tetrachloride. Immunohistochemistry showed that lactulose treatment promoted neurogenesis and increased the number of neurons and astrocytes in the hippocampus. Moreover, lactulose-treated rats showed shorter escape latencies than model rats in the Morris water maze, indicating that lactulose improved the cognitive impairments caused by hepatic encephalopathy. The present findings suggest that lactulose effectively improves cog- nitive function by enhancing neuroplasticity in a rat model of early hepatic encephalopathy.

Neuroplasticity in post-stroke gait recovery and noninvasive brain stimulation

Gait disorders drastically affect the quality of life of stroke survivors,making post-stroke rehabilitation an important research focus.Noninvasive brain stimulation has potential in facilitating neuroplasticity and improving post-stroke gait impairment.However,a large inter-individual variability in the response to noninvasive brain stimulation interventions has been increasingly recognized.We first review the neurophysiology of human gait and post-stroke neuroplasticity for gait recovery,and then discuss how noninvasive brain stimulation techniques could be utilized to enhance gait recovery.While post-stroke neuroplasticity for gait recovery is characterized by use-dependent plasticity,it evolves over time,is idiosyncratic,and may develop maladaptive elements.Furthermore,noninvasive brain stimulation has limited reach capability and is facilitative-only in nature.Therefore,we recommend that noninvasive brain stimulation be used adjunctively with rehabilitation training and other concurrent neuroplasticity facilitation techniques.Additionally,when noninvasive brain stimulation is applied for the rehabilitation of gait impairment in stroke survivors,stimulation montages should be customized according to the specific types of neuroplasticity found in each individual.This could be done using multiple mapping techniques.

Neuroplasticity and major depression, the role of modern antidepressant drugs

The pathophysiology of depression has been traditionally attributed to a chemical imbalance and critical interactions between genetic and environmental risk factors, and antidepressant drugs suggested to act predominantly amplifying monoaminergic neurotransmission. This conceptualization may be currently considered reductive. The current literature about the pathophysiological mechanisms underlying depression, stress-related disorders and antidepressant treatment was examined. In order to provide a critical overview about neuroplasticity, depression and antidepressant drugs, a detailed Pubmed/Medline, Scopus, Psyc Lit, and Psyc Info search to identify all papers and book chapters during the period between 1980 and 2011 was performed. Pathological stress and depression determine relevant brain changes such as loss of dendritic spines and synapses, dendritic atrophy as well as reduction of glial cells(both in number and size) in specific areas such as the hippocampus and prefrontal cortex. An increased dendritic arborisation and synaptogenesis may instead be observed in the amygdala as a consequence of depression and stress-related disorders. While hippocampal and prefrontal functioning was impaired, amygdala functioning was abnormally amplified. Most of molecular abnormalities and biological changes of aberrant neuroplasticity may be explained by the action of glutamate. Antidepressant treatment is associated with neurogenesis, gliogenesis, dendritic arborisation, new synapse formation and cell survival both in the hippocampus and prefrontal cortex. Antidepressants(ADs) induce neuroplasticity mechanisms reversing the pathological effects of depression and stress-related disorders. The neuroplasticity hypothesis may explain the therapeutic and prophylactic action of ADs representing a new innovative approach to the pathophysiology of depression and stress-related disorders.

Human survival and immune mediated mitophagy in neuroplasticity disorders

Dear editors,Neurodegenerative diseases are now associated with the global obesity and diabetes epidemic in the developing and developed world.Neurodegenerative diseases are a heterogeneous group of disorders with complex factors such as neurohumoral,endocrine and environmental factors involved in induction of these neurodegenerative diseases.The future of science and medicine in neurodegenerative diseases is now dependent on nutritional genomics with insulin resistance a major factor in the induction of neurodegenerative diseases.Nutritional genomics now involves the anti-aging gene Sirtuin 1(Sirt 1)that is important to the prevention of insulin resistance with its critical involvement in the immune system(Martins,2018a,b).Sirt 1 inactivation leads to toxic immune reactions connected to the acceleration of neuron death in various communities.Appetite control with relevance to immunometabolism has become of critical importance to the treatment of neurodegeneration(Figure 1).Nutritional diets activate the heat shock gene Sirt 1 to prevent the increase in heat shock proteins connected to autoimmune disease,mitophagy(Martins,2018a,b)and irreversible programmed cell death in global populations(Figure 1).

