RESUMEN
Photobiomodulation (PBM)-the irradiation of tissue with low-intensity light-mitigates neuropathology in rodent models of Parkinson's disease (PD) when targeted at the head ('transcranial PBM'). In humans, however, attenuation of light energy by the scalp and skull necessitates a different approach. We have reported that targeting PBM at the body also protects the brain by a mechanism that spreads from the irradiated tissue ('remote PBM'), although the optimal peripheral tissue target for remote PBM is currently unclear. This study compared the neuroprotective efficacy of remote PBM targeting the abdomen or leg with transcranial PBM, in mouse and non-human primate models of PD. In a pilot study, the neurotoxin MPTP was used to induce PD in non-human primates; PBM (670 nm, 50 mW/cm2 , 6 min/day) of the abdomen (n = 1) was associated with fewer clinical signs and more surviving midbrain dopaminergic cells relative to MPTP-injected non-human primates not treated with PBM. Validation studies in MPTP-injected mice (n = 10 per group) revealed a significant rescue of midbrain dopaminergic cells in mice receiving PBM to the abdomen (~80%, p < .0001) or legs (~80%, p < .0001), with comparable rescue of axonal terminals in the striatum. Strikingly, this degree of neuroprotection was at least as, if not more, pronounced than that achieved with transcranial PBM. These findings confirm that remote PBM provides neuroprotection against MPTP-induced destruction of the key circuitry underlying PD, with both the abdomen and legs serving as viable remote targets. This should provide the impetus for a comprehensive investigation of remote PBM-induced neuroprotection in other models of PD and, ultimately, human patients.
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Neuroprotección , Enfermedad de Parkinson , Humanos , Ratones , Animales , Pierna , Proyectos Piloto , Enfermedad de Parkinson/terapia , AbdomenRESUMEN
BACKGROUND: Obsessive-compulsive disorder (OCD) is a major cause of disability in western country and responsible for severe impairment of quality of life. About 10% of patients present with severe OCD symptoms and require innovative treatment such as deep brain stimulation (DBS). Among possible targets, the non-motor subthalamic nucleus (STN) is a key node of the basal ganglia circuitry, strongly connected to limbic cortical areas known to be involved in OCD. METHOD: We analysed, in a prospective, observational, monocentric, open label cohort, the effect of chronic non-motor STN-DBS in 19 patients with treatment-resistant OCD consecutively operated in a single centre. Severity of OCD was evaluated using the Yale and Brown Obsessive-Compulsive Scale (YBOCS). YBOCS scores at 6, 12 and 24 months postoperatively were compared with baseline. Responders were defined by >35% improvement of YBOCS scores. Global Assessment Functioning (GAF) scale was used to evaluate the impact of improvement. RESULTS: At a 24-month follow-up, the mean YBOCS score improved by 53.4% from 33.3±3.5 to 15.8±9.1 (95% CI 11.2-20.4; p<0.0001). Fourteen out of 19 patients were considered as responders, 5 out of 19 being improved over 75% and 10 out of 19 over 50%. GAF scale improved by 92% from 34.1±3.9 to 66.4±18.8 (95% CI 56.7-76.1; p=0.0003). The most frequent adverse events consisted of transient DBS-induced hypomania and anxiety. CONCLUSION: Chronic DBS of the non-motor STN is an effective and relatively safe procedure to treat severe OCD resistant to conventional management.
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Estimulación Encefálica Profunda/métodos , Trastorno Obsesivo Compulsivo/terapia , Núcleo Subtalámico , Adulto , Ansiedad/etiología , Estudios de Cohortes , Estimulación Encefálica Profunda/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Manía/etiología , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Brain source imaging and time frequency mapping (TFM) are commonly used in magneto/electro encephalography (M/EEG) imaging. However, these methods suffer from important limitations. Source imaging is based on an ill-posed inverse problem leading to instability of source localization solutions, has a limited capacity to localize high frequency oscillations and loses its robustness for induced responses (ill-defined trigger). The drawback of TFM is that it involves independent analysis of signals from a number of frequency bands, and from co-localized sensors. In the present article, a regression-based multi-sensor space-time-frequency analysis (MSA) approach, which integrates co-localized sensors and/or multi-frequency information, is proposed. To estimate task-specific brain activations, MSA uses cross-validated, shifted, multiple Pearson correlation, calculated from the time-frequency transformed brain signal and the binary signal of stimuli. The results are projected from the sensor space onto the cortical surface. To assess MSA performance, the proposed method was compared to the weighted minimum norm estimate (wMNE) source imaging method, in terms of spatial selectivity and robustness against an ill-defined trigger. Magnetoencephalography (MEG) recordings were performed in fourteen subjects during two motor tasks: finger tapping and elbow flexion/extension. In particular, our results show that the MSA approach provides good localization performance when compared to wMNE and statistically significant improvement of robustness against ill-defined trigger.
