Medical procedures are inherently invasive and carry the risk of inducing pain to the mind and body.Recently,efforts have been made to alleviate the discomfort associated with invasive medical procedures through the u...Medical procedures are inherently invasive and carry the risk of inducing pain to the mind and body.Recently,efforts have been made to alleviate the discomfort associated with invasive medical procedures through the use of virtual reality(VR)technology.VR has been demonstrated to be an effective treatment for pain associated with medical procedures,as well as for chronic pain conditions for which no effective treatment has been established.The precise mechanism by which the diversion from reality facilitated by VR contributes to the diminution of pain and anxiety has yet to be elucidated.However,the provision of positive images through VR-based visual stimulation may enhance the functionality of brain networks.The salience network is diminished,while the default mode network is enhanced.Additionally,the medial prefrontal cortex may establish a stronger connection with the default mode network,which could result in a reduction of pain and anxiety.Further research into the potential of VR technology to alleviate pain could lead to a reduction in the number of individuals who overdose on painkillers and contribute to positive change in the medical field.展开更多
Sepsis,a life-threatening condition,can lead to acute skin failure characterized by extensive skin damage.This is often due to decreased blood flow,inflammation,and increased susceptibility to infection.Acute skin fai...Sepsis,a life-threatening condition,can lead to acute skin failure characterized by extensive skin damage.This is often due to decreased blood flow,inflammation,and increased susceptibility to infection.Acute skin failure in people with sepsis is often associated with sleep disturbances,anxiety,and poor mood.Inflammatory markers and lactate levels correlate with these psychiatric symptoms,suggesting a link between skin and brain function.The skin and the central nervous system(CNS)have bidirectional communication.The CNS is also in close contact with the digestive tract.The gut,skin,and brain influence each other’s functions thr-ough nervous,hormonal,and immune pathways,forming a gut-skin-brain axis.Understanding the interaction among the gut,skin,and CNS is critical to the diag-nosis and treatment of various skin and neurological disorders.By recognizing individual variations in gut microbiota,immune responses,and neural pathways,treatments can be tailored to specific patient needs,enhancing efficacy and minimizing side effects.The gut plays a large role in mental health.Under-standing the gut skin brain axis,will lead to improved mental health outcomes.展开更多
The increasing global prevalence of mild cognitive impairment(MCI)necessitates a paradigm shift in early detection strategies.Conventional neuropsychological assessment methods,predominantly paper-and-pencil tests suc...The increasing global prevalence of mild cognitive impairment(MCI)necessitates a paradigm shift in early detection strategies.Conventional neuropsychological assessment methods,predominantly paper-and-pencil tests such as the Mini-Mental State Examination and the Montreal Cognitive Assessment,exhibit inherent limitations with respect to accessibility,administration burden,and sensitivity to subtle cognitive decline,particularly among diverse populations.This commentary critically examines a recent study that champions a novel approach:The integration of gait and handwriting kinematic parameters analyzed via machine learning for MCI screening.The present study positions itself within the broader landscape of MCI detection,with a view to comparing its advantages against established neuropsychological batteries,advanced neuroimaging(e.g.,positron emission tomography,magnetic resonance imaging),and emerging fluid biomarkers(e.g.,cerebrospinal fluid,blood-based assays).While the study demonstrates promising accuracy(74.44%area under the curve 0.74 with gait and graphic handwriting)and addresses key unmet needs in accessibility and objectivity,we highlight its cross-sectional nature,limited sample diversity,and lack of dual-task assessment as areas for future refinement.This commentary posits that kinematic biomarkers offer a distinctive,scalable,and ecologically valid approach to widespread MCI screening,thereby complementing existing methods by providing real-world functional insights.Future research should prioritize longitudinal validation,expansion to diverse cohorts,integration with multimodal data including dual-tasking,and the development of highly portable,artificial intelligence-driven solutions to achieve the democratization of early MCI detection and enable timely interventions.展开更多
A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit...A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.展开更多
Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias,a hypersensitive pain response induced by ...Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias,a hypersensitive pain response induced by non-painful stimulation.These allodynias,tested using thermal hyperalgesia,correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway,especially in the trigeminal nucleus caudalis.This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis,pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury,which are related to tactile allodynia,touch-pressure sensitivity,and visceral pain.Our results exhibited significant alterations in the excitatory monoamine,serotonin,in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity.Moreover,we also detected a robust alteration in the expression of serotonin,and inhibitory molecule norepinephrine in the nucleus tractus solitaries,which might indicate the possibility of an alteration in visceral pain,and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury.Collectively,widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.展开更多
MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochond...MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation(i.e.,miR-142-3p,miR-142-5p,and miR-146a)are altered in the hippocampus at 3–12 hours following a severe traumatic brain injury.In the present study,we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats.In addition,several inflammatory genes were analyzed in the cytosol fractions.The analysis showed that while elevated levels were observed in cytoplasm,the mitochondria-enriched miRNAs,miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury.Although not statistically significant,miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury,and recovered by 7 days.In contrast,miRNAs that are not enriched in mitochondria,including miR-124a,miR-150,miR-19b,miR-155,and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days.The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury.No major alterations were observed in sham operated animals.This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers.These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling.To test this,we utilized a novel peptide-based nanoparticle strategy for in vitro and in vivo delivery of a miR-146a mimic as a potential therapeutic strategy for targeting nuclear factor-kappa B inflammatory modulators in the injured brain.Nanoparticle delivery of miR-146a to BV-2 or SH-SY5Y cells significantly reduced expression of TNF receptor-associated factor 6(TRAF6)and interleukin-1 receptor-associated kinase 1(IRAK1),two important modulators of the nuclear factor-kappa B(NF-κB)pro-inflammatory pathway.Moreover,injections of miR-146a containing nanoparticles into the brain immediately following controlled cortical impact injury significantly reduced hippocampal TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 levels.Taken together,our studies demonstrate the subcellular alteration of inflammatory miRNAs after traumatic brain injury and establish proof of principle that nanoparticle delivery of miR-146a has therapeutic potential for modulating pro-inflammatory effectors in the injured brain.All of the studies performed were approved by the University of Kentucky Institutional Animal Care and Usage Committee(IACUC protocol#2014-1300)on August 17,2017.展开更多
According to clinical statistics,the mortality of patients with early brainstem hemorrhage is high.In this study,we established rat models of brainstem hemorrhage by injecting type Ⅶ collagenase into the right basote...According to clinical statistics,the mortality of patients with early brainstem hemorrhage is high.In this study,we established rat models of brainstem hemorrhage by injecting type Ⅶ collagenase into the right basotegmental pontine and investigated the pathological changes of early brainstem hemorrhage using multi-sequence magnetic resonance imaging and histopathological methods.We found that brainstem hematoma gradually formed in the injured rats over the first 3 days and then reduced after 7 days.The edema that occurred was mainly of the vasogenic type.No complete myelin sheath structure was found around the focus of the brainstem hemorrhage.The integrity and continuity of nerve fibers gradually deteriorated over the first 7 days.Neuronal degeneration was mild in the first 3 days and then obviously aggravated on the 7^(th)day.Inflammatory cytokines,interleukin-1β,and tumor necrosis factorαappeared on the 1st day after intracerebral hemorrhage,reached peak levels on the 3^(rd)day,and decreased from the 7^(th)day.Our findings show the characteristics of the progression of early brainstem hemorrhage.展开更多
Neuroscientists have emphasized visceral influences on consciousness and attention,but the potential neurophysiological pathways remain under exploration.Here,we found two neurophysiological pathways of heartbrain int...Neuroscientists have emphasized visceral influences on consciousness and attention,but the potential neurophysiological pathways remain under exploration.Here,we found two neurophysiological pathways of heartbrain interaction based on the relationship between oxygen-transport by red blood cells(RBCs)and consciousness/attention.To this end,we collected a dataset based on the routine physical examination,the breaking continuous flash suppression(b-CFS)paradigm,and an attention network test(ANT)in 140 immigrants under the hypoxic Tibetan environment.We combined electroencephalography and multilevel mediation analysis to investigate the relationship between RBC properties and consciousness/attention.The results showed that RBC function,via two independent neurophysiological pathways,not only triggered interoceptive re-representations in the insula and awareness connected to orienting attention but also induced an immune response corresponding to consciousness and executive control.Importantly,consciousness played a fundamental role in executive function which might be associated with the level of perceived stress.These results indicated the important role of oxygen-transport in heart-brain interactions,in which the related stress response affected consciousness and executive control.The findings provide new insights into the neurophysiological schema of heartbrain interactions.展开更多
