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BACKGROUND: Sugammadex has been associated with increases in the bispectral index (BIS). We evaluated the effects of sugammadex administration on quantitative electroencephalographic (EEG) and electromyographic (EMG) measures. METHODS: We performed a prospective observational study of adult male patients undergoing robot-assisted radical prostatectomy. All patients received a sevoflurane-based general anaesthetic and a continuous infusion of rocuronium, which was reversed with 2 mg kg-1 of sugammadex i.v. BIS, EEG, and EMG measures were captured with the BIS Vista™ monitor. RESULTS: Twenty-five patients were included in this study. Compared with baseline, BIS increased at 4-6 min (ß coefficient: 3.63; 95% confidence interval [CI]: 2.22-5.04; P<0.001), spectral edge frequency 95 (SEF95) increased at 2-4 min (ß coefficient: 0.29; 95% CI: 0.05-0.52; P=0.016) and 4-6 min (ß coefficient: 0.71; 95% CI: 0.47-0.94; P<0.001), and EMG increased at 4-6 min (ß coefficient: 1.91; 95% CI: 1.00-2.81; P<0.001) after sugammadex administration. Compared with baseline, increased beta power was observed at 2-4 min (ß coefficient: 93; 95% CI: 1-185; P=0.046) and 4-6 min (ß coefficient: 208; 95% CI: 116-300; P<0.001), and decreased delta power was observed at 4-6 min (ß coefficient: -526.72; 95% CI: -778 to -276; P<0.001) after sugammadex administration. Neither SEF95 nor frequency band data analysis adjusted for EMG showed substantial differences. None of the patients showed clinical signs of awakening. CONCLUSIONS: After neuromuscular block reversal with 2 mg kg-1 sugammadex, BIS, SEF95, EMG, and beta power showed small but statistically significant increases over time, while delta power decreased.
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Bloqueio Neuromuscular , Robótica , Adulto , Humanos , Masculino , Sugammadex/farmacologia , Prostatectomia , Eletroencefalografia , AndrostanóisRESUMO
Cognitive deficits and impaired sensory processing are hallmarks of several neurodevelopmental and neuropsychiatric disorders. N-methyl-d-aspartate receptor (NMDAR) hypofunction contributes to these deficits by disrupting the excitation-to-inhibition balance in neuronal networks. Although preclinical data suggest that the activation of gamma-Aminobutyric acid B receptors (GABAB R) may restore excitation-to-inhibition balance and rescues some behavioral deficits, GABAB R agonists have failed to meet their clinical study endpoints, suggesting more complex interactions at play. Here, we studied the effects of Baclofen (a GABAB R agonist) and MK-801 (a non-competitive NMDAR antagonist) on the neurophysiology of limbic-auditory circuits in freely-moving rats. The pharmacological effects were assessed using resting-state EEG, auditory-evoked oscillation, and mismatch negativity paradigms. MK-801 elevated resting-state oscillatory power, mainly in the gamma and higher frequency ranges, and impaired auditory-evoked responses. Baclofen partially normalized resting-state oscillations but failed to rescue auditory-evoked oscillatory abnormalities. Coherence analysis indicated that NMDAR hypofunction alters the functional coupling of limbic and thalamocortical circuits in several frequency bands. Baclofen normalized only a fraction of MK-801-induced abnormalities (e.g., theta coherence between frontal cortex and amygdala) while reducing delta-theta and augmenting gamma coherence in thalamocortical circuits. Finally, we report that Baclofen intensified the MK-801-induced deficits in auditory mismatch responses. In summary, while Baclofen partially normalizes MK-801-induced gamma abnormalities, it either fails to rescue or exacerbates deficits in other phenotypes like functional coupling and auditory processing. We hope that the presented complex interactions between pharmacologically induced NMDAR hypofunction and GABABR agonism inspire a new understanding of the therapeutic potential around GABAergic modulation.