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Mapeo Encefálico , Magnetoencefalografía , Corteza Motora , Electroencefalografía , Humanos , Análisis Espacio-TemporalRESUMEN
OBJECTIVE: To assess the feasibility of greater occipital nerve (GON) intermediate site infiltration with MRI guidance. METHODS: Eleven consecutive patients suffering from chronic refractory cranio-facial pain who underwent 16 GON infiltrations were included in this prospective study. All of the procedures were performed on an outpatient basis in the research facility of our institution, with a 1.5 T scanner. The fatty space between inferior obliquus and semispinalis muscles at C1-C2 level was defined as the target. Technical success was defined as the ability to accurately inject the products at the target, assessed by post-procedure axial and sagittal proton density-weighted sequences. Clinical success was defined as a 50% pain decrease at 1 month. RESULTS: Technical success was 100%. GON was depicted in 6/11 cases on planning MRI sequences. Mean duration of procedure was 22.5 min (range 16-41). Clinical success was obtained in 7/11 included patients (63.6%) with a mean self-reported improvement of 78%. CONCLUSION: Interventional MR-guidance for GON infiltration is a feasible technique offering similar results to an already established effective procedure. It may appear as a useful tool in specific populations, such as young patients and repeat infiltrations, and should be considered in these settings. KEY POINTS: ⢠MR guidance for GON infiltration is a feasible technique. ⢠Preliminary results are in agreement with other guidance modalities. ⢠MR guidance may be seen as a useful tool in specific populations. ⢠Specific populations include young patients and repeat infiltrations. ⢠Target patients may also include patients with potentionally previously reported complications (torticollis).
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Imagen por Resonancia Magnética , Bloqueo Nervioso/métodos , Neuralgia/terapia , Nervios Espinales/diagnóstico por imagen , Adulto , Anciano , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The original version of this article, published on 12 July 2017, unfortunately contained mistakes. The following corrections have therefore been made in the original.
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In this study, we examined the cellular distribution of encephalopsin (opsin 3; OPN3) expression in the striatum of non-human primates. In addition, because of our long standing interest in Parkinson's disease and neuroprotection, we examined whether parkinsonian (MPTP; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) insult and/or photobiomodulation (670 nm) had any impact on encephalopsin expression in this key area of the basal ganglia. Striatal sections of control naïve monkeys, together with those that were either MPTP- and/or photobiomodulation-treated were processed for immunohistochemistry. Our results revealed two populations of striatal interneurones that expressed encephalopsin, one of which was the giant, choline acetyltransferase-containing, cholinergic interneurones. The other population had smaller somata and was not cholinergic. Neither cell group expressed the calcium-binding protein, parvalbumin. There was also rich encephalopsin expression in a set of terminals forming striosome-like patches across the striatum. Finally, we found that neither parkinsonian (MPTP) insult nor photobiomodulation had any effect on encephalopsin expression in the striatum. In summary, our results revealed an extensive network of encephalopsin containing structures throughout the striatum, indicating that external light is in a position to influence a range of striatal activities at both the interneurone and striosome level.
