RESUMO
Humans are capable of generating extraordinarily diverse articulatory movement combinations to produce meaningful speech. This ability to orchestrate specific phonetic sequences, and their syllabification and inflection over subsecond timescales allows us to produce thousands of word sounds and is a core component of language1,2. The fundamental cellular units and constructs by which we plan and produce words during speech, however, remain largely unknown. Here, using acute ultrahigh-density Neuropixels recordings capable of sampling across the cortical column in humans, we discover neurons in the language-dominant prefrontal cortex that encoded detailed information about the phonetic arrangement and composition of planned words during the production of natural speech. These neurons represented the specific order and structure of articulatory events before utterance and reflected the segmentation of phonetic sequences into distinct syllables. They also accurately predicted the phonetic, syllabic and morphological components of upcoming words and showed a temporally ordered dynamic. Collectively, we show how these mixtures of cells are broadly organized along the cortical column and how their activity patterns transition from articulation planning to production. We also demonstrate how these cells reliably track the detailed composition of consonant and vowel sounds during perception and how they distinguish processes specifically related to speaking from those related to listening. Together, these findings reveal a remarkably structured organization and encoding cascade of phonetic representations by prefrontal neurons in humans and demonstrate a cellular process that can support the production of speech.
Assuntos
Neurônios , Fonética , Córtex Pré-Frontal , Fala , Humanos , Movimento , Neurônios/fisiologia , Fala/fisiologia , Percepção da Fala/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologiaRESUMO
The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Neurônios Dopaminérgicos , Sobrevivência de Enxerto , Doenças Neuroinflamatórias , Doença de Parkinson , Linfócitos T Reguladores , Tirosina 3-Mono-Oxigenase , Humanos , Dopamina/análogos & derivados , Dopamina/metabolismo , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/transplante , Mesencéfalo/patologia , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/prevenção & controle , Doenças Neuroinflamatórias/terapia , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Doença de Parkinson/cirurgia , Doença de Parkinson/terapia , Tirosina 3-Mono-Oxigenase/deficiência , Tirosina 3-Mono-Oxigenase/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Terapia Baseada em Transplante de Células e Tecidos/métodos , Animais , Camundongos , Ratos , Oxidopamina/metabolismo , Sobrevivência de Enxerto/imunologia , Morte Celular , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/imunologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Neostriado/metabolismo , Fatores de Tempo , Proliferação de Células , Resultado do TratamentoRESUMO
We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).
Assuntos
Neurônios Dopaminérgicos/citologia , Células-Tronco Pluripotentes Induzidas/transplante , Doença de Parkinson/terapia , Parte Compacta da Substância Negra/citologia , Idoso , Animais , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/transplante , Seguimentos , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Masculino , Camundongos , Camundongos SCID , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Transplante Autólogo , Transplante HomólogoRESUMO
Parkinson's disease (PD) is characterized by the selective death of substantia nigra pars compacta (SNpc) dopaminergic neurons and includes both motor and non-motor symptoms. While numerous models exist for the study of typical PD motor deficits, fewer exist for non-motor symptoms. Previous studies have shown that a Pitx3-/- mouse model (aphakia or ak mouse) has specific developmental failure of the dopaminergic neuron population in the SNpc and that it can be used for the study of PD-related gross motor dysfunction as well as cognitive functional deficits. It remains unclear whether the aphakia mouse, both male and female, might also be used to model fine motor deficits and for additional studies of non-motor deficits associated with PD. Here, using an extensive battery of behavioral tests, we demonstrate that the aphakia mouse shows both gross and fine motor functional deficits compared with control mice. Furthermore, aphakia mice show deficits of olfactory function in buried pellet, odor discrimination and odor habituation/dishabituation tests. We also found that aphakia mice suffer from gastrointestinal dysfunction (e.g., longer whole gut transit time and colon motility deficits), suggesting that the mutation also affects function of the gut-brain axis in this animal model. Moreover, our data demonstrate that in the aphakia mouse, L-DOPA, the gold standard PD medication, can rescue both gross and fine motor function deficits but neither olfactory nor gastrointestinal symptoms, a pattern much like that seen in PD patients. Altogether, this suggests that the aphakia mouse is a suitable model for fine motor, olfactory and gastrointestinal behavioral studies of PD as well as for the development of novel disease-modifying therapeutics. SIGNIFICANCE STATEMENT: While several animal models are available to study the major motor symptoms of PD, there are fewer that replicate non-motor symptoms, which constitute a major source of morbidity for patients. Moreover, available models often require manipulations resulting in sudden massive cell loss and inflammation, both of which may interfere with understanding of the direct effects of dopaminergic neuronal loss in the SNpc. We describe a model of congenital SNpc cell deficiency in a Pitx3-/- mouse and characterize it with a battery of behavioral tests suggesting that it closely mimics non-motor as well as motor symptoms of PD, providing a useful insight into the effects of the nigrostriatal dopamine deficit. Taken together, these data suggest that the ak mouse represents a useful model to study dopaminergic system function for both motor and non-motor symptoms of PD.