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Maleato de Dizocilpina , Esquizofrenia , Animais , Baclofeno/toxicidade , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Percepção , Ratos , Receptores de N-Metil-D-Aspartato , Esquizofrenia/induzido quimicamenteRESUMO
BACKGROUND: Dexmedetomidine is frequently used for sedation during deep brain stimulator implantation in patients with Parkinson's disease, but its effect on subthalamic nucleus activity is not well known. The aim of this study was to quantify the effect of increasing doses of dexmedetomidine in this population. METHODS: Controlled clinical trial assessing changes in subthalamic activity with increasing doses of dexmedetomidine (from 0.2 to 0.6 µg kg-1 h-1) in a non-operating theatre setting. We recorded local field potentials in 12 patients with Parkinson's disease with bilateral deep brain stimulators (24 nuclei) and compared basal activity in the nuclei of each patient and activity recorded with different doses. Plasma levels of dexmedetomidine were obtained and correlated with the dose administered. RESULTS: With dexmedetomidine infusion, patients became clinically sedated, and at higher doses (0.5-0.6 µg kg-1 h-1) a significant decrease in the characteristic Parkinsonian subthalamic activity was observed (P<0.05 in beta activity). All subjects awoke to external stimulus over a median of 1 (range: 0-9) min, showing full restoration of subthalamic activity. Dexmedetomidine dose administered and plasma levels showed a positive correlation (repeated measures correlation coefficient=0.504; P<0.001). CONCLUSIONS: Patients needing some degree of sedation throughout subthalamic deep brain stimulator implantation for Parkinson's disease can probably receive dexmedetomidine up to 0.6 µg kg-1 h-1 without significant alteration of their characteristic subthalamic activity. If patients achieve a 'sedated' state, subthalamic activity decreases, but they can be easily awakened with a non-pharmacological external stimulus and recover baseline subthalamic activity patterns in less than 10 min. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002680-34; NCT-02982512.
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Estimulação Encefálica Profunda/métodos , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Doença de Parkinson/terapia , Núcleo Subtalâmico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , EspanhaRESUMO
α-Synuclein (aSyn) is the main driver of neurodegenerative diseases known as "synucleinopathies," but the mechanisms underlying this toxicity remain poorly understood. To investigate aSyn toxic mechanisms, we have developed a primary neuronal model in which a longitudinal survival analysis can be performed by following the overexpression of fluorescently tagged WT or pathologically mutant aSyn constructs. Most aSyn mutations linked to neurodegenerative disease hindered neuronal survival in this model; of these mutations, the E46K mutation proved to be the most toxic. While E46K induced robust PLK2-dependent aSyn phosphorylation at serine 129, inhibiting this phosphorylation did not alleviate aSyn toxicity, strongly suggesting that this pathological hallmark of synucleinopathies is an epiphenomenon. Optical pulse-chase experiments with Dendra2-tagged aSyn versions indicated that the E46K mutation does not alter aSyn protein turnover. Moreover, since the mutation did not promote overt aSyn aggregation, we conclude that E46K toxicity was driven by soluble species. Finally, we developed an assay to assess whether neurons expressing E46K aSyn affect the survival of neighboring control neurons. Although we identified a minor non-cell-autonomous component spatially restricted to proximal neurons, most E46K aSyn toxicity was cell autonomous. Thus, we have been able to recapitulate the toxicity of soluble aSyn species at a stage preceding aggregation, detecting non-cell-autonomous toxicity and evaluating how some of the main aSyn hallmarks are related to neuronal survival.
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Mutação de Sentido Incorreto , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , Substituição de Aminoácidos , Animais , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Fosforilação , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Ratos , Ratos Sprague-Dawley , alfa-Sinucleína/genéticaRESUMO
Although cerebellar-cortical interactions have been studied extensively in animal models and humans using modern neuroimaging techniques, the effects of cerebellar stroke and focal lesions on cerebral cortical processing remain unknown. In the present study, we analyzed the large-scale functional connectivity at the cortical level by combining high-density electroencephalography (EEG) and source imaging techniques to evaluate and quantify the compensatory reorganization of brain networks after cerebellar damage. The experimental protocol comprised a repetitive finger extension task by 10 patients with unilateral focal cerebellar lesions and 10 matched healthy controls. A graph theoretical approach was used to investigate the functional reorganization of cortical networks. Our patients, compared with controls, exhibited significant differences at global and local topological level of their brain networks. An abnormal rise in small-world network efficiency was observed in the gamma band (30-40 Hz) during execution of the task, paralleled by increased long-range connectivity between cortical hemispheres. Our findings show that a pervasive reorganization of the brain network is associated with cerebellar focal damage and support the idea that the cerebellum boosts or refines cortical functions. Clinically, these results suggest that cortical changes after cerebellar damage are achieved through an increase in the interactions between remote cortical areas and that rehabilitation should aim to reshape functional activation patterns. Future studies should determine whether these hypotheses are limited to motor tasks or if they also apply to cerebro-cerebellar dysfunction in general.