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Cuerpo Estriado/metabolismo , Interneuronas/metabolismo , Terapia por Luz de Baja Intensidad , Intoxicación por MPTP/metabolismo , Opsinas de Bastones/metabolismo , Animales , Inmunohistoquímica , Intoxicación por MPTP/terapia , Macaca fascicularisRESUMEN
BACKGROUND: Brain Computer Interface (BCI) studies are performed in an increasing number of applications. Questions are raised about electrodes, data processing and effectors. Experiments are needed to solve these issues. OBJECTIVE: To develop a simple BCI set-up to easier studies for improving the mathematical tools to process the ECoG to control an effector. METHOD: We designed a simple BCI using transcranial electrodes (17 screws, three mechanically linked to create a common reference, 14 used as recording electrodes) to record Electro-Cortico-Graphic (ECoG) neuronal activities in rodents. The data processing is based on an online self-paced non-supervised (asynchronous) BCI paradigm. N-way partial least squares algorithm together with Continuous Wavelet Transformation of ECoG recordings detect signatures related to motor activities. Signature detection in freely moving rats may activate external effectors during a behavioral task, which involved pushing a lever to obtain a reward. RESULTS: After routine training, we showed that peak brain activity preceding a lever push (LP) to obtain food reward was located mostly in the cerebellar cortex with a higher correlation coefficient, suggesting a strong postural component and also in the occipital cerebral cortex. Analysis of brain activities provided a stable signature in the high gamma band (â¼180Hz) occurring within 1500 msec before the lever push approximately around -400 msec to -500 msec. Detection of the signature from a single cerebellar cortical electrode triggers the effector with high efficiency (68% Offline and 30% Online) and rare false positives per minute in sessions about 30 minutes and up to one hour (â¼2 online and offline). CONCLUSIONS: In summary, our results are original as compared to the rest of the literature, which involves rarely rodents, a simple BCI set-up has been developed in rats, the data show for the first time long-term, up to one year, unsupervised online control of an effector.
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Interfaces Cerebro-Computador , Encéfalo/fisiología , Potenciales Evocados/fisiología , Vigilia/fisiología , Algoritmos , Animales , Mapeo Encefálico , Electrodos Implantados , Electroencefalografía , Femenino , Estudios Longitudinales , Sistemas en Línea , Estimulación Física , Desempeño Psicomotor/fisiología , Ratas , Factores de Tiempo , Interfaz Usuario-ComputadorRESUMEN
OBJECTIVE: To examine whether near-infrared light (NIr) treatment reduces clinical signs and/or offers neuroprotection in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson disease. METHODS: We implanted an optical fiber device that delivered NIr (670 nm) to the midbrain of macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.5-2.1mg/kg) were made over a 5- to 7-day period, during which time the NIr device was turned on. This was then followed by a 3-week survival period. Monkeys were evaluated clinically (eg, posture, bradykinesia) and behaviorally (open field test), and their brains were processed for immunohistochemistry and stereology. RESULTS: All monkeys in the MPTP group developed severe clinical and behavioral impairment (mean clinical scores = 21-34; n = 11). By contrast, the MPTP-NIr group developed much less clinical and behavioral impairment (n = 9); some monkeys developed moderate clinical signs (mean scores = 11-15; n = 3), whereas the majority--quite remarkably--developed few clinical signs (mean scores = 1-6; n = 6). The monkeys that developed moderate clinical signs had hematic fluid in their optical fibers at postmortem, presumably limiting NIr exposure and overall clinical improvement. NIr was not toxic to brain tissue and offered neuroprotection to dopaminergic cells and their terminations against MPTP insult, particularly in animals that developed few clinical signs. INTERPRETATION: Our findings indicate NIr to be an effective therapeutic agent in a primate model of the disease and create the template for translation into clinical trials.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Conducta Animal/efectos de la radiación , Rayos Infrarrojos/uso terapéutico , Intoxicación por MPTP/prevención & control , Mesencéfalo/efectos de la radiación , Neurotoxinas/farmacología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Terapia por Luz de Baja Intensidad , Intoxicación por MPTP/fisiopatología , Macaca fascicularis , Masculino , Mesencéfalo/efectos de los fármacos , Neurotoxinas/administración & dosificación , Fibras ÓpticasRESUMEN
BACKGROUND: Pallidal deep brain stimulation (globus pallidus internus (GPi) DBS) is the best therapeutic option for disabling isolated idiopathic (IID) and inherited (INH) dystonia. Acquired dystonia (AD) may also benefit from GPi DBS. Efficacy and safety in the long-term remained to be established. OBJECTIVE: To retrospectively assess long-term clinical outcomes and safety in dystonic patients who underwent GPi DBS. METHODS: Patients were videotaped and assessed preoperatively and postoperatively (1-year and at last available follow-up) using the Burke-Fahn-Marsden Dystonia Rating Scale (motor score (BFMDRS-M); disability score (BFMDRS-D)). RESULTS: Sixty-one patients were included (follow-up 7.9±5.9 years; range 1-20.7). In IID and INH (n=37), the BFMDRS-M improved at first (20.4±24.5; p<0.00001) and last (22.2±18.2; p<0.001) follow-ups compared with preoperatively (50.5±28.0). In AD (n=19), the BFMDRS-M ameliorated at 1-year (40.8±26.5; p<0.02) and late follow-ups (44.3±24.3; p<0.04) compared with preoperatively (52.8±24.2). In INH dystonia with other neurological features (n=4) there was no motor benefit. In IID and INH, the BFMDRS-D improved at 1-year (9.5±7.5; p<0.0002) and late follow-ups (10.4±7.8; p<0.016) compared with preoperatively (13.3±6.9). In AD, the BFMDRS-D reduced at 1-year (12.0±8.1; p<0.01) and late follow-ups (12.7 ±6.1; p=0.2) compared with preoperatively (14.35±5.7). Most adverse events were hardware related. CONCLUSIONS: GPi DBS is an effective and safe treatment in most patients with dystonia.