Severe body stress induced by hypoxemia and hypotension may lead to total body energy state deterioration.The perfusion of the most vital organs is maintained at the expense of“less vital”organs.In the present study...Severe body stress induced by hypoxemia and hypotension may lead to total body energy state deterioration.The perfusion of the most vital organs is maintained at the expense of“less vital”organs.In the present study,we used a multi-site multiparametric(MSMP)monitoring system for real-time evaluation of tissue blood flow(TBF)and mitochondrial NADH fluorescence of the brain and the small intestine following hemorrhage.In Group 1,uncontrolled hemorrhage,mean arterial pressure(MAP)was decreased to 40mmHg within 2 minutes and shed blood was re-infused after 30minutes.In Group 2,controlled hemorrhage,during the 30minutes of hemorrhage,MAP was kept at 40mmHg.During hemorrhage,in both groups,the intestinal TBF and NADH deteriorated,while the brain remained relatively well protected.In Group 1,all parameters partly recovered within the hemorrhage phase,while in Group 2,complete recovery occurred only after resuscitation.At the end of the experiment,both models showed a decrease in intestinal viability(TBF decreased,NADH increased),while the brain metabolic state in Group 2 declined slightly.Our unique multi-parametric monitoring device demonstrated that,under hemorrhage,the small intestine responded entirely differently from the brain.This may suggest the potential usefulness of the monitoring of less vital organs,as proxy organs,in critical conditions such as massive hemorrhage.The present study also highlights the importance of mitochondrial function monitoring in similar conditions in the clinical environment.展开更多
Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy ...Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy and minimal toxicity is under controversy.However,it can be evaluated by monitoring oxygen delivery,saturation,and consumption.In this study,the monitoring system fixed on the rats’brain cortex included a time-sharing fluorometer-reflectometer for monitoring mitochondrial NADH and hemoglobin oxygenation(HbO_(2))combined with Laser Doppler Flowmetry(LDF)for blood-flow monitoring.Rats were located in a hyperbaric chamber and exposed to different pressures.The HBO pressure caused an increase in HbO_(2)and a decrease in NADH in proportion to the increase in hyperbaric pressure,up to a nearly maximum effect at 2.5ATA.At 6ATA,15 minutes before convulsions started,blood volume and NADH started to increase,while tissue O_(2)supply by hemoglobin remained stable.Oxygen pool includes oxygen dissolved in the plasma and also bounded to hemoglobin.Above 2.5ATA,hemoglobin is fully saturated and the oxygen pool nourishment derives only from the oxygen dissolved in the plasma,exceeding the physiological ability for autoregulation;hence,homeostasis is disturbed and convulsions appear.This information is vital because pressures around 2.5ATA–3ATA are standard clinically applied pressures used to treat most of the pathophysiological problems considering the potential benefit which must be balanced against the potential toxicity.This study enables,for the first time,to evaluate the oxygenation level of hemoglobin in the microcirculation.Furthermore,our study showed that additional oxygen pressure(above 2.5ATA)caused brain oxygen toxicity within a short variable period of time after the pressure elevation.展开更多
Objective: To investigate the development and distribution of phosphate-activated glutaminase like immunoreactive (PAG-LI) neurons in the central pathway of trigeminal proprioception of the rat brainstem. Methods: The...Objective: To investigate the development and distribution of phosphate-activated glutaminase like immunoreactive (PAG-LI) neurons in the central pathway of trigeminal proprioception of the rat brainstem. Methods: The immunohistochemitry techniques were used. Results: (1) At embryonic day 17 (E17), PAG-LI neurons were initially observed in the mesencephalic trigeminal nucleus (Vme). All PAG-LI neurons were large round neurons with moderate immunostaining. The immunoreactivity grew intense and attained adult-like pattern at P10. (2) Not until postnatal day 10 (P10) did a few PAG-LI neurons appear in the area ven-tral to the motor trigeminal nucleus (AVM) and area dorsal to the superior olivery nucleus (ADO), and not until P12 in the dorsomedial part of the subnucleus oralis of the spinal trigeminal nucleus (Vodm) and dorso-medial part of the principal sensory trigeminal nucleus (Vpdm). As development proceeded, more and more neurons in them were immunostained, and some PAG-LI neurons were detected in the lateral reticular forma-tion adjacent to the Vodm(LRF)and the caudolateral part of the supratrigeminal nucleus (Vsup-CL) at P21. Conclusion: In the central pathway of trigeminal proprioception of the rat brainstem, PAG-LI neurons ap-peared during two stages: The first stage from E17 to P10, PAG-LI neurons appeared in the Vme and reached adult-like pattern; the second stage from P10 to P21, PAG-LI neurons appeared in the Vodm, LRF, Vpdm, Vsup-CL, ADO, AVM and gradually reached adult-like pattern. This might be relative to the estab-lishment of jaw movement patterns.展开更多
