RESUMEN
Ultrasound-mediated transdermal delivery is a promising parenteral administration method for large-molecule or unstable medications. This study evaluated skin health and systemic delivery when administering enfuvirtide, an injectable anti-retroviral medication, over a 1-mo period in a porcine model using a low-frequency cymbal transducer. Three groups received twice-daily treatments: (i) enfuvirtide injection control (nâ¯=â¯12); (ii) saline ultrasound control (nâ¯=â¯6); and (iii) enfuvirtide ultrasound treatment (nâ¯=â¯13). Ultrasound parameters were as follows: 30-min exposure, 90 mW/cm², 24-26 kHz and 15% duty cycle. No statistical difference in trans-epidermal water loss, a measure of skin health and function, was seen between ultrasound-treated and control skin sites for either saline (pâ¯=â¯0.50) or enfuvirtide (pâ¯=â¯0.29) groups. Average trough plasma concentrations of enfuvirtide were 0.6 ± 0.2 and 2.8 ± 0.8 µg/mL for ultrasound and injection, respectively. Tolerability and efficacy results indicate that chronic, low-frequency ultrasound exposure can be a practical means for transdermal delivery of medications such as enfuvirtide.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Enfuvirtida/administración & dosificación , Inhibidores de Fusión de VIH/administración & dosificación , Parche Transdérmico , Ultrasonido/métodos , Administración Cutánea , Animales , Femenino , Masculino , Modelos Animales , Absorción Cutánea , Porcinos , TransductoresRESUMEN
Blood collection is commonplace in biomedical research. Obtaining sufficient sample while minimizing animal stress requires significant skill and practice. Repeated needle punctures can cause discomfort and lead to variable release of stress hormones, potentially confounding analysis. We designed a handheld device to reduce the force necessary for needle insertion by using low-frequency, axial (forward and backward) micromotions (that is, vibration) delivered to the needle during venipuncture. Tests with cadaver rat-tail segments (n = 18) confirmed that peak insertion forces were reduced by 73% on average with needle vibration. A serial blood-sampling study was then conducted by using Sprague-Dawley rats divided into 2 groups based on needle condition used to cause bleeds: vibration on (n = 10) and vibration off (n = 9). On 3 days (1 wk apart), 3 tail-vein blood collections were performed in each subject at 1-h intervals. To evaluate associated stress levels, plasma corticosterone concentration was quantified by radioimmunoassay and behavior (that is, movement and vocalization) was scored by blinded review of blood-sampling videos. After the initial trial, average corticosterone was lower (46% difference), the mean intrasubject variance trended lower (72%), and behavioral indications of stress were rated lower for the vibration-on group compared with the vibration-off group. Adding controlled vibrations to needles during insertion may decrease the stress associated with blood sampling from rats--an important methodologic advance for investigators studying and assessing stress processes and a refinement over current blood sampling techniques.
Asunto(s)
Recolección de Muestras de Sangre/veterinaria , Corticosterona/sangre , Ratas Sprague-Dawley , Animales , Recolección de Muestras de Sangre/métodos , Femenino , Masculino , Agujas , Flebotomía/métodos , Radioinmunoensayo , Ratas , Estrés Fisiológico , VibraciónRESUMEN
Intracortical microelectrode arrays record multi-unit extracellular activity for neurophysiology studies and for brain-machine interface applications. The common first step is neural spike-detection; a process complicated by common-noise signals from motion artifacts, electromyographic activity, and electric field pickup, especially in awake/behaving subjects. Often common-noise spikes are very similar to neural spikes in their magnitude, spectral, and temporal features. Provided sufficient spacing exists between electrodes of the array, a local neural spike is rarely recorded on multiple electrodes simultaneously. This is not true for distant common-noise sources. Two new techniques compatible with standard spike-detection schemes are introduced and evaluated. The first method, virtual referencing (VR), takes the average recording from all functional electrodes in the array (represents the signal from a virtual-electrode at the array's center) and subtracts it from the test electrode signal. The second method, inter-electrode correlation (IEC), computes a correlation coefficient between threshold exceeding candidate spike segments on the test electrode and concurrent segments from remaining electrodes. When sufficient correlation is detected, the candidate spike is rejected as originating from a distant common-noise source. The performance of these algorithms was compared with standard thresholding and differential referencing approaches using neural recordings from un-anaesthetized rats. By evaluating characteristics of mean-spike waveforms generated by each method under different levels of common-noise, it was found that IEC consistently offered the most robust means of neural spike-detection. Furthermore, IEC's rejection of supra-threshold events not likely originating from local neurons significantly reduces data handling for downstream spike sorting and processing operations.