Assuntos
Afacia , Doença de Parkinson , Animais , Afacia/complicações , Afacia/genética , Modelos Animais de Doenças , Dopamina , Neurônios Dopaminérgicos , Feminino , Proteínas de Homeodomínio/genética , Humanos , Levodopa/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/complicações , Doença de Parkinson/genética , Substância Negra , Fatores de Transcrição/genéticaRESUMO
PURPOSE: Develop a deflectable intracardiac MR imaging (ICMRI) guiding-sheath to accelerate imaging during MR-guided electrophysiological (EP) interventions for radiofrequency (500 kHz) ablation (RFA) of arrythmia. Requirements include imaging at three to five times surface-coil SNR in cardiac chambers, vascular insertion, steerable-active-navigation into cardiac chambers, operation with ablation catheters, and safe levels of MR-induced heating. METHODS: ICMRI's 6 mm outer-diameter (OD) metallic-braided shaft had a 2.6 mm OD internal lumen for ablation-catheter insertion. Miniature-Baluns (MBaluns) on ICMRI's 1 m shaft reduced body-coil-induced heating. Distal section was a folded "star"-shaped imaging-coil mounted on an expandable frame, with an integrated miniature low-noise-amplifier overcoming cable losses. A handle-activated movable-shaft expanded imaging-coil to 35 mm OD for imaging within cardiac-chambers. Four MR-tracking micro-coils enabled navigation and motion-compensation, assuming a tetrahedron-shape when expanded. A second handle-lever enabled distal-tip deflection. ICMRI with a protruding deflectable EP catheter were used for MR-tracked navigation and RFA using a dedicated 3D-slicer user-interface. ICMRI was tested at 3T and 1.5T in swine to evaluate (a) heating, (b) cardiac-chamber access, (c) imaging field-of-view and SNR, and (d) intraprocedural RFA lesion monitoring. RESULTS: The 3T and 1.5T imaging SNR demonstrated >400% SNR boost over a 4 × 4 × 4 cm3 FOV in the heart, relative to body and spine arrays. ICMRI with MBaluns met ASTM/IEC heating limits during navigation. Tip-deflection allowed navigating ICMRI and EP catheter into atria and ventricles. Acute-lesion long-inversion-time-T1-weighted 3D-imaging (TWILITE) ablation-monitoring using ICMRI required 5:30 min, half the time needed with surface arrays alone. CONCLUSION: ICMRI assisted EP-catheter navigation to difficult targets and accelerated RFA monitoring.