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Cerebelo/fisiopatologia , Lateralidade Funcional/fisiologia , Atividade Motora/fisiologia , Plasticidade Neuronal/fisiologia , Adolescente , Adulto , Idoso , Cerebelo/cirurgia , Eletroencefalografia , Eletromiografia , Feminino , Dedos/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Vias Neurais/fisiopatologia , Vias Neurais/cirurgia , Procedimentos Neurocirúrgicos/efeitos adversos , Processamento de Sinais Assistido por Computador , Acidente Vascular Cerebral/fisiopatologiaRESUMO
BACKGROUND: Deep brain stimulation electrodes can record oscillatory activity from deep brain structures, known as local field potentials. The authors' objective was to evaluate and quantify the effects of dexmedetomidine (0.2 µg·kg·h) on local field potentials in patients with Parkinson disease undergoing deep brain stimulation surgery compared with control recording (primary outcome), as well as the effect of propofol at different estimated peak effect site concentrations (0.5, 1.0, 1.5, 2.0, and 2.5 µg/ml) from control recording. METHODS: A nonrandomized, nonblinded controlled clinical trial was carried out to assess the change in local field potentials activity over time in 10 patients with Parkinson disease who underwent deep brain stimulation placement surgery (18 subthalamic nuclei). The relationship was assessed between the activity in nuclei in the same patient at a given time and repeated measures from the same nucleus over time. RESULTS: No significant difference was observed between the relative beta power of local field potentials in dexmedetomidine and control recordings (-7.7; 95% CI, -18.9 to 7.6). By contrast, there was a significant decline of 12.7% (95% CI, -21.3 to -4.7) in the relative beta power of the local field potentials for each increment in the estimated peak propofol concentrations at the effect site relative to the control recordings. CONCLUSIONS: Dexmedetomidine (0.2 µg·kg·h) did not show effect on local field potentials compared with control recording. A significant deep brain activity decline from control recording was observed with incremental doses of propofol.
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Gânglios da Base/efeitos dos fármacos , Estimulação Encefálica Profunda , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Doença de Parkinson/cirurgia , Propofol/farmacologia , Potenciais de Ação/efeitos dos fármacos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The central nervous system has the ability to adapt our locomotor pattern to produce a wide range of gait modalities and velocities. In reacting to external pacing stimuli, deviations from an individual preferred cadence provoke a concurrent decrease in accuracy that suggests the existence of a trade-off between frequency and precision; a compromise that could result from the specialization within the control centers of locomotion to ensure a stable transition and optimal adaptation to changing environment. Here, we explore the neural correlates of such adaptive mechanisms by visually guiding a group of healthy subjects to follow three comfortable stepping frequencies while simultaneously recording their BOLD responses and lower limb kinematics with the use of a custom-built treadmill device. In following the visual stimuli, subjects adopt a common pattern of symmetric and anti-phase movements across pace conditions. However, when increasing the stimulus frequency, an improvement in motor performance (precision and stability) was found, which suggests a change in the control mode from reactive to predictive schemes. Brain activity patterns showed similar BOLD responses across pace conditions though significant differences were observed in parietal and cerebellar regions. Neural correlates of stepping precision were found in the insula, cerebellum, dorsolateral pons and inferior olivary nucleus, whereas neural correlates of stepping stability were found in a distributed network, suggesting a transition in the control strategy across the stimulated range of frequencies: from unstable/reactive at lower paces (i.e., stepping stability managed by subcortical regions) to stable/predictive at higher paces (i.e., stability managed by cortical regions). Hum Brain Mapp 37:1722-1737, 2016. © 2016 Wiley Periodicals, Inc.