Neuroplasticity, limbic neuroblastosis and neuro-regenerative disorders

The brain is a dynamic organ of the biological renaissance due to the existence of neuroplasticity. Adult neurogenesis abides by every aspect of neuroplasticity in the intact brain and contributes to neural regeneration in response to brain diseases and injury. The occurrence of adult neurogenesis has unequivocally been witnessed in human subjects, experimental and wildlife research including rodents, bats and cetaceans. Adult neurogenesis is a complex cellular process, in which generation of neuroblasts namely, neuroblastosis appears to be an integral process that occur in the limbic system and basal ganglia in addition to the canonical neurogenic niches. Neuroblastosis can be regulated by various factors and contributes to different functions of the brain. The characteristics and fate of neuroblasts have been found to be different among mammals regardless of their cognitive functions. Recently, regulation of neuroblastosis has been proposed for the sensorimotor interface and regenerative neuroplasticity of the adult brain. Hence, the understanding of adult neurogenesis at the functional level of neuroblasts requires a great scientific attention. Therefore, this mini-review provides a glimpse into the conceptual development of neuroplasticity, discusses the possible role of different types of neuroblasts and signifies neuroregenerative failure as a potential cause of dementia.

How do serotonergic psychedelics treat depression:The potential role of neuroplasticity

Depression is a common mental disorder and one of the leading causes of disability around the world.Monoaminergic antidepressants often take weeks to months to work and are not effective for all patients.This has led to a search for a better understanding of the pathogenesis of depression as well as to the development of novel antidepressants.One such novel antidepressant is ketamine,which has demonstrated both clinically promising results and contributed to new explanatory models of depression,including the potential role of neuroplasticity in depression.Early clinical trials are now showing promising results of serotonergic psychedelics for depression;however,their mechanism of action remains poorly understood.This paper seeks to review the effect of depression,classic antidepressants,ketamine,and serotonergic psychedelics on markers of neuroplasticity at a cellular,molecular,electrophysiological,functional,structural,and psychological level to explore the potential role that neuroplasticity plays in the treatment response of serotonergic psychedelics.

Cerebellar pathology in motor neuron disease:neuroplasticity and neurodegeneration

Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition.The clinical picture is dominated by upper and lower motor neuron degeneration,but extra-motor pathology is increasingly recognized,including cerebellar pathology.Post-mortem and neuroimaging studies primarily focus on the chara cterization of supratentorial disease,des pite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis.Cardinal clinical features of amyotrophic lateral sclerosis,such as dysarthria,dysphagia,cognitive and behavioral deficits,saccade abnormalities,gait impairment,respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology.This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral scle rosis.Structural imaging studies consistently capture cerebellar grey matter volume reductions,diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alte rations and functional imaging studies commonly report increased functional connectivity with supratentorial regions.Increased functional connectivity is commonly interpreted as evidence of neuro plasticity representing compensatory processes despite the lack of post-mortem validation.There is a scarcity of post-mortem studies focusing on cerebellar alte rations,but these detect pTDP-43 in cerebellar nuclei.Ce rebellar pathology is an overloo ked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms,wides p read connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.

Use of sensory substitution devices as a model system for investigating cross-modal neuroplasticity in humans

Blindness provides an unparalleled opportunity to study plasticity of the nervous system in humans.Seminal work in this area examined the often dramatic modifications to the visual cortex that result when visual input is completely absent from birth or very early in life（Kupers and Ptito,2014）.More recent studies explored what happens to the visual pathways in the context of acquired blindness.This is particularly relevant as the majority of diseases that cause vision loss occur in the elderly.

Can Digital Games Be a Way of Improving the Neuroplasticity in Stroke Damage? Can the Adult Brain Grow New Cells or Rewire Itself in Response to a New Experience?

Exploratory studies developed at several neurosciences laboratories at universities around the world show us through the experience that there is a biological process called neuroplasticity. Because of this oldest concept about the neuronal formation, scientists also thought that if a particular area of the adult brain was damaged, the nerve cells could not form new connections and the functions controlled by this field of the brain would be permanently lost or could not be regenerate. However, studies have overturned this old view, and currently, scientists recognize that the brain continues to reorganize itself by forming new neural connections during the life. This phenomenon is called neuroplasticity that refers to the potential which the brain should be reorganized by creating new neural pathways to adapt, as it needs.