Asunto(s)
Potenciales de Acción/fisiología , Artefactos , Corteza Cerebral/citología , Microelectrodos , Neuronas/fisiología , Interfaz Usuario-Computador , Animales , Ratas , Valores de Referencia , Reproducibilidad de los Resultados , Procesamiento de Señales Asistido por Computador , Estadística como AsuntoRESUMEN
Intracortical microelectrodes puncture the intact pia mater membrane during insertion, a process that can cause brain dimpling and trauma. To ensure that the device is able to withstand forces during implantation without buckling, the selection of acceptable implant materials and geometries is limited to rigid designs with large cross-sectional areas. Such designs likely increase insertion trauma and potentially exacerbate the chronic tissue response. In this paper, a technique that may relax the mechanical requirements of implanted microelectrodes through enzymatic (collagenase mediated) manipulation of the pia mater is quantified experimentally. Measurements of the insertion force profiles were obtained with a load cell during computer controlled (10 microm/s) insertion of microwire arrays into the cortex of rats. It was observed that collagenase application reduced the peak insertion force experienced by the microwire arrays by almost 40% on average (4.04 +/-2.03 mN versus 2.36 +/-1.17 mN; control versus treated sites). Peak insertion force magnitudes were highly dependent on implant location with anterior sites registering lower peaks than more posterior sites. Chronic neural recording performance (up to one month) did not appear to be adversely affected by the collagenase treatment, suggesting the overall safety of the technique. Our data suggest that controlled application of collagenase is a useful method in enabling implantation of thinner microelectrodes, potentially facilitating reduced insertion trauma and lower immune response. Furthermore, due to dependence of insertion force on anatomical location, the intended target region should be considered in implant design.
Asunto(s)
Corteza Cerebral/fisiología , Colagenasas/administración & dosificación , Electrodos Implantados , Microelectrodos , Implantación de Prótesis/métodos , Animales , Corteza Cerebral/efectos de los fármacos , Materiales Biocompatibles Revestidos/farmacología , Diseño de Equipo , Análisis de Falla de Equipo , Masculino , Ratas , Ratas Sprague-Dawley , Estrés MecánicoRESUMEN
Implanted intra-cortical micro-electrode arrays record multi-unit extracellular spike activity that is used in deciphering the neural basis for adaptation, learning, plasticity and as command signal for brain-machine interfaces (BMI). Detection of spike activity is the first step in successful implementation of all the aforementioned applications. However, with awake and behaving animals, micro-electrode arrays typically also record non-neuronal signals induced by the animal's movement, feeding and grooming actions. The spectral and temporal nature of these artifacts is similar to neural spikes, which complicates accurate detection. The distal source and higher strength of non-neuronal signals result in their near simultaneous registration on most electrodes, while neural spiking event is rarely recorded on more than one electrode of an array. This difference is utilized in identifying non-neuronal content from acquired data by performing a correlation analysis. The efficacy of the method is evaluated by comparing outcomes from algorithms that use absolute threshold and Principal Component Analysis (PCA) as a means of identifying neural spikes with the same methods incorporating correlation analysis.
