—Clinical studies have shown that drugs delivered intrathecally distribute much faster than can b... more —Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be accounted for by pure molecular diffusion. However, drug transport inside the cerebrospinal fluid (CSF)-filled spinal canal is poorly understood. In this study, comprehensive experimental and computational studies were conducted to quantify the effect of pulsatile CSF flow on the accelerated drug dispersion in the spinal canal. Infusion tests with a radionucleotide and fluorescent dye under stagnant and pulsatile flow conditions were conducted inside an experimental surrogate model of the human spinal canal. The tracer distributions were quantified optically and by single photon emission computed tomography (SPECT). The experimental results show that CSF flow oscillations substantially enhance fluorescent dye and radionucleotide dispersion in the spinal canal experiment. The experimental observations were interpreted by rigorous computer simulations. To demonstrate the clinical significance, the dispersion of intrathecally infused baclofen, an anti-spasticity drug, was predicted by using patient-specific spinal data and CSF flow measurements. The computational predictions are expected to enable the rational design of intrathecal drug therapies.
OBJECT The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemis... more OBJECT The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemispheric limbic epileptic circuit using closed-loop direct neurostimulation therapy in tandem with "on-demand'" convection-enhanced intracerebral delivery of the antiepileptic drug (AED) carisbamate. A rat model of electrically induced self-sustained focal-onset epilepsy was employed. METHODS A 16-contact depth-recording microelectrode was implanted bilaterally in the dentate gyrus (DG) of the hippocampus of Fischer 344 rats. The right microelectrode array included an integrated microcatheter for drug delivery at the distal tip. Bihemispheric spontaneous self-sustained limbic status epilepticus (SSLSE) was induced in freely moving rats using a 90-minute stimulation paradigm delivered to the right medial perforant white matter pathway. Immediately following SSLSE induction, closed-loop right PP stimulation therapy concurrent with on-demand nanoboluses of the AED [(14)C]-carisbamate (n = 4), or on-demand [(14)C]-carisbamate alone (n = 4), was introduced for a mean of 10 hours. In addition, 2 reference groups received either closed-loop stimulation therapy alone (n = 4) or stimulation therapy with saline vehicle only (n = 4). All animals were sacrificed after completing the specified therapy regimen. In situ [(14)C]-autoradiography was used to determine AED distribution. RESULTS Closed-loop direct stimulation therapy delivered unilaterally in the right PP aborted ictal runs detected in either ipsi- or contralateral hippocampi. Freely moving rats receiving closed-loop direct stimulation therapy with ondemand intracerebral carisbamate delivery experienced a significant reduction in seizure frequency (p < 0.001) and minimized seizure frequency variability during the final 50% of the therapy/recording session compared with closed-loop stimulation therapy alone. CONCLUSIONS Unilateral closed-loop direct stimulation therapy delivered to afferent hippocampal white matter pathways concurrent with on-demand ipsilateral intracerebral delivery of nano-bolused carisbamate can rapidly decrease the frequency of electrographic seizures in an active bihemispheric epileptic network. Additionally, direct pulsatile delivery of carisbamate can stabilize seizure frequency variability compared with direct stimulation therapy alone.
ABSTRACT Intrathecal drug delivery bypasses the blood brain barrier by infusing therapeutic agent... more ABSTRACT Intrathecal drug delivery bypasses the blood brain barrier by infusing therapeutic agents into the cerebrospinal fluid. Clinical studies have observed rapid distribution of intrathecally infused drugs. We hypothesize that naturally occurring cerebrospinal fluid pulsations inside the spinal canal accelerate drug transport. An experimental model of the human spinal canal was built for infusion tests of a radionucleotide in stagnant and pulsatile flow fields. The distribution of infused Technitium-99m in the spinal canal model was quantified and validated with computational study. The results show that the oscillatory flow of the cerebrospinal fluid accelerates species dispersion in the spinal canal model by a factor of two to four. To demonstrate a clinically relevant application, physiological cerebrospinal fluid pulsations were reproduced in an anatomically consistent computational model and the dispersion of baclofen, an anti-spasticity drug, inside the central nervous system was predicted. The successful characterization of accelerated drug transport due to cerebrospinal fluid pulsations aids in the rational design of intrathecal drug infusion therapies.
Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be... more Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be accounted for by pure molecular diffusion. However, drug transport inside the cerebrospinal fluid (CSF)-filled spinal canal is poorly understood. In this study, comprehensive experimental and computational studies were conducted to quantify the effect of pulsatile CSF flow on the accelerated drug dispersion in the spinal canal. Infusion tests with a radionucleotide and fluorescent dye under stagnant and pulsatile flow conditions were conducted inside an experimental surrogate model of the human spinal canal. The tracer distributions were quantified optically and by single photon emission computed tomography (SPECT). The experimental results show that CSF flow oscillations substantially enhance fluorescent dye and radionucleotide dispersion in the spinal canal experiment. The experimental observations were interpreted by rigorous computer simulations. To demonstrate the clinical significance, the dispersion of intrathecally infused baclofen, an anti-spasticity drug, was predicted by using patient-specific spinal data and CSF flow measurements. The computational predictions are expected to enable the rational design of intrathecal drug therapies.
