Vision restoration presents a considerable challenge in the realm of regenerative medicine,while recent progress in ultrasound stimulation has displayed potential as a non-invasive therapeutic approach.This narrative ...Vision restoration presents a considerable challenge in the realm of regenerative medicine,while recent progress in ultrasound stimulation has displayed potential as a non-invasive therapeutic approach.This narrative review offers a comprehensive overview of current research on ultrasound-stimulated neuromodulation,emphasizing its potential as a treatment modality for various nerve injuries.By examining of the efficacy of different types of ultrasound stimulation in modulating peripheral and optic nerves,we can delve into their underlying molecular mechanisms.Furthermore,the review underscores the potential of sonogenetics in vision restoration,which involves leveraging pharmacological and genetic manipulations to inhibit or enhance the expression of related mechanosensitive channels,thereby modulating the strength of the ultrasound response.We also address how methods such as viral transcription can be utilized to render specific neurons or organs highly responsive to ultrasound,leading to significantly improved therapeutic outcomes.展开更多
Repetitive transcranial magnetic stimulation （rTMS） has been utilized as a therapeutic tool for neurodegenerative disorders including Alzheimer＇s disease. However, the precise mechanisms of its clinical effects rem...Repetitive transcranial magnetic stimulation （rTMS） has been utilized as a therapeutic tool for neurodegenerative disorders including Alzheimer＇s disease. However, the precise mechanisms of its clinical effects remain unknown. β-amyloid （Aβ） exhibits direct neurotoxic effects and is closely related to neuronal degeneration in Alzheimer＇s disease. Therefore, it has been hypothesized that the neuroprotective effects of rTMS are related to the mechanisms of protection against Aβ neurotoxicity. Organotypic hippocampal slices were prepared from 8-day old, Sprague Dawley rats. The tissue slices were exposed to 100 μmol/L Al3142 since day 12 in vitro with and without high-frequency （20 Hz） magnetic stimulation. Magnetic stimulation efficacy was evaluated by measuring neuronal nuclei （NeuN） protein expression and by observing cultures following propidium iodide fluorescence staining and bromodeoxyuridine （BrdU） immunohistochemistry. Lactate dehydrogenase activity was detected in the culture media to evaluate hippocampal neuronal damage. Our results demonstrated that high-frequency magnetic stimulation significantly reversed the reduction of NeuN protein expression because of Aβ1-42 exposure （P 〈 0.05） and significantly reduced the number of damaged cells in the hippocampal slices （P 〈 0.05）. However, lactate dehydrogenase levels and anti-BrdU staining results did not reveal any statistical differences These findings indicate that high-frequency magnetic stimulation might have protective effect on hippocampal neurons from Aβ1-42 neurotoxicity.展开更多
Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors,leading to progressive photoreceptor loss.Previous research supports the beneficial effect of electrical stimulation on pho...Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors,leading to progressive photoreceptor loss.Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival.This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation(tcES)in mice affected by inherited retinal degeneration.Additionally,the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans.In this study,we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular,sine,and ramp waveforms.To investigate the functional effects of electrical stimulation on photoreceptors,we used human retinal explant cultures and rhodopsin knockout(Rho^(-/-))mice,demonstrating progressive photoreceptor degeneration with age.Human retinal explants isolated from the donors’eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro.Photoreceptor density was evaluated by rhodopsin immunolabeling.In vivo Rho^(-/-)mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms.Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response(OMR),respectively.Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas.Oscilloscope recordings indicated effective delivery of rectangular,sine,and ramp waveforms to the retina by transcorneal electrical stimulation,of which the ramp waveform required the lowest voltage.Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes.The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro(~0.5-1.5°C).Electrical stimulation increased photoreceptor survival in human retinal explant cultures,particularly at the ramp waveform.Transcorneal electrical stimulation(rectangular+ramp)waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results.Histology and immunolabeling demonstrated increased photoreceptor survival,improved outer nuclear layer thickness,and increased bipolar cell sprouting in Rho^(-/-)mice.These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina,improves photoreceptor survival in both human and mouse retinas,and increases visual function in Rho^(-/-)mice.Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion.展开更多
Optic nerve degeneration is a major cause of irreversible blindness worldwide with glaucoma being the most common optic neuropathy,affecting approximately 76 million people worldwide in 2020.The optic nerve comprises ...Optic nerve degeneration is a major cause of irreversible blindness worldwide with glaucoma being the most common optic neuropathy,affecting approximately 76 million people worldwide in 2020.The optic nerve comprises axons of retinal ganglion cells(RGCs),the output neurons of the inner retina.Protecting RGCs and axons from degeneration and regenerating RGC axons to preserve and recover vision in patients with progressive optic neuropathy is an unmet need.Unlike embryonic neurons,mature neurons of the mammalian central nervous system fail to regenerate their axons following injury.The age-related loss of axon regenerative capacity of RGCs over time renders vision loss from optic neuropathy irreversible.The failure of injured RGCs to regenerate axons is largely attributed to inhibitory molecules in the extrinsic environment and a change in the intrinsic molecular makeup of aging cells.Early studies have demonstrated that RGCs require specific molecular signals for the stimulation of axon growth even without inhibitory molecules in the extrinsic environment,leading successive efforts to focus on uncovering the intrinsic signaling pathways that control axon extension during RGC development.展开更多
基金supported by R01EY032229(Biomechanical Mapping of the Optic Nerve Head and Peripapillary Sclera Using High Frequency Ultrasonic Elastography)R01EY028662(High-resolution Elastographic Assessment of the Optic Nerve Head)+2 种基金R01EY030126(Non-invasive Ultrasound Stimulated Retinal Prosthesis)(to QZ)Unrestricted Grant to the Department of Ophthalmology from Research to Prevent Blindness,New York,NY(to MSH)the National Eye Institute of the National Institutes of Health under Award Number P30EY029220(to MSH)。
文摘Vision restoration presents a considerable challenge in the realm of regenerative medicine,while recent progress in ultrasound stimulation has displayed potential as a non-invasive therapeutic approach.This narrative review offers a comprehensive overview of current research on ultrasound-stimulated neuromodulation,emphasizing its potential as a treatment modality for various nerve injuries.By examining of the efficacy of different types of ultrasound stimulation in modulating peripheral and optic nerves,we can delve into their underlying molecular mechanisms.Furthermore,the review underscores the potential of sonogenetics in vision restoration,which involves leveraging pharmacological and genetic manipulations to inhibit or enhance the expression of related mechanosensitive channels,thereby modulating the strength of the ultrasound response.We also address how methods such as viral transcription can be utilized to render specific neurons or organs highly responsive to ultrasound,leading to significantly improved therapeutic outcomes.