Assuntos
Ablação por Cateter , Imageamento por Ressonância Magnética , Animais , Arritmias Cardíacas , Ablação por Cateter/métodos , Desenho de Equipamento , Átrios do Coração , Imageamento por Ressonância Magnética/métodos , SuínosRESUMO
BACKGROUND: Spreading depolarizations (SDs) are associated with worse outcome following subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI), but gold standard detection requires electrocorticography with a subdural strip electrode. Electroencephalography (EEG) ictal-interictal continuum abnormalities are associated with poor outcomes after TBI and with both delayed cerebral ischemia (DCI) and poor outcomes after SAH. We examined rates of SD detection in patients with SAH and TBI with intraparenchymal and subdural strip electrodes and assessed which continuous EEG (cEEG) measures were associated with intracranially quantified SDs. METHODS: In this single-center cohort, we included patients with SAH and TBI undergoing ≥ 24 h of interpretable intracranial monitoring via eight-contact intraparenchymal or six-contact subdural strip platinum electrodes or both. SDs were rated according to established consensus criteria and compared with cEEG findings rated according to the American Clinical Neurophysiology Society critical care EEG monitoring consensus criteria: lateralized rhythmic delta activity, generalized rhythmic delta activity, lateralized periodic discharges, generalized periodic discharges, any ictal-interictal continuum, or a composite scalp EEG tool for seizure risk estimation: the 2HELPS2B score. Among patients with SAH, cEEG was assessed for validated DCI biomarkers: new or worsening epileptiform abnormalities and new background deterioration. RESULTS: Over 6 years, SDs were recorded in 5 (18%) of 28 patients recorded with intraparenchymal electrodes and 4 (40%) of 10 patients recorded with subdural strip electrodes. There was no significant association between occurrence of SDs and day 1 cEEG findings (American Clinical Neurophysiology Society main terms lateralized periodic discharges, generalized periodic discharges, lateralized rhythmic delta activity, or seizures, individually or in combination). After SAH, established cEEG DCI predictors were not associated with SDs. CONCLUSIONS: Intraparenchymal recordings yielded low rates of SD, and documented SDs were not associated with ictal-interictal continuum abnormalities or other cEEG DCI predictors. Identifying scalp EEG correlates of SD may require training computational EEG analytics and use of gold standard subdural strip electrocorticography recordings.
Assuntos
Lesões Encefálicas Traumáticas , Isquemia Encefálica , Hemorragia Subaracnóidea , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico , Infarto Cerebral/complicações , Eletroencefalografia , Humanos , Couro Cabeludo , Convulsões/diagnóstico , Convulsões/epidemiologia , Convulsões/etiologia , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnósticoRESUMO
PURPOSE: Voltage-based device-tracking (VDT) systems are commonly used for tracking invasive devices in electrophysiological cardiac-arrhythmia therapy. During electrophysiological procedures, electro-anatomic mapping workstations provide guidance by integrating VDT location and intracardiac electrocardiogram information with X-ray, computerized tomography, ultrasound, and MR images. MR assists navigation, mapping, and radiofrequency ablation. Multimodality interventions require multiple patient transfers between an MRI and the X-ray/ultrasound electrophysiological suite, increasing the likelihood of patient-motion and image misregistration. An MRI-compatible VDT system may increase efficiency, as there is currently no single method to track devices both inside and outside the MRI scanner. METHODS: An MRI-compatible VDT system was constructed by modifying a commercial system. Hardware was added to reduce MRI gradient-ramp and radiofrequency unblanking pulse interference. VDT patches and cables were modified to reduce heating. Five swine cardiac VDT electro-anatomic mapping interventions were performed, navigating inside and thereafter outside the MRI. RESULTS: Three-catheter VDT interventions were performed at >12 frames per second both inside and outside the MRI scanner with <3 mm error. Catheters were followed on VDT- and MRI-derived maps. Simultaneous VDT and imaging was possible in repetition time >32 ms sequences with <0.5 mm errors, and <5% MRI signal-to-noise ratio (SNR) loss. At shorter repetition times, only intracardiac electrocardiogram was reliable. Radiofrequency heating was <1.5°C. CONCLUSION: An MRI-compatible VDT system is feasible.