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Estimulación Encefálica Profunda , Trastornos Distónicos/terapia , Globo Pálido/fisiopatología , Adulto , Trastornos Distónicos/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
In this study, we explored the effects of a longer term application, up to 12 weeks, of photobiomodulation in normal, naïve macaque monkeys. Monkeys (n = 5) were implanted intracranially with an optical fibre device delivering photobiomodulation (red light, 670 nm) to a midline midbrain region. Animals were then aldehyde-fixed and their brains were processed for immunohistochemistry. In general, our results showed that longer term intracranial application of photobiomodulation had no adverse effects on the surrounding brain parenchyma or on the nearby dopaminergic cell system. We found no evidence for photobiomodulation generating an inflammatory glial response or neuronal degeneration near the implant site; further, photobiomodulation did not induce an abnormal activation or mitochondrial stress in nearby cells, nor did it cause an abnormal arrangement of the surrounding vasculature (endothelial basement membrane). Finally, because of our interest in Parkinson's disease, we noted that photobiomodulation had no impact on the number of midbrain dopaminergic cells and the density of their terminations in the striatum. In summary, we found no histological basis for any major biosafety concerns associated with photobiomodulation delivered by our intracranial approach and our findings set a key template for progress onto clinical trial on patients with Parkinson's disease.
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Cuerpo Estriado , Neuronas Dopaminérgicas , Terapia por Luz de Baja Intensidad/efectos adversos , Mesencéfalo , Fibras Ópticas/efectos adversos , Prótesis e Implantes/efectos adversos , Animales , Terapia por Luz de Baja Intensidad/instrumentación , Macaca fascicularisRESUMEN
Intracranial application of red to infrared light, known also as photobiomodulation (PBM), has been shown to improve locomotor activity and to neuroprotect midbrain dopaminergic cells in rodent and monkey models of Parkinson's disease. In this study, we explored whether PBM has any influence on the number of tyrosine hydroxylase (TH)+cells and the expression of GDNF (glial-derived neurotrophic factor) in the striatum. Striatal sections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice and monkeys and 6-hydroxydopamine (6OHDA)-lesioned rats that had PBM optical fibres implanted intracranially (or not) were processed for immunohistochemistry (all species) or western blot analysis (monkeys). In our MPTP monkey model, which showed a clear loss in striatal dopaminergic terminations, PBM generated a striking increase in striatal TH+ cell number, 60% higher compared to MPTP monkeys not treated with PBM and 80% higher than controls. This increase was not evident in our MPTP mouse and 6OHDA rat models, both of which showed minimal loss in striatal terminations. In monkeys, the increase in striatal TH+ cell number in MPTP-PBM cases was accompanied by similar increases in GDNF expression, as determined from western blots, from MPTP and control cases. In summary, these results offer insights into the mechanisms by which PBM generates its beneficial effects, potentially with the use of trophic factors, such as GDNF.
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Núcleo Caudado/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Terapia por Luz de Baja Intensidad/métodos , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/terapia , Putamen/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Animales , Recuento de Células , Modelos Animales de Enfermedad , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Ratas , Ratas WistarRESUMEN
Although there have been many pharmacological agents considered to be neuroprotective therapy in Parkinson's disease (PD) patients, neurosurgical approaches aimed to neuroprotect or restore the degenerative nigrostriatal system have rarely been the focus of in depth reviews. Here, we explore the neuroprotective strategies involving invasive surgical approaches (NSI) using neurotoxic models 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), which have led to clinical trials. We focus on several NSI approaches, namely deep brain stimulation of the subthalamic nucleus, glial neurotrophic derived factor (GDNF) administration and cell grafting methods. Although most of these interventions have produced positive results in preclinical animal models, either from behavioral or histological studies, they have generally failed to pass randomized clinical trials to validate each approach. We argue that NSI are promising approaches for neurorestoration in PD, but preclinical studies should be planned carefully in order not only to detect benefits but also to detect potential adverse effects. Further, clinical trials should be designed to be able to detect and disentangle neuroprotection from symptomatic effects. In summary, our review study evaluates the pertinence of preclinical models to study NSI for PD and how this affects their efficacy when translated into clinical trials.