ABSTRACT The current treatment of hydrocephalus involves removing excess cerebrospinal fluid (CSF... more ABSTRACT The current treatment of hydrocephalus involves removing excess cerebrospinal fluid (CSF) from the ventricular system using a passive pressure driven shunt. However, existing shunt technology is characterized by high failure rates, and many revisions are necessary during the course of the disease. We postulate that direct measurements of ventricular volume using an impedance sensor may lead to greater efficacy of shunt treatment. The technique produces an electric field and measures the voltage potential change with volume. To fabricate such a sensor, we design the sensor using patient specific models using image reconstruction algorithms. Design decisions such as interelectrode distance and surface area are initially guessed and later verified by simulation. Simulations are performed on the model using finite element analysis. Dynamic equations simulating the expansion of the ventricular boundary are solved in conjunction with the steady state solution of Maxwell's equations. Many sensor designs are simulated and an optimal design is defined as one with the highest sensitivity. Fabrication of the optimal design includes microfabrication techniques. The sensors are then tested in benchtop models. Agarose gel mimics the electrical conductivity of the brain, and silicone dielectric gel matches the viscoelastic property of the brain. These simulations along with our experimental results show promising progress towards improved treatment methods for hydrocephalic patients. Project Overview. Reconstructed images from patients are used in the design of the sensor. The simulated measurements can be assessed for optimal design and placement of volume sensor. The fabricated sensor is conducted in collaboration with the Nanotechnology Core Facility at UIC.
Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be... more Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be accounted for by pure molecular diffusion. However, drug transport inside the cerebrospinal fluid (CSF)-filled spinal canal is poorly understood. In this study, comprehensive experimental and computational studies were conducted to quantify the effect of pulsatile CSF flow on the accelerated drug dispersion in the spinal canal. Infusion tests with a radionucleotide and fluorescent dye under stagnant and pulsatile flow conditions were conducted inside an experimental surrogate model of the human spinal canal. The tracer distributions were quantified optically and by single photon emission computed tomography (SPECT). The experimental results show that CSF flow oscillations substantially enhance fluorescent dye and radionucleotide dispersion in the spinal canal experiment. The experimental observations were interpreted by rigorous computer simulations. To demonstrate the clinical significance, the dispersion of intrathecally infused baclofen, an anti-spasticity drug, was predicted by using patient-specific spinal data and CSF flow measurements. The computational predictions are expected to enable the rational design of intrathecal drug therapies.
—Clinical studies have shown that drugs delivered intrathecally distribute much faster than can b... more —Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be accounted for by pure molecular diffusion. However, drug transport inside the cerebrospinal fluid (CSF)-filled spinal canal is poorly understood. In this study, comprehensive experimental and computational studies were conducted to quantify the effect of pulsatile CSF flow on the accelerated drug dispersion in the spinal canal. Infusion tests with a radionucleotide and fluorescent dye under stagnant and pulsatile flow conditions were conducted inside an experimental surrogate model of the human spinal canal. The tracer distributions were quantified optically and by single photon emission computed tomography (SPECT). The experimental results show that CSF flow oscillations substantially enhance fluorescent dye and radionucleotide dispersion in the spinal canal experiment. The experimental observations were interpreted by rigorous computer simulations. To demonstrate the clinical significance, the dispersion of intrathecally infused baclofen, an anti-spasticity drug, was predicted by using patient-specific spinal data and CSF flow measurements. The computational predictions are expected to enable the rational design of intrathecal drug therapies.
OBJECT The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemis... more OBJECT The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemispheric limbic epileptic circuit using closed-loop direct neurostimulation therapy in tandem with "on-demand'" convection-enhanced intracerebral delivery of the antiepileptic drug (AED) carisbamate. A rat model of electrically induced self-sustained focal-onset epilepsy was employed. METHODS A 16-contact depth-recording microelectrode was implanted bilaterally in the dentate gyrus (DG) of the hippocampus of Fischer 344 rats. The right microelectrode array included an integrated microcatheter for drug delivery at the distal tip. Bihemispheric spontaneous self-sustained limbic status epilepticus (SSLSE) was induced in freely moving rats using a 90-minute stimulation paradigm delivered to the right medial perforant white matter pathway. Immediately following SSLSE induction, closed-loop right PP stimulation therapy concurrent with on-demand nanoboluses of the AED [(14)C]-carisbamate (n = 4), or on-demand [(14)C]-carisbamate alone (n = 4), was introduced for a mean of 10 hours. In addition, 2 reference groups received either closed-loop stimulation therapy alone (n = 4) or stimulation therapy with saline vehicle only (n = 4). All animals were sacrificed after completing the specified therapy regimen. In situ [(14)C]-autoradiography was used to determine AED distribution. RESULTS Closed-loop direct stimulation therapy delivered unilaterally in the right PP aborted ictal runs detected in either ipsi- or contralateral hippocampi. Freely moving rats receiving closed-loop direct stimulation therapy with ondemand intracerebral carisbamate delivery experienced a significant reduction in seizure frequency (p < 0.001) and minimized seizure frequency variability during the final 50% of the therapy/recording session compared with closed-loop stimulation therapy alone. CONCLUSIONS Unilateral closed-loop direct stimulation therapy delivered to afferent hippocampal white matter pathways concurrent with on-demand ipsilateral intracerebral delivery of nano-bolused carisbamate can rapidly decrease the frequency of electrographic seizures in an active bihemispheric epileptic network. Additionally, direct pulsatile delivery of carisbamate can stabilize seizure frequency variability compared with direct stimulation therapy alone.