Assuntos
Imageamento por Ressonância Magnética/instrumentação , Magnetismo/instrumentação , Pletismografia de Impedância/instrumentação , Próteses e Implantes , Tecnologia sem Fio/instrumentação , Animais , Desenho de Equipamento , Análise de Falha de Equipamento , Projetos Piloto , SuínosRESUMO
Cell replacement therapy is an area of increasing interest for treating Parkinson's disease (PD). However, to become a clinically practical option for PD patients, it must first overcome significant barriers, including establishment of safe and standardized surgical procedures, determination of appropriate perioperative medication regimens, demonstration of long-term graft survival and incorporation, and standardized, clinically meaningful follow-up measures. In this review, we will describe the current status of cell therapy for PD with special attention to these critical requirements, to define guideposts on the road to bring the benefit of this therapy to the Parkinson's clinic.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Terapia Baseada em Transplante de Células e TecidosRESUMO
High-density microelectrode arrays (MEAs) have opened new possibilities for systems neuroscience in human and non-human animals, but brain tissue motion relative to the array poses a challenge for downstream analyses, particularly in human recordings. We introduce DREDge (Decentralized Registration of Electrophysiology Data), a robust algorithm which is well suited for the registration of noisy, nonstationary extracellular electrophysiology recordings. In addition to estimating motion from spikes in the action potential (AP) frequency band, DREDge enables automated tracking of motion at high temporal resolution in the local field potential (LFP) frequency band. In human intraoperative recordings, which often feature fast (period <1s) motion, DREDge correction in the LFP band enabled reliable recovery of evoked potentials, and significantly reduced single-unit spike shape variability and spike sorting error. Applying DREDge to recordings made during deep probe insertions in nonhuman primates demonstrated the possibility of tracking probe motion of centimeters across several brain regions while simultaneously mapping single unit electrophysiological features. DREDge reliably delivered improved motion correction in acute mouse recordings, especially in those made with an recent ultra-high density probe. We also implemented a procedure for applying DREDge to recordings made across tens of days in chronic implantations in mice, reliably yielding stable motion tracking despite changes in neural activity across experimental sessions. Together, these advances enable automated, scalable registration of electrophysiological data across multiple species, probe types, and drift cases, providing a stable foundation for downstream scientific analyses of these rich datasets.
RESUMO
We review contemporary scientific research on the relationship between visual perception and visual mental imagery in the context of Cheves Perky's (1910) landmark article on imagery and imagination. This body of research has firmly established a strong connection between the psychology of imagery and perception and has contributed a strong voice to the imagery debate. We then use the concept of embodiment to discuss additional avenues of inquiry at which Perky's work hinted. These include a more thorough examination of the relationship between imagery and emotion, the creative, active aspects of imagery and imagination, and the methods we can bring to bear on understanding imagery and imagination as a human experience.
Assuntos
Emoções , Imaginação , Psicologia/história , Percepção Visual , História do Século XX , HumanosRESUMO
In a recently published study, Xu et al. used two surface markers, CLSTN2 and PTPRO, to generate highly purified donor dopaminergic neurons and achieved stable and predictable therapeutic outcomes by transplantation into the brain of PD animal models (Xu et al., 2022).
Assuntos
Ouro , Células-Tronco Pluripotentes , Animais , Diferenciação Celular/fisiologia , Dopamina , Neurônios Dopaminérgicos , Humanos , MesencéfaloRESUMO
In a recent report in Nature Medicine, Tao et al. (2021) demonstrate that MPTP-treated monkeys receiving autologous, but not allogeneic, transplantation showed significant long-term improvement in motor and depressive behaviors, supporting the feasibility of autologous cell therapy for Parkinson's disease (PD).