The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithe...The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithesin on brain vitality in these models.Traumatic Brain Injury(TBI)was induced using thefluid percussion injury model in four levels:mild,moderate and two levels of severe TBI.Brain real-time evaluation was performed by the multiparametric monitoring assembly(MPA)which enable cerebral bloodflow(CBF)monitoring by laser Dopplerflowmetry,mitochondrial NADH(Nicotinamide adenine dinucleotide)monitoring by thefluorometric technique,ionic homehostasis using special mini-electrodes,intracranial pressure(ICP)by the ICP camino device and needle electrodes for ECoG(Electrocorticogram)recording.Our results showed high correlation between the level of impact and the extent of changes in the physiological properties of the injury as indicated by the changes in all parameters monitored using the MPA device.Moreover,Equithesin improved CBF,ionic extracellular level and mitochondrial redox state following mild and moderate TBI while in severe TBI,Equithesin did not improve the metabolic state of the cerebral cortex,although it decreased the mortality rate from 66%to 20%,and following extra-severe TBI level,Equithesin did not improve survival rate.In conclusion it seems that Equithesin's protective effect exists under mild to moderate levels of injury and not in case of severe injuries.展开更多
Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter ...Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter of fact,there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage.展开更多
Traumatic brain inju ry-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines,especially epinephrine,although few preclinical studies have examined th...Traumatic brain inju ry-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines,especially epinephrine,although few preclinical studies have examined the epinephrine level in the central nervous system after traumatic brain injury.Epinephrine has been shown to regulate the activities of spinal motoneurons as well as increase the heart rate,blood pressure,and blood flow to the hindlimb muscles.Therefore,the purpose of the present study was to determine the impact of repeated blast-induced traumatic brain injury on the epinephrine levels in seve ral function-s pecific central nervous system regions in rats.Following three repeated blast injuries at 3-day intervals,the hippocampus,motor cortex,locus coeruleus,vestibular nuclei,and lumbar spinal cord were harvested at post-injury day eight and processed for epinephrine assays using a high-sensitive electrochemical detector cou pled with high-performance liquid chromatography.Our results showed that the epinephrine levels were significantly decreased in the lumbar spinal cord tissues of blast-induced traumatic brain injury animals compared to the levels detected in age-and sex-matched sham controls.In other function-specific central nervous system regions,although the epinephrine levels were slightly altered following blast-induced tra u matic brain injury,they were not statistically significant.These results suggest that blast injury-induced significant downregulation of epinephrine in the lumbar spinal cord could negatively impact the motor and cardiovascular function.This is the first repo rt to show altered epinephrine levels in the spinal cord following repetitive mild blast-induced traumatic brain injury.展开更多
Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at th...Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1;however,whether KIF21A modulates dendritic structure and function in neurons remains unknown.In this study,we found that KIF21A was distributed in a subset of dendritic spines,and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines.Furthermore,the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity.Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching,and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1,but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1.Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals’cognitive abilities.Taken together,our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.展开更多
文摘Medical procedures are inherently invasive and carry the risk of inducing pain to the mind and body.Recently,efforts have been made to alleviate the discomfort associated with invasive medical procedures through the use of virtual reality(VR)technology.VR has been demonstrated to be an effective treatment for pain associated with medical procedures,as well as for chronic pain conditions for which no effective treatment has been established.The precise mechanism by which the diversion from reality facilitated by VR contributes to the diminution of pain and anxiety has yet to be elucidated.However,the provision of positive images through VR-based visual stimulation may enhance the functionality of brain networks.The salience network is diminished,while the default mode network is enhanced.Additionally,the medial prefrontal cortex may establish a stronger connection with the default mode network,which could result in a reduction of pain and anxiety.Further research into the potential of VR technology to alleviate pain could lead to a reduction in the number of individuals who overdose on painkillers and contribute to positive change in the medical field.