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Mapeamento Encefálico , Encéfalo/irrigação sanguínea , Movimento/fisiologia , Adulto , Fenômenos Biomecânicos , Encéfalo/diagnóstico por imagem , Feminino , Voluntários Saudáveis , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Estimulação Luminosa , DescansoRESUMO
BACKGROUND: Cardiac autonomic tone after long-term continuous positive airway pressure therapy in patients with obstructive sleep apnea remains unexplored. METHODS: Thirty patients with obstructive sleep apnea (14 with moderate and 16 with severe obstructive sleep apnea) were studied during a baseline polysomnographic study, after a full night of acute continuous positive airway pressure treatment, and after long-term (~2 years) chronic continuous positive airway pressure therapy. Twenty age- and gender-matched controls with baseline sleep study were selected for comparison purposes. Cross-spectral analysis and the low-frequency (LF) and high-frequency (HF) components of the heart rate variability were computed separately over 10-min ECG epochs during rapid eye movement sleep, non-rapid eye movement sleep, and wakefulness. RESULTS: During the baseline study, obstructive sleep apnea patients exhibited increased LF, decreased HF, and increased LF/HF ratio during sleep when compared to controls. In a multiple regression model, the mean oxygen saturation explained the increased LF during rapid and non-rapid eye movement sleep in obstructive sleep apnea patients. Acute continuous positive airway pressure therapy decreased the LF modulations and the LF/HF ratio and increased the HF modulations during sleep in patients with severe obstructive sleep apnea. Long-term continuous positive airway pressure therapy decreased LF modulations and LF/HF ratio with increased HF modulations during sleep in patients with moderate and severe obstructive sleep apnea. CONCLUSIONS: Long-term continuous positive airway pressure reduces the sympathovagal imbalance in patients with moderate and severe obstructive sleep apnea, both during rapid and non-rapid eye movement sleep. Continuous positive airway pressure seems to exert its changes in cardiac autonomic modulation by decreasing the burden of nocturnal hypoxia.
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Pressão Sanguínea/fisiologia , Pressão Positiva Contínua nas Vias Aéreas/tendências , Frequência Cardíaca/fisiologia , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/terapia , Fases do Sono/fisiologia , Adulto , Idoso , Sistema Nervoso Autônomo/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia/tendências , Estudos Prospectivos , Apneia Obstrutiva do Sono/fisiopatologia , Fatores de Tempo , Resultado do TratamentoRESUMO
The activity of the basal ganglia is altered in Parkinson's disease (PD) as a consequence of the degeneration of dopamine neurons in the substantia nigra pars compacta. This results in aberrant discharge patterns and expression of exaggerated oscillatory activity across the basal ganglia circuit. Altered activity has also been reported in some of the targets of the basal ganglia, including the pedunculopontine nucleus (PPN), possibly due to its close interconnectivity with most regions of the basal ganglia. However, the nature of the involvement of the PPN in the pathophysiology of PD has not been fully elucidated. Here, we recorded local field potentials in the motor cortex and the PPN in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD under urethane anesthesia. By means of linear and nonlinear statistics, we analyzed the synchrony between the motor cortex and the PPN and the delay in the interaction between these two structures. We observed the presence of coherent activity between the cortex and the PPN in low (5-15 Hz)- and high (25-35 Hz)-frequency bands during episodes of cortical activation. In each case, the cortex led the PPN. Dopamine depletion strengthened the interaction of the low-frequency activities by increasing the coherence specifically in the theta and alpha ranges and reduced the delay of the interaction in the gamma band. Our data show that cortical inputs play a determinant role in leading the coherent activity with the PPN and support the involvement of the PPN in the pathophysiology of PD.
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Sincronização Cortical , Córtex Motor/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Núcleo Tegmental Pedunculopontino/fisiopatologia , Ritmo alfa , Animais , Oxidopamina/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Oscillatory activity in the beta band is increased in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients. Rigidity and bradykinesia are associated with the low-beta component (13-20Hz) but the neurophysiological correlate of freezing of gait in PD has not been ascertained. METHODS: We evaluated the power and coherence of the low- and high-beta bands in the STN and cortex (EEG) of PD patients with (p-FOG) (n=14) or without freezing of gait (n-FOG) (n=8) in whom electrodes for chronic stimulation in the STN had been implanted for treatment with deep brain stimulation. RESULTS: p-FOG patients showed higher power in the high-beta band (F=11.6, p=0.002) that was significantly reduced after l-dopa administration along with suppression of FOG (F=4.6, p=0.042). High-beta cortico-STN coherence was maximal for midline cortical EEG electrodes, whereas the low-beta band was maximal for lateral electrodes (χ(2)=20.60, p<0.0001). CONCLUSIONS: The association between freezing of gait, high-beta STN oscillations and cortico-STN coherence suggests that this oscillatory activity might interfere in the frontal cortex-basal ganglia networks, thereby participating in the pathophysiology of FOG in PD.