Assuntos
Doença de Parkinson , Animais , Terapia Baseada em Transplante de Células e Tecidos , Haplorrinos , Doença de Parkinson/terapia , Transplante Autólogo , Transplante HomólogoRESUMO
BACKGROUND: Surgical implantation of cellular grafts into the brain is of increasing importance, as stem cell-based therapies for Parkinson and other diseases continue to develop. The effect of grafting technique on development and survival of the graft has received less attention. Rate and method of graft delivery may impact the cell viability and success of these therapies. Understanding the final location of the graft with respect to the intended target location is also critical. OBJECTIVE: To describe a "columnar injection" technique designed to reduce damage to host tissue and result in a column of graft material with greater surface area to volume ratio than traditional injection techniques. METHODS: Using a clinically relevant model system of human embryonic stem cell-derived dopaminergic progenitors injected into athymic rat host brain, we describe a novel device that allows separate control of syringe barrel and plunger, permitting precise deposition of the contents into the cannula tract during withdrawal. Controls consist of contralateral injection using traditional techniques. Graft histology was examined at graft maturity. RESULTS: Bolus grafts were centered on the injection tract but were largely proximal to the "target" location. These grafts displayed a conspicuous peripheral distribution of cells, particularly of mature dopaminergic neurons. In contrast, column injections remained centered at the intended target, contained more evenly distributed cells, and had significantly more mature dopaminergic neurons. CONCLUSION: We suggest that this columnar injection technique may allow better engraftment and development of intracerebral grafts, enhancing outcomes of cell therapy, compared to fixed-point injection techniques.
Assuntos
Encéfalo , Dopamina , Animais , Terapia Baseada em Transplante de Células e Tecidos , Humanos , RatosRESUMO
OBJECTIVE: Cardiovascular interventional devices typically have long metallic braids or backbones to aid in steerability and pushability. However, electromagnetic coupling of metallic-based cardiovascular interventional devices with the radiofrequency (RF) fields present during Magnetic Resonance Imaging (MRI) can make a device unsafe for use in an MRI scanner. We aimed to develop MRI conditional actively-tracked cardiovascular interventional devices by sufficiently attenuating induced currents on the metallic braid/tube and internal-cabling using miniaturized resonant floating RF traps (MBaluns). METHOD: MBaluns were designed for placement at multiple locations along a conducting cardiovascular device to prevent the establishment of standing waves and to dissipate RF-induced energy. The MBaluns were constructed with loosely-wound solenoids to be sensitive to transverse magnetic fields created by both surface currents on the device's metallic backbone and common-mode currents on internal cables. Electromagnetic simulations were used to optimize MBalun parameters. Following optimization, two different MBalun designs were applied to MR-actively-tracked metallic guidewires and metallic-braided electrophysiology ablation catheters. Control-devices were constructed without MBaluns. MBalun performance was validated using network-analyzer quantification of current attenuation, electromagnetic Specific-Absorption-Rate (SAR) analysis, thermal tests during high SAR pulse sequences, and MRI-guided cardiovascular navigation in swine. RESULTS: Electromagnetic SAR simulations resulted in ≈20 dB attenuation at the tip of the wire using six successive MBaluns. Network-analyzer tests confirmed â¼17 dB/MBalun surface-current attenuation. Thermal tests indicated temperature decreases of 5.9 °C in the MBalun-equipped guidewire tip. Both devices allowed rapid vascular navigation resulting from good torquability and MR-Tracking visibility. CONCLUSION: MBaluns increased device diameter by 20%, relative to conventional devices, providing a spatially-efficient means to prevent heating during MRI. SIGNIFICANCE: MBaluns allow use of long metallic components, which improves mechanical performance in active MR-guided interventional devices.
Assuntos
Imageamento por Ressonância Magnética , Ondas de Rádio , Animais , Catéteres , Eletrofisiologia , Desenho de Equipamento , Imagens de Fantasmas , SuínosRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder associated with loss of striatal dopamine, secondary to degeneration of midbrain dopamine (mDA) neurons in the substantia nigra, rendering cell transplantation a promising therapeutic strategy. To establish human induced pluripotent stem cell-based (hiPSC-based) autologous cell therapy, we report a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, we developed a method to more efficiently generate clinical-grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, we established a "spotting"-based in vitro differentiation methodology to generate functional and healthy mDA cells in a scalable manner. Third, we developed a chemical method that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restores motor function and reinnervates host brain, while showing no evidence of tumor formation or redistribution of the implanted cells. We propose that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.