文摘Sepsis,a life-threatening condition,can lead to acute skin failure characterized by extensive skin damage.This is often due to decreased blood flow,inflammation,and increased susceptibility to infection.Acute skin failure in people with sepsis is often associated with sleep disturbances,anxiety,and poor mood.Inflammatory markers and lactate levels correlate with these psychiatric symptoms,suggesting a link between skin and brain function.The skin and the central nervous system(CNS)have bidirectional communication.The CNS is also in close contact with the digestive tract.The gut,skin,and brain influence each other’s functions thr-ough nervous,hormonal,and immune pathways,forming a gut-skin-brain axis.Understanding the interaction among the gut,skin,and CNS is critical to the diag-nosis and treatment of various skin and neurological disorders.By recognizing individual variations in gut microbiota,immune responses,and neural pathways,treatments can be tailored to specific patient needs,enhancing efficacy and minimizing side effects.The gut plays a large role in mental health.Under-standing the gut skin brain axis,will lead to improved mental health outcomes.
文摘The increasing global prevalence of mild cognitive impairment(MCI)necessitates a paradigm shift in early detection strategies.Conventional neuropsychological assessment methods,predominantly paper-and-pencil tests such as the Mini-Mental State Examination and the Montreal Cognitive Assessment,exhibit inherent limitations with respect to accessibility,administration burden,and sensitivity to subtle cognitive decline,particularly among diverse populations.This commentary critically examines a recent study that champions a novel approach:The integration of gait and handwriting kinematic parameters analyzed via machine learning for MCI screening.The present study positions itself within the broader landscape of MCI detection,with a view to comparing its advantages against established neuropsychological batteries,advanced neuroimaging(e.g.,positron emission tomography,magnetic resonance imaging),and emerging fluid biomarkers(e.g.,cerebrospinal fluid,blood-based assays).While the study demonstrates promising accuracy(74.44%area under the curve 0.74 with gait and graphic handwriting)and addresses key unmet needs in accessibility and objectivity,we highlight its cross-sectional nature,limited sample diversity,and lack of dual-task assessment as areas for future refinement.This commentary posits that kinematic biomarkers offer a distinctive,scalable,and ecologically valid approach to widespread MCI screening,thereby complementing existing methods by providing real-world functional insights.Future research should prioritize longitudinal validation,expansion to diverse cohorts,integration with multimodal data including dual-tasking,and the development of highly portable,artificial intelligence-driven solutions to achieve the democratization of early MCI detection and enable timely interventions.
基金supported in part by a Kentucky Spinal and Head Injury Trust trainee fellowshipsupported by National Institutes of Health under award numbers R00 AG044445(to ADB)P30 GM110787(to ADB)
文摘A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.
基金supported by Merit Review Awards(No.B6570R,B78071,and B1005-R)from the United States(U.S.)Department of Veterans Affairs Rehabilitation Research and Development Service
文摘Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias,a hypersensitive pain response induced by non-painful stimulation.These allodynias,tested using thermal hyperalgesia,correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway,especially in the trigeminal nucleus caudalis.This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis,pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury,which are related to tactile allodynia,touch-pressure sensitivity,and visceral pain.Our results exhibited significant alterations in the excitatory monoamine,serotonin,in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity.Moreover,we also detected a robust alteration in the expression of serotonin,and inhibitory molecule norepinephrine in the nucleus tractus solitaries,which might indicate the possibility of an alteration in visceral pain,and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury.Collectively,widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.