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Ritmo beta/fisiologia , Apraxia da Marcha/etiologia , Apraxia da Marcha/fisiopatologia , Doença de Parkinson/complicações , Doença de Parkinson/fisiopatologia , Núcleo Subtalâmico/fisiopatologia , Antiparkinsonianos/uso terapêutico , Ritmo beta/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Estimulação Encefálica Profunda , Eletroencefalografia , Feminino , Apraxia da Marcha/tratamento farmacológico , Apraxia da Marcha/terapia , Humanos , Neuroestimuladores Implantáveis , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/terapia , Núcleo Subtalâmico/efeitos dos fármacosRESUMO
The relationship between the autonomic nervous system and periodic leg movements during sleep (PLMS) is not completely understood. We aimed to determine whether patients with PLMS exhibit any changes in their basal heart rate variability (HRV), excluding episodes of leg movements and arousals. To investigate this, we conducted a cross-sectional study including 13 patients with PLMS (PLMS ≥ 20) and 13 matched controls, free of cardiovascular diseases and medications. Time-and frequency-domain HRV measures [mean R-R interval, low frequency (LF), high frequency (HF), LF/HF] were calculated across all sleep stages as well during wakefulness just before and after sleep during one-night polysomnography. We only took ECG segments of sleep without arousals and excluded periods of 30 s before and after the leg movements. No statistical differences between PLMS and control subjects were found in any of the time- or frequency-domain HRV measures across sleep stages. Basal cardiac autonomic modulation in patients with PLMS is similar to that of control subjects. Our results argue against a role for a basal disturbance of the cardiac autonomic nervous system in the pathogenesis of PLMS.
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Sistema Nervoso Autônomo/fisiologia , Frequência Cardíaca/fisiologia , Síndrome da Mioclonia Noturna/fisiopatologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PolissonografiaRESUMO
Aberrant neuronal circuit dynamics are at the core of complex neuropsychiatric disorders, such as schizophrenia (SZ). Clinical assessment of the integrity of neuronal circuits in SZ has consistently described aberrant resting-state gamma oscillatory activity, decreased auditory-evoked gamma responses, and abnormal mismatch responses. We hypothesized that corticothalamic circuit manipulation could recapitulate SZ circuit phenotypes in rodent models. In this study, we optogenetically inhibited the mediodorsal thalamus-to-prefrontal cortex (MDT-to-PFC) or the PFC-to-MDT projection in rats and assessed circuit function through electrophysiological readouts. We found that MDT-PFC perturbation could not recapitulate SZ-linked phenotypes such as broadband gamma disruption, altered evoked oscillatory activity, and diminished mismatch negativity responses. Therefore, the induced functional impairment of the MDT-PFC pathways cannot account for the oscillatory abnormalities described in SZ.
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Potenciais Evocados Auditivos , Optogenética , Córtex Pré-Frontal , Tálamo , Animais , Optogenética/métodos , Ratos , Córtex Pré-Frontal/fisiologia , Masculino , Tálamo/fisiologia , Esquizofrenia/fisiopatologia , Vias Neurais , Ratos Sprague-Dawley , Ritmo Gama/fisiologia , Sistema Límbico/fisiologiaRESUMO
OBJECTIVES: Motor symptoms of Parkinson's disease improve during REM sleep behavior disorder movement episodes. Our aim was to study cortical activity during these movement episodes, in patients with and without Parkinson's disease, in order to investigate the cortical involvement in the generation of its electromyographic activity and its potential relationship with Parkinson's disease. METHODS: We looked retrospectively in our polysomnography database for patients with REM sleep behavior disorder, analyzing fifteen patients in total, seven with idiopathic REM sleep behavior disorder and eight associated with Parkinson's disease. We selected segments of REM sleep with the presence of movements (evidenced by electromyographic activation), and studied movement-related changes in cortical activity by averaging the electroencephalographic signal (premotor potential) and by means of time/frequency transforms. RESULTS: We found a premotor potential and an energy decrease of alpha-beta oscillatory activity preceding the onset of electromyographic activity, together with an increase of gamma activity for the duration of the movement. All these changes were similarly present in REM sleep behavior disorder patients with and without Parkinson's disease. CONCLUSIONS: Movement-related changes in electroencephalographic activity observed in REM sleep behavior disorder are similar to those observed during voluntary movements, regardless of the presence of Parkinson's disease motor symptoms. SIGNIFICANCE: These results suggest a main involvement of the cortex in the generation of the movements during REM sleep.