Neuroplasticity in Spinal Trauma: A Current Narrative Review of Treatments

Neuroplasticity is a condition that is present from birth, being found in the central and peripheral nervous system, in both physiological and pathological terms. Based on the findings, therapeutic and non-therapeutic attempts were tested on spinal cord trauma to recover locomotor function below the level of the injury. The work defined and showed other forms of the term neuroplasticity, talk about some pathological and non-pathological conditions, and, finally, show neuroplasticity and some of its treatments in the spinal cord injury process. A narrative literature review from 2000 to 2020 of the PubMed platform was conducted and analysis of two books for the elaboration of this work. Animal/human studies were included that addressed pathologies, forms of treatment for spinal trauma, and qualis from B1 to A1. Pre-2000 articles, which addressed neuroplasticity only to understand the molecular mechanisms and articles that were not in English, were excluded. As a result, the main molecules and structures that inhibit neuroplasticity were found, and, based on their knowledge, forms of treatments were developed to inhibit these molecules and structures to assist in neuroplasticity and assist in possible functional recovery. It can be concluded that the physiological barriers are already being overcome by the most recent forms of treatment and that soon new studies may propose a form of treatment that is protocoled for all patients.

Neuroplasticity: a camouflaged cardinal in musculoskeletal rehabilitation

The rehabilitation of musculoskeletal dysfunctions(MSD)such as osteoarthritis,anterior cruciate ligament injuries and low back pain focuses on symptomatic management of pain followed by stretching and strengthening.However,these interventions focus just on symptomatic pain management and addressing musculoskeletal impairments.But it has been found that neuroplastic changes continue to occur throughout these pathologies and sometimes even are persistent,as conventional rehabilitation doesn’t focus on these changes therefore chances of reinjury increase.Therefore this article discusses underlying neuroplastic changes associated with MSD and neuroplasticity-based interventions for better clinical outcomes.

Vagus nerve stimulation in cerebral stroke:biological mechanisms,therapeutic modalities,clinical applications,and future directions

Stroke is a major disorder of the central nervous system that poses a serious threat to human life and quality of life.Many stro ke victims are left with long-term neurological dysfunction,which adversely affects the well-being of the individual and the broader socioeconomic impact.Currently,poststroke brain dysfunction is a major and difficult area of treatment.Vagus nerve stimulation is a Food and Drug Administration-approved exploratory treatment option for autis m,refractory depression,epilepsy,and Alzheimer’s disease.It is expected to be a novel therapeutic technique for the treatment of stroke owing to its association with multiple mechanisms such as alte ring neurotransmitters and the plasticity of central neuro ns.In animal models of acute ischemic stroke,vagus nerve stimulation has been shown to reduce infarct size,reduce post-stroke neurological damage,and improve learning and memory capacity in rats with stroke by reducing the inflammatory response,regulating bloodbrain barrier permeability,and promoting angiogenesis and neurogenesis.At present,vagus nerve stimulation includes both invasive and non-invasive vagus nerve stimulation.Clinical studies have found that invasive vagus nerve stimulation combined with rehabilitation therapy is effective in im proving upper limb motor and cognitive abilities in stroke patients.Further clinical studies have shown that non-invasive vagus nerve stimulation,including ear/ce rvical vagus nerve stimulation,can stimulate vagal projections to the central nervous system similarly to invasive vagus nerve stimulation and can have the same effect.In this paper,we first describe the multiple effects of vagus nerve stimulation in stroke,and then discuss in depth its neuroprotective mechanisms in ischemic stroke.We go on to outline the res ults of the current major clinical applications of invasive and non-invasive vagus nerve stimulation.Finally,we provide a more comprehensive evaluation of the advantages and disadvantages of different types of vagus nerve stimulation in the treatment of cerebral ischemia and provide an outlook on the developmental trends.We believe that vagus nerve stimulation,as an effective treatment for stroke,will be widely used in clinical practice to promote the recovery of stroke patients and reduce the incidence of disability.

Mesenchymal stem cell-derived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration

Traumatic brain injury is a serious and complex neurological condition that affects millions of people worldwide.Despite significant advancements in the field of medicine,effective treatments for traumatic brain injury remain limited.Recently,extracellular vesicles released from mesenchymal stem/stromal cells have emerged as a promising novel therapy for traumatic brain injury.Extracellular vesicles are small membrane-bound vesicles that are naturally released by cells,including those in the brain,and can be engineered to contain therapeutic cargo,such as anti-inflammatory molecules,growth factors,and microRNAs.When administered intravenously,extra cellular vesicles can cross the blood-brain barrier and deliver their cargos to the site of injury,where they can be taken up by recipient cells and modulate the inflammatory response,promote neuroregeneration,and improve functional outcomes.In preclinical studies,extracellular vesicle-based therapies have shown promising results in promoting recove ry after traumatic brain injury,including reducing neuronal damage,improving cognitive function,and enhancing motor recovery.While further research is needed to establish the safety and efficacy of extra cellular vesicle-based therapies in humans,extra cellular vesicles represent a promising novel approach for the treatment of traumatic brain injury.In this review,we summarize mesenchymal ste m/stromal cell-de rived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration and brainderived extracellular vesicles as potential biofluid biomarkers in small and large animal models of traumatic brain injury.

Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

Glucocorticoid receptor signaling in the brain and its involvement in cognitive function

The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.

Decoding molecular mechanisms:brain aging and Alzheimer's disease

The complex morphological,anatomical,physiological,and chemical mechanisms within the aging brain have been the hot topic of research for centuries.The aging process alters the brain structure that affects functions and cognitions,but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders,such as Alzheimer's disease.Beyond these observable,mild morphological shifts,significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain.Understanding these changes is important for maintaining cognitive health,especially given the increasing prevalence of age-related conditions that affect cognition.This review aims to explore the age-induced changes in brain plasticity and molecular processes,differentiating normal aging from the pathogenesis of Alzheimer's disease,thereby providing insights into predicting the risk of dementia,particularly Alzheimer's disease.

Hydrogen sulfide reduces oxidative stress in Huntington's disease via Nrf2

The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.

Psychiatric outcomes in outpatients affected by long COVID:A link between mental health and persistence of olfactory complaint

BACKGROUND Anosmia was one of the main symptoms of coronavirus disease 2019(COVID-19).A psychiatric history(i.e.,depression)may be an independent contributor to the risk of COVID-19 diagnosis,and COVID-19 survivors appear to have an increased risk of neuropsychiatric sequelae(bidirectional association).AIM To compare the rate of psychiatric disorder among post-COVID patients without anosmia vs patients with persistent olfactory complaints.METHODS We conducted a prospective case control study from March 2020 to May 2021.Patients recruited at the ENT department of Nice University Hospital had a subjective olfactory complaint(visual analogue scale)for over 6 wk and a molecular or CT-proven severe acute respiratory syndrome coronavirus 2 diagnosis confirmed by serology.Post-COVID patients without persistent olfactory disorders were recruited at the university hospital infectiology department.Psychiatric medical histories were collected by a psychiatrist during the assessments.RESULTS Thirty-four patients with post-COVID-19 olfactory complaints were included in the first group of the study.Fifty percent of the patients were female(n=17).The group’s mean age was 40.5±12.9 years.The control group included 32 participants,of which 34.4%were female(n=11),and had a mean age of 61.2±12.2 years.The rate of psychiatric disorder among post-COVID patients with olfactory complaints was significatively higher(41.7%)than among patients without(18.8%)(χ2=5.9,P=0.015).CONCLUSION The presence of a psychiatric history may constitute a potential risk factor for the development of long COVID due to persistent anosmia.It therefore seems important to establish reinforced health monitoring after a COVID 19 infection in at-risk patients.Further prospective,translational,and collaborative studies are needed to extrapolate these results to the general population.

Dynamic structural neuroplasticity during and after epileptogenesis in a pilocarpine rat model of epilepsy

Background:The role of neuroplasticity in epilepsy has been widely studied in experimental models and human brain samples.However,the results are contradictory and it remains unclear if neuroplasticity is more related to the cause or the consequence of epileptic seizures.Clarifying this issue can provide insights into epilepsy therapies that target the disease mechanism and etiology rather than symptoms.Therefore,this study was aimed to investigate the dynamic changes of structural plasticity in a pilocarpine rat model of epilepsy.Methods:A single acute dose of pilocarpine(380 mg/kg,i.p.)was injected into adult male Wistar rats to induce status epilepticus(SE).Animal behavior was monitored for 2 h.Immunohistochemical staining was performed to evaluate neurogenesis in the CA3 and dentate gyrus(DG)regions of hippocampus using biomarkers Ki67 and doublecortin(DCX).The Golgi-Cox method was performed to analyze dendritic length and complexity.All experiments were performed in control rats(baseline),at 24 h after SE,on day 20 after SE(latent phase),after the first and 10th spontaneous recurrent seizures(SRS;chronic phase),and in non-epileptic rats(which did not manifest SRS 36 days after pilocarpine injection).Results:SE significantly increased the number of Ki67 and DCX-positive cells,suggesting neurogenesis during the latent phase.The dendritic complexity monitoring showed that plasticity was altered differently during epilepsy and epileptogenesis,suggesting that the two processes are completely separate at molecular and physiological levels.The numbers of spines and mushroom-type spines were increased in the latent phase.However,the dendritogenesis and spine numbers did not increase in rats that were unable to manifest spontaneous seizures after SE.Conclusion:All parameters of structural plasticity that increase during epileptogenesis,are reduced by spontaneous seizure occurrence,which suggests that the development of epilepsy involves maladaptive plastic changes.Therefore,the maladaptive plasticity biomarkers can be used to predict epilepsy before development of SRS in the cases of serious brain injury.