基金supported by a grant(15-12A)from the Kentucky Spinal Cord and Head Injury Research Trust to JES and WXW。
文摘MicroRNAs(miRNAs)are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function.We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation(i.e.,miR-142-3p,miR-142-5p,and miR-146a)are altered in the hippocampus at 3–12 hours following a severe traumatic brain injury.In the present study,we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats.In addition,several inflammatory genes were analyzed in the cytosol fractions.The analysis showed that while elevated levels were observed in cytoplasm,the mitochondria-enriched miRNAs,miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury.Although not statistically significant,miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury,and recovered by 7 days.In contrast,miRNAs that are not enriched in mitochondria,including miR-124a,miR-150,miR-19b,miR-155,and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days.The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury.No major alterations were observed in sham operated animals.This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers.These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling.To test this,we utilized a novel peptide-based nanoparticle strategy for in vitro and in vivo delivery of a miR-146a mimic as a potential therapeutic strategy for targeting nuclear factor-kappa B inflammatory modulators in the injured brain.Nanoparticle delivery of miR-146a to BV-2 or SH-SY5Y cells significantly reduced expression of TNF receptor-associated factor 6(TRAF6)and interleukin-1 receptor-associated kinase 1(IRAK1),two important modulators of the nuclear factor-kappa B(NF-κB)pro-inflammatory pathway.Moreover,injections of miR-146a containing nanoparticles into the brain immediately following controlled cortical impact injury significantly reduced hippocampal TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 levels.Taken together,our studies demonstrate the subcellular alteration of inflammatory miRNAs after traumatic brain injury and establish proof of principle that nanoparticle delivery of miR-146a has therapeutic potential for modulating pro-inflammatory effectors in the injured brain.All of the studies performed were approved by the University of Kentucky Institutional Animal Care and Usage Committee(IACUC protocol#2014-1300)on August 17,2017.
基金supported by the Natural Science Foundation of Xinjiang Uygur Autonomous Region, No. 2020D01A13 (to CWW)Chengdu Science and Technology Bureau, No. 2019-YF05-00511-SN (to MT)1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University, Nos. ZY2016102 (to MT), and ZY2016203 (to CY)
文摘According to clinical statistics,the mortality of patients with early brainstem hemorrhage is high.In this study,we established rat models of brainstem hemorrhage by injecting type Ⅶ collagenase into the right basotegmental pontine and investigated the pathological changes of early brainstem hemorrhage using multi-sequence magnetic resonance imaging and histopathological methods.We found that brainstem hematoma gradually formed in the injured rats over the first 3 days and then reduced after 7 days.The edema that occurred was mainly of the vasogenic type.No complete myelin sheath structure was found around the focus of the brainstem hemorrhage.The integrity and continuity of nerve fibers gradually deteriorated over the first 7 days.Neuronal degeneration was mild in the first 3 days and then obviously aggravated on the 7^(th)day.Inflammatory cytokines,interleukin-1β,and tumor necrosis factorαappeared on the 1st day after intracerebral hemorrhage,reached peak levels on the 3^(rd)day,and decreased from the 7^(th)day.Our findings show the characteristics of the progression of early brainstem hemorrhage.
基金supported by the National Natural Science Foundation of China(31660274,31771247,and 31600907)the Reformation and Development Funds for Local Region Universities from the Chinese Government in 2020(00060607,ZCJK 2020-11).
文摘Neuroscientists have emphasized visceral influences on consciousness and attention,but the potential neurophysiological pathways remain under exploration.Here,we found two neurophysiological pathways of heartbrain interaction based on the relationship between oxygen-transport by red blood cells(RBCs)and consciousness/attention.To this end,we collected a dataset based on the routine physical examination,the breaking continuous flash suppression(b-CFS)paradigm,and an attention network test(ANT)in 140 immigrants under the hypoxic Tibetan environment.We combined electroencephalography and multilevel mediation analysis to investigate the relationship between RBC properties and consciousness/attention.The results showed that RBC function,via two independent neurophysiological pathways,not only triggered interoceptive re-representations in the insula and awareness connected to orienting attention but also induced an immune response corresponding to consciousness and executive control.Importantly,consciousness played a fundamental role in executive function which might be associated with the level of perceived stress.These results indicated the important role of oxygen-transport in heart-brain interactions,in which the related stress response affected consciousness and executive control.The findings provide new insights into the neurophysiological schema of heartbrain interactions.
基金supported by grant 358/04-3 of“The Israeli Science Foundation”.