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BACKGROUND AND PURPOSE: The integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, which mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (Integrated Stress Response InhiBitor, an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB-like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1G93A mice. EXPERIMENTAL APPROACH: After biochemical characterization in primary neurons, SOD1G93A mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with the hanging wire motor test. Motor neuronal survival was assessed by immunohistochemistry. KEY RESULTS: In primary neurons, 2BAct and PRXS571 relieve the ISR-imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1G93A mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time. CONCLUSION AND IMPLICATIONS: 2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1G93A mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients.
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Esclerose Lateral Amiotrófica , Humanos , Camundongos , Animais , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/metabolismo , Superóxido Dismutase-1/genética , Fator de Iniciação 2B em Eucariotos , Superóxido Dismutase/metabolismo , Camundongos Transgênicos , Progressão da Doença , Modelos Animais de DoençasRESUMO
Miami-Dade County (MDC) has over 112,000 septic systems, some of which are at risk of compromise due to water table rise associated with sea level rise. MDC is surrounded by protected water bodies, including Biscayne Bay, with environmentally sensitive ecosystems and is underlain by highly transmissive karstic limestone. The main objective of the study is to provide first estimates of the locations and magnitudes of septic return flows to discharge endpoints. This is accomplished by leveraging MDC's county-scale surface-groundwater model using pathline analysis to estimate the transport and discharge fate of septic system flows under the complex time history of groundwater flow response to pumping, canal management, storms, and other environmental factors. The model covers an area of 4772 km2 in Southeast Florida. Outputs from the model were used to create a 30-year (2010 to 2040) simulation of the spatial-temporal pathlines from septic input locations to their termination points, allowing us to map flow paths and the spatial distribution of the septic flow discharge endpoints under the simulated conditions. Most septic return flows were discharged to surface water, primarily canals 52,830 m3/d and Biscayne Bay (5696 m3/d), and well fields (14,066 m3/d). Results allow us to identify "hotspots" to guide water quality sampling efforts and to provide recommendations for septic-to-sewer conversion areas that should provide most benefit by reducing nutrient loading to water bodies.
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We study a Kuramoto model in which the oscillators are associated with the nodes of a complex network and the interactions include a phase frustration, thus preventing full synchronization. The system organizes into a regime of remote synchronization where pairs of nodes with the same network symmetry are fully synchronized, despite their distance on the graph. We provide analytical arguments to explain this result, and we show how the frustration parameter affects the distribution of phases. An application to brain networks suggests that anatomical symmetry plays a role in neural synchronization by determining correlated functional modules across distant locations.
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Modelos Teóricos , Modelos BiológicosRESUMO
BACKGROUND: Fibrocystic breast disease is one of the most frequent conditions of the breast among women from 30 to 49 years, with a frequency of about 60%, hence the interest in studying and treating it with the most advanced and effective resources. OBJECTIVE: To compare the efficacy and adverse events of alpha dihydroergocryptine with cabergoline in patients with fibrocystic breast disease. MATERIAL AND METHODS: A prospective, longitudinal, open, comparative study between alpha-dihydroergocryptine and cabergoline, made in the service of Gynecology and Obstetrics at the Dr. Miguel Silva General Hospital in Morelia, Michoacán. 171 patients diagnosed with fibrocystic breast disease were randomly assigned to the alpha-dihydroergocryptine or the cabergoline group. Assessments were made at baseline and every month subsequently. The following symptoms were evaluated: breast tenderness, breast pain, lumps and nipple discharge. The concentrations of prolactin were determined and an ultrasound was performed at baseline and at 3 and 6 months, patients were questioned about adverse events. RESULTS: 171 patients were included (81treated with alpha-dihydroergocryptine and 90 with cabergoline); 156 completed the study. The age limits were 18 and 51 years. The evolution time prior to study entry was 17.71 +/- 18.3 months for the alpha-dihydroergocryptine group and 18.57 +/- 20.35 for the cabergoline group. 15 patients discontinued treatment due to adverse events (8 of the alpha-dihydroergocryptine group and 7 of the cabergoline group). The most common adverse event was headache. CONCLUSIONS: In this study alpha-dihydroergocryptine was better tolerated and had better clinical response compared with cabergoline; breast pain and breast tenderness disappeared within the first month of treatment. Adverse events were similar for both treatments.