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Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Estimulación Encefálica Profunda/métodos , Factor Neurotrófico Derivado de la Línea Celular Glial/administración & dosificación , Enfermedad de Parkinson/prevención & control , Animales , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Factor Neurotrófico Derivado de la Línea Celular Glial/farmacología , Humanos , Neuroprotección , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/terapia , Resultado del TratamientoRESUMEN
We have shown previously that near-infrared light (NIr), when applied at the same time as a parkinsonian insult (e.g. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP), reduces behavioural deficits and offers neuroprotection. Here, we explored whether the timing of NIr intervention-either before, at the same time or after the MPTP insult-was important. Mice received MPTP injections (total of 50 mg/kg) and, at various stages in relation to these injections, extracranial application of NIr. Locomotor activity was tested with an open-field test, and brains were processed for immunohistochemistry. Our results showed that regardless of when NIr was applied in relation to MPTP insult, behavioural impairment was reduced by a similar magnitude. The beneficial effect of NIr was fast-acting (within minutes) and long-lasting (for several days). There were more dopaminergic cells in the NIr-treated MPTP groups than in the MPTP group; there was no clear indication that a particular combination of NIr treatment and MPTP injection resulted in a higher cell number. In summary, irrespective of whether it was applied before, at the same time as or after MPTP insult, NIr reduced both behavioural and structural measures of damage by a similar magnitude. There was a broad therapeutic time window of NIr application in relation to the stage of toxic insult, and the NIr was fast-acting and long-lasting.
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Conducta Animal/efectos de la radiación , Rayos Infrarrojos/uso terapéutico , Intoxicación por MPTP/terapia , Actividad Motora/efectos de la radiación , Fototerapia/métodos , Animales , Modelos Animales de Enfermedad , Terapia por Luz de Baja Intensidad , Intoxicación por MPTP/prevención & control , Masculino , Ratones , Ratones Endogámicos BALB C , Espectroscopía Infrarroja Corta , Factores de TiempoRESUMEN
We have reported previously that intracranial application of near-infrared light (NIr) reduces clinical signs and offers neuroprotection in a subacute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of Parkinson's disease. In this study, we explored whether NIr reduces the gliosis in this animal model. Sections of midbrain (containing the substantia nigra pars compacta; SNc) and striatum were processed for glial fibrillary acidic protein (to label astrocytes; GFAP) and ionised calcium-binding adaptor molecule 1 (to label microglia; IBA1) immunohistochemistry. Cell counts were undertaken using stereology, and cell body sizes were measured using ImageJ. Our results showed that NIr treatment reduced dramatically (~75 %) MPTP-induced astrogliosis in both the SNc and striatum. Among microglia, however, NIr had a more limited impact in both nuclei; although there was a reduction in overall cell size, there were no changes in the number of microglia in the MPTP-treated monkeys after NIr treatment. In summary, we showed that NIr treatment influenced the glial response, particularly that of the astrocytes, in our monkey MPTP model of Parkinson's disease. Our findings raise the possibility of glial cells as a future therapeutic target using NIr.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Gliosis/etiología , Gliosis/terapia , Rayos Infrarrojos/uso terapéutico , Intoxicación por MPTP/complicaciones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Análisis de Varianza , Animales , Proteínas de Unión al Calcio , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Terapia por Luz de Baja Intensidad , Intoxicación por MPTP/patología , Macaca fascicularis , Masculino , Proteínas de Microfilamentos , Neuroglía/efectos de los fármacos , Neuroglía/efectos de la radiación , Neurotoxinas/toxicidad , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
We have used the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model to explore whether (i) the neuroprotective effect of near infrared light (NIr) treatment in the SNc is dose-dependent and (ii) the relationship between tyrosine hydroxylase (TH)+ terminal density and glial cells in the caudate-putamen complex (CPu). Mice received MPTP injections (50 mg/kg) and 2 J/cm2 NIr dose with either 2 d or 7 d survival period. In another series, with a longer 14 d survival period, mice had a stronger MPTP regime (100 mg/kg) and either 2 J/cm2 or 4 J/cm2 NIr dose. Brains were processed for routine immunohistochemistry and cell counts were made using stereology. Our findings were that in the 2 d series, no change in SNc TH+ cell number was evident after any treatment. In the 7 d series however, MPTP insult resulted in â¼45% reduction in TH+ cell number; after NIr (2 J/cm2) treatment, many cells were protected from the toxic insult. In the 14 d series, MPTP induced a similar reduction in TH+ cell number. NIr mitigated the loss of TH+ cells, but only at the higher dose of 4 J/cm2; the lower dose of 2 J/cm2 had no neuroprotective effect in this series. The higher dose of NIr, unlike the lower dose, also mitigated the MPTP- induced increase in CPu astrocytes after 14 d; these changes were independent of TH+ terminal density, of which, did not vary across the different experimental groups. In summary, we showed that neuroprotection by NIr irradiation in MPTP-treated mice was dose-dependent; with increasing MPTP toxicity, higher doses of NIr were required to protect cells and reduce astrogliosis.