文摘Severe body stress induced by hypoxemia and hypotension may lead to total body energy state deterioration.The perfusion of the most vital organs is maintained at the expense of“less vital”organs.In the present study,we used a multi-site multiparametric(MSMP)monitoring system for real-time evaluation of tissue blood flow(TBF)and mitochondrial NADH fluorescence of the brain and the small intestine following hemorrhage.In Group 1,uncontrolled hemorrhage,mean arterial pressure(MAP)was decreased to 40mmHg within 2 minutes and shed blood was re-infused after 30minutes.In Group 2,controlled hemorrhage,during the 30minutes of hemorrhage,MAP was kept at 40mmHg.During hemorrhage,in both groups,the intestinal TBF and NADH deteriorated,while the brain remained relatively well protected.In Group 1,all parameters partly recovered within the hemorrhage phase,while in Group 2,complete recovery occurred only after resuscitation.At the end of the experiment,both models showed a decrease in intestinal viability(TBF decreased,NADH increased),while the brain metabolic state in Group 2 declined slightly.Our unique multi-parametric monitoring device demonstrated that,under hemorrhage,the small intestine responded entirely differently from the brain.This may suggest the potential usefulness of the monitoring of less vital organs,as proxy organs,in critical conditions such as massive hemorrhage.The present study also highlights the importance of mitochondrial function monitoring in similar conditions in the clinical environment.
文摘Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy and minimal toxicity is under controversy.However,it can be evaluated by monitoring oxygen delivery,saturation,and consumption.In this study,the monitoring system fixed on the rats’brain cortex included a time-sharing fluorometer-reflectometer for monitoring mitochondrial NADH and hemoglobin oxygenation(HbO_(2))combined with Laser Doppler Flowmetry(LDF)for blood-flow monitoring.Rats were located in a hyperbaric chamber and exposed to different pressures.The HBO pressure caused an increase in HbO_(2)and a decrease in NADH in proportion to the increase in hyperbaric pressure,up to a nearly maximum effect at 2.5ATA.At 6ATA,15 minutes before convulsions started,blood volume and NADH started to increase,while tissue O_(2)supply by hemoglobin remained stable.Oxygen pool includes oxygen dissolved in the plasma and also bounded to hemoglobin.Above 2.5ATA,hemoglobin is fully saturated and the oxygen pool nourishment derives only from the oxygen dissolved in the plasma,exceeding the physiological ability for autoregulation;hence,homeostasis is disturbed and convulsions appear.This information is vital because pressures around 2.5ATA–3ATA are standard clinically applied pressures used to treat most of the pathophysiological problems considering the potential benefit which must be balanced against the potential toxicity.This study enables,for the first time,to evaluate the oxygenation level of hemoglobin in the microcirculation.Furthermore,our study showed that additional oxygen pressure(above 2.5ATA)caused brain oxygen toxicity within a short variable period of time after the pressure elevation.
基金the National Nature Science Foundation of China (No. 39870262) by Foundation for University Key Teacher by the Ministry of Education of China
文摘Objective: To investigate the development and distribution of phosphate-activated glutaminase like immunoreactive (PAG-LI) neurons in the central pathway of trigeminal proprioception of the rat brainstem. Methods: The immunohistochemitry techniques were used. Results: (1) At embryonic day 17 (E17), PAG-LI neurons were initially observed in the mesencephalic trigeminal nucleus (Vme). All PAG-LI neurons were large round neurons with moderate immunostaining. The immunoreactivity grew intense and attained adult-like pattern at P10. (2) Not until postnatal day 10 (P10) did a few PAG-LI neurons appear in the area ven-tral to the motor trigeminal nucleus (AVM) and area dorsal to the superior olivery nucleus (ADO), and not until P12 in the dorsomedial part of the subnucleus oralis of the spinal trigeminal nucleus (Vodm) and dorso-medial part of the principal sensory trigeminal nucleus (Vpdm). As development proceeded, more and more neurons in them were immunostained, and some PAG-LI neurons were detected in the lateral reticular forma-tion adjacent to the Vodm(LRF)and the caudolateral part of the supratrigeminal nucleus (Vsup-CL) at P21. Conclusion: In the central pathway of trigeminal proprioception of the rat brainstem, PAG-LI neurons ap-peared during two stages: The first stage from E17 to P10, PAG-LI neurons appeared in the Vme and reached adult-like pattern; the second stage from P10 to P21, PAG-LI neurons appeared in the Vodm, LRF, Vpdm, Vsup-CL, ADO, AVM and gradually reached adult-like pattern. This might be relative to the estab-lishment of jaw movement patterns.