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Di-Hidroergocriptina/uso terapêutico , Ergolinas/uso terapêutico , Doença da Mama Fibrocística/tratamento farmacológico , Adolescente , Adulto , Cabergolina , Di-Hidroergocriptina/efeitos adversos , Ergolinas/efeitos adversos , Feminino , Doença da Mama Fibrocística/sangue , Galactorreia/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Cefaleia/induzido quimicamente , Humanos , Mastodinia/induzido quimicamente , Mastodinia/etiologia , Pessoa de Meia-Idade , Prolactina/sangue , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Adaptive deep brain stimulation (aDBS) is a promising concept in the field of DBS that consists of delivering electrical stimulation in response to specific events. Dynamic adaptivity arises when stimulation targets dynamically changing states, which often calls for a reliable and fast causal estimation of the phase and amplitude of the signals. Here, we present an open-hardware implementation that exploits the concepts of resonators and Hilbert filters embedded in an open-hardware platform. To emulate real-world scenarios, we built a hardware setup that included a system to replay and process different types of physiological signals and test the accuracy of the instantaneous phase and amplitude estimates. The results show that the system can provide a precise and reliable estimation of the phase even in the challenging scenario of dealing with high-frequency oscillations (~250 Hz) in real-time. The framework might be adopted in neuromodulation studies to quickly test biomarkers in clinical and preclinical settings, supporting the advancement of aDBS.
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Brain function depends on complex circuit interactions between excitatory and inhibitory neurons embedded in local and long-range networks. Systemic GABAA-receptor (GABAAR) or NMDA-receptor (NMDAR) modulation alters the excitatory-inhibitory balance (EIB), measurable with electroencephalography (EEG). However, EEG signatures are complex in localization and spectral composition. We developed and applied analytical tools to investigate the effects of two EIB modulators, MK801 (NMDAR antagonist) and diazepam (GABAAR modulator), on periodic and aperiodic EEG features in freely-moving male Sprague Dawley rats. We investigated how, across three brain regions, EEG features are correlated with EIB modulation. We found that the periodic component was composed of seven frequency bands that presented region-dependent and compound-dependent changes. The aperiodic component was also different between compounds and brain regions. Importantly, the parametrization into periodic and aperiodic components unveiled correlations between quantitative EEG and plasma concentrations of pharmacological compounds. MK-801 exposures were positively correlated with the slope of the aperiodic component. Concerning the periodic component, MK-801 exposures correlated negatively with the peak frequency of low-γ oscillations but positively with those of high-γ and high-frequency oscillations (HFOs). As for the power, θ and low-γ oscillations correlated negatively with MK-801, whereas mid-γ correlated positively. Diazepam correlated negatively with the knee of the aperiodic component, positively to ß and negatively to low-γ oscillatory power, and positively to the modal frequency of θ, low-γ, mid-γ, and high-γ. In conclusion, correlations between exposures and pharmacodynamic effects can be better-understood thanks to the parametrization of EEG into periodic and aperiodic components. Such parametrization could be key in functional biomarker discovery.
Assuntos
Maleato de Dizocilpina , Receptores de GABA-A , Ratos , Animais , Masculino , Maleato de Dizocilpina/farmacologia , Ratos Sprague-Dawley , Eletroencefalografia , Diazepam/farmacologiaRESUMO
BACKGROUND: Diphasic dyskinesias are a subtype of levodopa-induced dyskinesias that appear typically at the onset and end of levodopa antiparkinsonian action. The pathophysiology of diphasic dyskinesias is not well understood. METHODS: We analyzed local field potentials recorded from the subthalamic nucleus in 7 Parkinson's disease (PD) patients who showed typical diphasic dyskinesias during postoperative recordings through a deep brain stimulation electrode. The evolution of the different oscillatory activities related to the onset and end of diphasic dyskinesias was studied by windowed fast Fourier transforms. RESULTS: Typical "off"-state beta activity disappeared with the onset of diphasic dyskinesias, whereas gamma activity was absent or minimal until their end. Theta activity during diphasic dyskinesias was similar to that observed during peak-dose dyskinesias. CONCLUSIONS: From a neurophysiological viewpoint, patients exhibited oscillatory activity typical of the "on" medication state during diphasic dyskinesias. The minimal presence of gamma activity during diphasic dyskinesias, however, suggests that this "on" state might be incomplete or limited to dopaminergic mechanisms affecting the lower limbs.