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Neuronas Dopaminérgicas/efectos de la radiación , Gliosis/radioterapia , Rayos Infrarrojos/uso terapéutico , Intoxicación por MPTP/radioterapia , Trastornos Parkinsonianos/radioterapia , Porción Compacta de la Sustancia Negra/efectos de la radiación , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Animales , Astrocitos/patología , Astrocitos/efectos de la radiación , Núcleo Caudado/patología , Núcleo Caudado/efectos de la radiación , Recuento de Células , Supervivencia Celular/efectos de la radiación , Neuronas Dopaminérgicas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Gliosis/patología , Terapia por Luz de Baja Intensidad , Intoxicación por MPTP/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas del Tejido Nervioso/análisis , Trastornos Parkinsonianos/patología , Porción Compacta de la Sustancia Negra/patología , Putamen/patología , Putamen/efectos de la radiación , Tirosina 3-Monooxigenasa/análisisRESUMEN
BACKGROUND: We have shown previously that near-infrared light (NIr) treatment or photobiomodulation neuroprotects dopaminergic cells in substantia nigra pars compacta (SNc) from degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Balb/c albino mice, a well-known model for Parkinson's disease. The present study explores whether NIr treatment offers neuroprotection to these cells in C57BL/6 pigmented mice. In addition, we examine whether NIr influences behavioural activity in both strains after MPTP treatment. We tested for various locomotive parameters in an open-field test, namely velocity, high mobility and immobility. RESULTS: Balb/c (albino) and C57BL/6 (pigmented) mice received injections of MPTP (total of 50 mg/kg) or saline and NIr treatments (or not) over 48 hours. After each injection and/or NIr treatment, the locomotor activity of the mice was tested. After six days survival, brains were processed for TH (tyrosine hydroxylase) immunochemistry and the number of TH⺠cells in the substantia nigra pars compacta (SNc) was estimated using stereology. Results showed higher numbers of TH⺠cells in the MPTP-NIr groups of both strains, compared to the MPTP groups, with the protection greater in the Balb/c mice (30% vs 20%). The behavioural tests revealed strain differences also. For Balb/c mice, the MPTP-NIr group showed greater preservation of locomotor activity than the MPTP group. Behavioural preservation was less evident in the C57BL/6 strain however, with little effect of NIr being recorded in the MPTP-treated cases of this strain. Finally, there were differences between the two strains in terms of NIr penetration across the skin and fur. Our measurements indicated that NIr penetration was considerably less in the pigmented C57BL/6, compared to the albino Balb/c mice. CONCLUSIONS: In summary, our results revealed the neuroprotective benefits of NIr treatment after parkinsonian insult at both cellular and behavioural levels and suggest that Balb/c strain, due to greater penetration of NIr through skin and fur, provides a clearer model of protection than the C57BL/6 strain.