ABSTRACT Intrathecal drug delivery bypasses the blood brain barrier by infusing therapeutic agent... more ABSTRACT Intrathecal drug delivery bypasses the blood brain barrier by infusing therapeutic agents into the cerebrospinal fluid. Clinical studies have observed rapid distribution of intrathecally infused drugs. We hypothesize that naturally occurring cerebrospinal fluid pulsations inside the spinal canal accelerate drug transport. An experimental model of the human spinal canal was built for infusion tests of a radionucleotide in stagnant and pulsatile flow fields. The distribution of infused Technitium-99m in the spinal canal model was quantified and validated with computational study. The results show that the oscillatory flow of the cerebrospinal fluid accelerates species dispersion in the spinal canal model by a factor of two to four. To demonstrate a clinically relevant application, physiological cerebrospinal fluid pulsations were reproduced in an anatomically consistent computational model and the dispersion of baclofen, an anti-spasticity drug, inside the central nervous system was predicted. The successful characterization of accelerated drug transport due to cerebrospinal fluid pulsations aids in the rational design of intrathecal drug infusion therapies.
Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be... more Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be accounted for by pure molecular diffusion. However, drug transport inside the cerebrospinal fluid (CSF)-filled spinal canal is poorly understood. In this study, comprehensive experimental and computational studies were conducted to quantify the effect of pulsatile CSF flow on the accelerated drug dispersion in the spinal canal. Infusion tests with a radionucleotide and fluorescent dye under stagnant and pulsatile flow conditions were conducted inside an experimental surrogate model of the human spinal canal. The tracer distributions were quantified optically and by single photon emission computed tomography (SPECT). The experimental results show that CSF flow oscillations substantially enhance fluorescent dye and radionucleotide dispersion in the spinal canal experiment. The experimental observations were interpreted by rigorous computer simulations. To demonstrate the clinical significance, the dispersion of intrathecally infused baclofen, an anti-spasticity drug, was predicted by using patient-specific spinal data and CSF flow measurements. The computational predictions are expected to enable the rational design of intrathecal drug therapies.
ABSTRACT The current treatment of hydrocephalus involves removing excess cerebrospinal fluid (CSF... more ABSTRACT The current treatment of hydrocephalus involves removing excess cerebrospinal fluid (CSF) from the ventricular system using a passive pressure driven shunt. However, existing shunt technology is characterized by high failure rates, and many revisions are necessary during the course of the disease. We postulate that direct measurements of ventricular volume using an impedance sensor may lead to greater efficacy of shunt treatment. The technique produces an electric field and measures the voltage potential change with volume. To fabricate such a sensor, we design the sensor using patient specific models using image reconstruction algorithms. Design decisions such as interelectrode distance and surface area are initially guessed and later verified by simulation. Simulations are performed on the model using finite element analysis. Dynamic equations simulating the expansion of the ventricular boundary are solved in conjunction with the steady state solution of Maxwell's equations. Many sensor designs are simulated and an optimal design is defined as one with the highest sensitivity. Fabrication of the optimal design includes microfabrication techniques. The sensors are then tested in benchtop models. Agarose gel mimics the electrical conductivity of the brain, and silicone dielectric gel matches the viscoelastic property of the brain. These simulations along with our experimental results show promising progress towards improved treatment methods for hydrocephalic patients. Project Overview. Reconstructed images from patients are used in the design of the sensor. The simulated measurements can be assessed for optimal design and placement of volume sensor. The fabricated sensor is conducted in collaboration with the Nanotechnology Core Facility at UIC.
Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be... more Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be accounted for by pure molecular diffusion. However, drug transport inside the cerebrospinal fluid (CSF)-filled spinal canal is poorly understood. In this study, comprehensive experimental and computational studies were conducted to quantify the effect of pulsatile CSF flow on the accelerated drug dispersion in the spinal canal. Infusion tests with a radionucleotide and fluorescent dye under stagnant and pulsatile flow conditions were conducted inside an experimental surrogate model of the human spinal canal. The tracer distributions were quantified optically and by single photon emission computed tomography (SPECT). The experimental results show that CSF flow oscillations substantially enhance fluorescent dye and radionucleotide dispersion in the spinal canal experiment. The experimental observations were interpreted by rigorous computer simulations. To demonstrate the clinical significance, the dispersion of intrathecally infused baclofen, an anti-spasticity drug, was predicted by using patient-specific spinal data and CSF flow measurements. The computational predictions are expected to enable the rational design of intrathecal drug therapies.
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Papers by Timothy Harris Jr.