文摘Repetitive transcranial magnetic stimulation （rTMS） has been utilized as a therapeutic tool for neurodegenerative disorders including Alzheimer＇s disease. However, the precise mechanisms of its clinical effects remain unknown. β-amyloid （Aβ） exhibits direct neurotoxic effects and is closely related to neuronal degeneration in Alzheimer＇s disease. Therefore, it has been hypothesized that the neuroprotective effects of rTMS are related to the mechanisms of protection against Aβ neurotoxicity. Organotypic hippocampal slices were prepared from 8-day old, Sprague Dawley rats. The tissue slices were exposed to 100 μmol/L Al3142 since day 12 in vitro with and without high-frequency （20 Hz） magnetic stimulation. Magnetic stimulation efficacy was evaluated by measuring neuronal nuclei （NeuN） protein expression and by observing cultures following propidium iodide fluorescence staining and bromodeoxyuridine （BrdU） immunohistochemistry. Lactate dehydrogenase activity was detected in the culture media to evaluate hippocampal neuronal damage. Our results demonstrated that high-frequency magnetic stimulation significantly reversed the reduction of NeuN protein expression because of Aβ1-42 exposure （P 〈 0.05） and significantly reduced the number of damaged cells in the hippocampal slices （P 〈 0.05）. However, lactate dehydrogenase levels and anti-BrdU staining results did not reveal any statistical differences These findings indicate that high-frequency magnetic stimulation might have protective effect on hippocampal neurons from Aβ1-42 neurotoxicity.
基金supported by The Norwegian Research CouncilDepartment of Ophthalmology,Oslo University Hospital,Oslo,Norway(to TPU)+10 种基金Department of Medical Biochemistry,Oslo University Hospital,Oslo,Norway(to TPU)The Norwegian Association for the Blind and Partially Sighted(to TPU)The Ministry of Science and Technology of Taiwan,China MOST 105-2917-I-002-031,MOST 109-2917-I-564-032(to KC)The Scientific and Technological Research Council of Turkiye-TUBITAK(to KG)BrightFocus Foundation(to KSC)the Massachusetts Lions Foundation(to KSC)National Eye Institute Grant EY031696(to DFC)Harvard NeuroDiscovery Center Grant(to DFC)Department of Defense(USA)HT9425-23-1-1045(to DFC and AL)Core Grant for Vision Research from NIH/NEI to the Schepens Eye Research Institute(P30EY003790)South-Eastern Norway Regional Health Authority and the Norwegian Society of the Blind(to TPU).
文摘Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors,leading to progressive photoreceptor loss.Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival.This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation(tcES)in mice affected by inherited retinal degeneration.Additionally,the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans.In this study,we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular,sine,and ramp waveforms.To investigate the functional effects of electrical stimulation on photoreceptors,we used human retinal explant cultures and rhodopsin knockout(Rho^(-/-))mice,demonstrating progressive photoreceptor degeneration with age.Human retinal explants isolated from the donors’eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro.Photoreceptor density was evaluated by rhodopsin immunolabeling.In vivo Rho^(-/-)mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms.Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response(OMR),respectively.Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas.Oscilloscope recordings indicated effective delivery of rectangular,sine,and ramp waveforms to the retina by transcorneal electrical stimulation,of which the ramp waveform required the lowest voltage.Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes.The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro(~0.5-1.5°C).Electrical stimulation increased photoreceptor survival in human retinal explant cultures,particularly at the ramp waveform.Transcorneal electrical stimulation(rectangular+ramp)waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results.Histology and immunolabeling demonstrated increased photoreceptor survival,improved outer nuclear layer thickness,and increased bipolar cell sprouting in Rho^(-/-)mice.These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina,improves photoreceptor survival in both human and mouse retinas,and increases visual function in Rho^(-/-)mice.Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion.
文摘Optic nerve degeneration is a major cause of irreversible blindness worldwide with glaucoma being the most common optic neuropathy,affecting approximately 76 million people worldwide in 2020.The optic nerve comprises axons of retinal ganglion cells(RGCs),the output neurons of the inner retina.Protecting RGCs and axons from degeneration and regenerating RGC axons to preserve and recover vision in patients with progressive optic neuropathy is an unmet need.Unlike embryonic neurons,mature neurons of the mammalian central nervous system fail to regenerate their axons following injury.The age-related loss of axon regenerative capacity of RGCs over time renders vision loss from optic neuropathy irreversible.The failure of injured RGCs to regenerate axons is largely attributed to inhibitory molecules in the extrinsic environment and a change in the intrinsic molecular makeup of aging cells.Early studies have demonstrated that RGCs require specific molecular signals for the stimulation of axon growth even without inhibitory molecules in the extrinsic environment,leading successive efforts to focus on uncovering the intrinsic signaling pathways that control axon extension during RGC development.