Asunto(s)
Algoritmos , Artefactos , Encéfalo/fisiología , Electroencefalografía/instrumentación , Electroencefalografía/métodos , Potenciales Evocados/fisiología , Microelectrodos , Neuronas/fisiología , Animales , Electrodos Implantados , Reconocimiento de Normas Patrones Automatizadas/métodos , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estadística como AsuntoRESUMEN
Brain-machine interfaces (BMIs) have shown promise in augmenting people's control of their surroundings, especially for those suffering from paralysis due to neurological disorders. This paper describes an experiment using the rodent model to explore information available in neural signals recorded from chronically implanted intracortical microelectrode arrays. In offline experiments, a number of neural feature extraction methods were utilized to obtain neural activity vectors (NAVs) describing the activity of the underlying neural population while rats performed a discrimination task. The methods evaluated included standard techniques such as binned spike rates and local field potential spectra as well as more novel approaches including matched-filter energy, raw signal spectra, and an autocorrelation energy measure (AEM) approach. Support vector machines (SVMs) were trained offline to classify left from right going movements by utilizing features contained in the NAVs obtained by the different methods. Each method was evaluated for accuracy and robustness. Results show that most algorithms worked well for decoding neural signals both during and prior to movement, with spectral methods providing the best stability.
Asunto(s)
Inteligencia Artificial , Mapeo Encefálico/métodos , Electroencefalografía/métodos , Potenciales Evocados Visuales/fisiología , Reconocimiento de Normas Patrones Automatizadas/métodos , Interfaz Usuario-Computador , Corteza Visual/fisiología , Animales , Estimulación Luminosa/métodos , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Typically intracortical electrodes are required to puncture the intact pia mater during insertion which in the process can lead to brain dimpling and trauma. Furthermore, there is interest in the development of more flexible substrates to reduce relative micromotion after implantation, but such device have difficulty penetrating the pia without buckling. In this paper a strategy for reducing the mechanical integrity of the pia's collagen network by treatment with collagenase is evaluated experimentally. Measurements of the insertion force were carried out with a load cell during computer controlled slow (10 microm/sec) electrode insertion into the cortex of rats. It is shown that controlled application of collagenase reduces the peak insertion force experienced by the microwire arrays around 30% on average. In addition, chronic neural recordings (up to 1 month) suggest that there is no appreciable difference in the signal quality as recorded from the collagenase treated and the control sites. The results suggest the technique is useful for reducing insertion forces without compromising neural recording capabilities.
Asunto(s)
Corteza Cerebral/fisiología , Corteza Cerebral/cirugía , Electrodos Implantados , Microelectrodos , Animales , Ingeniería Biomédica , Colagenasas , Electrofisiología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Previous studies have demonstrated a correlation between cochlear implant recipients' comfort levels (C level, upper limit of dynamic range of stimulation) and the contralateral electrical stapedius reflex (ESR) threshold, detected by acoustic impedance change. However, the utility of the approach is limited because many recipients have no detectable impedance change. The goals of this study were to investigate the utility of the stapedial electromyogram (EMG) for estimating onset and strength of the ESR. Ketamine-anesthetized guinea pigs were implanted with Nucleus electrode arrays and stimulated with biphasic current pulse trains (250 pps) via a Cochlear Corporation CI24M stimulator. Typical EMG recordings (obtained with bipolar microwire electrodes) contained easily detectable unit potentials up to 300 microV in amplitude. Growth response curves (obtained from threshold-crossing counts or rms of the EMG signal) were typically monotonic with dynamic ranges spanning 700 microA or 8 dB. Based on adaptation and temporal properties, the stimulus protocol (500 ms duration with 4-5 s interstimulus intervals) was adequate for producing independent responses. The data presented are consistent with ESR characteristics (acoustic impedance technique) of cochlear implant recipients and with EMG properties of acoustically stimulated guinea pigs. Use of the EMG for characterizing the ESR may eventually be applied to human cochlear implant recipients as a guide in setting the upper limit of the dynamic range.