基金This work was supported by the Mina and Everard Goodman Faculty of Life Sciences,and the Leslie and Susan Gonda Multidisciplinary Brain Research Center,Bar-Ilan University,Ramat-Gan,Israel.
文摘The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithesin on brain vitality in these models.Traumatic Brain Injury(TBI)was induced using thefluid percussion injury model in four levels:mild,moderate and two levels of severe TBI.Brain real-time evaluation was performed by the multiparametric monitoring assembly(MPA)which enable cerebral bloodflow(CBF)monitoring by laser Dopplerflowmetry,mitochondrial NADH(Nicotinamide adenine dinucleotide)monitoring by thefluorometric technique,ionic homehostasis using special mini-electrodes,intracranial pressure(ICP)by the ICP camino device and needle electrodes for ECoG(Electrocorticogram)recording.Our results showed high correlation between the level of impact and the extent of changes in the physiological properties of the injury as indicated by the changes in all parameters monitored using the MPA device.Moreover,Equithesin improved CBF,ionic extracellular level and mitochondrial redox state following mild and moderate TBI while in severe TBI,Equithesin did not improve the metabolic state of the cerebral cortex,although it decreased the mortality rate from 66%to 20%,and following extra-severe TBI level,Equithesin did not improve survival rate.In conclusion it seems that Equithesin's protective effect exists under mild to moderate levels of injury and not in case of severe injuries.
基金supported by NIH,Nos.NIH R01 NS116068(to JCG)and NIH T32 NS077889(to OHW)。
文摘Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter of fact,there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage.
基金supported by the United States Department of Veterans Affairs Rehabilitation Research and Development Service(RR&D)[Merit Review Award numbers B3123-I/101 RX003123 and B3986-R/I01 RX003986-01A1]。
文摘Traumatic brain inju ry-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines,especially epinephrine,although few preclinical studies have examined the epinephrine level in the central nervous system after traumatic brain injury.Epinephrine has been shown to regulate the activities of spinal motoneurons as well as increase the heart rate,blood pressure,and blood flow to the hindlimb muscles.Therefore,the purpose of the present study was to determine the impact of repeated blast-induced traumatic brain injury on the epinephrine levels in seve ral function-s pecific central nervous system regions in rats.Following three repeated blast injuries at 3-day intervals,the hippocampus,motor cortex,locus coeruleus,vestibular nuclei,and lumbar spinal cord were harvested at post-injury day eight and processed for epinephrine assays using a high-sensitive electrochemical detector cou pled with high-performance liquid chromatography.Our results showed that the epinephrine levels were significantly decreased in the lumbar spinal cord tissues of blast-induced traumatic brain injury animals compared to the levels detected in age-and sex-matched sham controls.In other function-specific central nervous system regions,although the epinephrine levels were slightly altered following blast-induced tra u matic brain injury,they were not statistically significant.These results suggest that blast injury-induced significant downregulation of epinephrine in the lumbar spinal cord could negatively impact the motor and cardiovascular function.This is the first repo rt to show altered epinephrine levels in the spinal cord following repetitive mild blast-induced traumatic brain injury.
基金supported by the National Key Research and Development Program of China,No.2021ZD0202503(to AHT)the National Natural Science Foundation of China,Nos.31872759(to AHT)and 32070707(to CF)+1 种基金Shenzhen Science and Technology Program,No.RCJC20210609104333007(to ZW)Shenzhen-Hong Kong Institute of Brain Science,Shenzhen Fundamental Research Institutions,No.2021SHIBS0002(to ZW).
文摘Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory.Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1;however,whether KIF21A modulates dendritic structure and function in neurons remains unknown.In this study,we found that KIF21A was distributed in a subset of dendritic spines,and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines.Furthermore,the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity.Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching,and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1,but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1.Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals’cognitive abilities.Taken together,our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.