Assuntos
Células-Tronco Pluripotentes Induzidas , Atividade Motora , Doença de Parkinson Secundária , Recuperação de Função Fisiológica , Transplante de Células-Tronco , Animais , Autoenxertos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Pluripotentes Induzidas/transplante , Masculino , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/terapia , Ratos , Ratos NusRESUMO
Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which affects about 0.3% of the general population. As the population in the developed world ages, this creates an escalating burden on society both in economic terms and in quality of life for these patients and for the families that support them. Although currently available pharmacological or surgical treatments may significantly improve the quality of life of many patients with PD, these are symptomatic treatments that do not slow or stop the progressive course of the disease. Because motor impairments in PD largely result from loss of midbrain dopamine neurons in the substantia nigra pars compacta, PD has long been considered to be one of the most promising target diseases for cell-based therapy. Indeed, numerous clinical and preclinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells as a standardized therapeutic regimen has been fraught with fundamental ethical, practical, and clinical issues, prompting scientists to explore alternative cell sources. Based on groundbreaking establishments of human embryonic stem cells and induced pluripotent stem cells, these human pluripotent stem cells have been the subject of extensive research, leading to tremendous advancement in our understanding of these novel classes of stem cells and promising great potential for regenerative medicine. In this review, we discuss the prospects and challenges of human pluripotent stem cell-based cell therapy for PD.
Assuntos
Doença de Parkinson/cirurgia , Células-Tronco Pluripotentes/transplante , Transplante de Células-Tronco/métodos , Humanos , Transplante de Células-Tronco/tendênciasRESUMO
To study the efficacy of vagus nerve stimulation (VNS) therapy as an adjunctive treatment for intractable epilepsy in patients under 12 years of age, we analyzed 2-year postimplant data of 35 consecutive patients. Of the 35 patients, 18 (51.4%) at 6 months, 18 (51.4%) at 12 months, and 21 (60.1%) at 24 months showed ≥50% reduction in seizure frequency (responders). Although incremental seizure freedom was noted, no patient remained seizure-free throughout the 3 study periods. Partial response (≥50% seizure reduction in 2 or less study periods) was seen in 8 (22.9%) patients. Twelve patients (34.3%) were nonresponders. Out of 29 patients with primary generalized epilepsy, 20 (68.9%) and, out of 6 patients with focal epilepsy, 3 (50%) had ≥50% seizure control in at least one study period. No major complications or side effects requiring discontinuation of VNS therapy were encountered. We conclude that (1) patients with intractable primary generalized epilepsy respond better to VNS therapy, (2) cumulative effect of neuromodulation with improving responder rate to seizure freedom with continuation of VNS therapy is noted, and (3) VNS therapy is safe and is well tolerated in children receiving implant under 12 years of age.
RESUMO
Microvascular (capillary) proliferation is a readily observed, but largely ignored phenomenon of the mesial temporal lobe epilepsy (MTLE) hippocampus. Here, we report that the proliferated capillaries in surgically resected MTLE hippocampi were strongly immunoreactive for erythropoietin receptor (EPO-r). Further, we found that these capillaries were most prominent in areas of the MTLE hippocampus with extensive neuronal loss and gliosis, i.e. the CA3, CA1, and dentate hilus. High-resolution immunogold electron microscopy revealed that the capillary EPO-r was localized to the luminal and abluminal plasma membrane of endothelial cells, to endosome-like structures of these cells, and to pericapillary astrocytic end-feet. Previous studies have shown that systemically administered EPO appears in the cerebrospinal fluid in experimental animals, and the present results are consistent with the idea that EPO enters the brain via receptor-mediated endocytosis. The enrichment of EPO-r shown here suggests a highly efficient uptake of plasma EPO into the MTLE hippocampus and a possible role for this cytokine in epileptogenesis. Moreover, the presence of EPO-r in the MTLE hippocampus may provide a new vehicle for highly efficient delivery of hitherto impermeable drugs into the epileptic brain.