Asunto(s)
Neuronas Dopaminérgicas/efectos de la radiación , Rayos Infrarrojos , Intoxicación por MPTP/patología , Intoxicación por MPTP/terapia , Mesencéfalo/patología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Conducta Exploratoria/efectos de la radiación , Terapia por Luz de Baja Intensidad , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Actividad Motora/efectos de la radiación , Neurotoxinas/toxicidad , Especificidad de la Especie , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Addictions to dopaminergic drugs or to pleasant behaviours are frequent and potentially devastating neuropsychiatric disorders observed in Parkinson's disease. They encompass impulse control disorders, punding and dopamine dysregulation syndrome. A relationship with dopaminergic treatment is strongly suggested. Subthalamic stimulation improves motor complications and allows for drastic reductions in medication. This treatment might, therefore, be considered for patients with behavioural addictions, when attempts to reduce dopaminergic medication have failed. However, conflicting data have reported suppression, alleviation, worsening or new onset of behavioural addictions after subthalamic stimulation. Non-motor fluctuations are also a disabling feature of the disease. We prospectively investigated behaviour in a cohort of 63 patients with Parkinson's disease, before and 1 year after subthalamic stimulation using the Ardouin scale, with systematic evaluation of functioning in overall appetitive or apathetic modes, non-motor fluctuations, dopaminergic dysregulation syndrome, as well as behavioural addictions (including impulse control disorders and punding) and compulsive use of dopaminergic medication. Defined drug management included immediate postoperative discontinuation of dopamine agonists and reduction in levodopa. Motor and cognitive statuses were controlled (Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, frontal score). After surgery, the OFF medication motor score improved (-45.2%), allowing for a 73% reduction in dopaminergic treatment, while overall cognitive evaluation was unchanged. Preoperative dopamine dysregulation syndrome had disappeared in 4/4, behavioural addictions in 17/17 and compulsive dopaminergic medication use in 9/9 patients. New onset of levodopa abuse occurred in one patient with surgical failure. Non-motor fluctuations were significantly reduced with improvements in off-dysphoria (P ≤ 0.001) and reduction in on-euphoria (P ≤ 0.001). There was an inversion in the number of patients functioning in an overall appetitive mode (29 before versus 2 after surgery, P ≤ 0.0001) to an overall apathetic mode (3 before versus 13 after surgery, P < 0.05). Two patients attempted suicide. Improvement in motor fluctuations is linked to the direct effect of stimulation on the sensory-motor subthalamic territory, while improvement in dyskinesias is mainly explained by an indirect effect related to the decrease in dopaminergic drugs. Our data suggest that non-motor fluctuations could similarly be directly alleviated through stimulation of the non-motor subthalamic territories, and hyperdopaminergic side effects might improve mainly due to the decrease in dopaminergic medication. We show an overall improvement in neuropsychiatric symptomatology and propose that disabling non-motor fluctuations, dopaminergic treatment abuse and drug-induced behavioural addictions in Parkinson's disease may be considered as new indications for subthalamic stimulation.
Asunto(s)
Estimulación Encefálica Profunda/métodos , Trastornos Disruptivos, del Control de Impulso y de la Conducta/terapia , Discinesia Inducida por Medicamentos/terapia , Motivación/fisiología , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Anciano , Antiparkinsonianos/efectos adversos , Estudios de Cohortes , Trastornos Disruptivos, del Control de Impulso y de la Conducta/etiología , Discinesia Inducida por Medicamentos/etiología , Femenino , Humanos , Levodopa/efectos adversos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Motivación/efectos de los fármacos , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Estadísticas no ParamétricasRESUMEN
Astrocytes are not only the most populous cell type in the human brain, but they also have the most extensive and diverse sets of connections, across synapses, axons, blood vessels, as well as having their own internal network. Unsurprisingly, they are associated with many brain functions; from the synaptic transmission to energy metabolism and fluid homeostasis, and from cerebral blood flow and blood-brain barrier maintenance to neuroprotection, memory, immune defenses and detoxification, sleep, and early development. And yet, notwithstanding these key roles, so many current therapeutic approaches to a range of brain disorders have largely neglected their potential involvement. In this review, we consider the role of astrocytes in three brain therapies; two are emerging treatments (photobiomodulation and ultrasound), while the other is well-established (deep brain stimulation). In essence, we explore the issue of whether external sources, such as light, sound, or electricity, can influence the function of astrocytes, as they do neurons. We find that, when taken all together, each of these external sources can influence many, if not, all of the functions associated with astrocytes. These include influencing neuronal activity, prompting neuroprotection, reducing inflammation (astrogliosis) and potentially increasing cerebral blood flow and stimulating the glymphatic system. We suggest that astrocytes, just like neurons, can respond positively to each of these external applications and that their activation could each impart many beneficial outcomes on brain function; they are likely to be key players underpinning the mechanisms behind many therapeutic strategies.