Delineating potential epileptogenic areas utilizing resting functional magnetic resonance imaging (fMRI) in epilepsy patients.

Seizure localization includes neuroimaging like electroencephalogram, and magnetic resonance imaging (MRI) with limited ability to characterize the epileptogenic network. Temporal clustering analysis (TCA) characterizes epileptogenic network congruent with interictal epileptiform discharges by clustering together voxels with transient signals. We generated epileptogenic areas for 12 of 13 epilepsy patients with TCA, congruent with different areas of seizure onset. Resting functional MRI (fMRI) scans are noninvasive, and can be acquired quickly, in patients with different levels of severity and function. Analyzing resting fMRI data using TCA is quick and can complement clinical methods to characterize the epileptogenic network.

Awake Neurophysiologically Guided versus Asleep MRI-Guided STN DBS for Parkinson Disease: A Comparison of Outcomes Using Levodopa Equivalents.

BACKGROUND: Deep brain stimulation (DBS) for Parkinson's disease (PD) has traditionally been performed in awake patients. Some patients are unable to tolerate awake surgery or extensive time off their medication to allow for neurophysiological testing during traditional DBS implantation, which has previously limited surgical options for these patients. Recently, asleep image-guided lead placement using intraoperative MRI or CT for verification has been proposed as an alternative for patients unable or unwilling to undergo awake DBS surgery. METHODS: We conducted a retrospective chart review comparing PD patients who underwent asleep MRI-guided subthalamic nucleus (STN) DBS lead placement (n = 14) and awake neurophysiologically guided STN DBS lead placement (n = 23) at our institution. Both groups' levodopa equivalent daily doses (LEDDs) and complications at approximately 6 months of follow-up were compared, along with operative times. RESULTS: Both groups showed statistically similar reductions in LEDD at 6 months of therapy (38.27% for awake, 49.27% for asleep; p = 0.4447), and similar complications. Operative times were initially longer for MRI-guided DBS but improved with surgical experience. CONCLUSION: Asleep MRI-guided DBS is a viable option for PD patients unable or unwilling to undergo awake placement, with similar results in terms of LEDD reduction and complications.

Pathways of infusate loss during convection-enhanced delivery into the putamen nucleus.

BACKGROUND: New strategies aiming to treat Parkinson's disease, such as delivery of trophic factors via protein infusion or gene transfer, depend upon localized intracerebral infusion, mainly into the putamen nucleus. Convection-enhanced delivery (CED) has been proposed as a method to improve intracerebral distribution of therapies. Yet analysis of controversial results during the clinical translation of these strategies suggests that intracerebral misdistribution of infusate may have affected the outcomes by limiting the amount of treatment into the target region. OBJECTIVES: This study aimed to identify possible pathways of infusate loss and their relative impact in the success of targeted CED into the postcommissural ventral putamen nucleus. METHODS: Thirteen adult macaque monkeys received intraputaminal CED infusions of 100 µl of 2.0 mM gadoteridol and bromophenol blue (0.16 mg/ml) solution at a rate of 1.0 µl/min under intraoperative magnetic resonance imaging (MRI) guidance. Quantitative maps of infusate concentration were computed at 10-min intervals throughout the procedure in a 3-Tesla MRI scanner. The fraction of tracer lost from the putamen as well as the path of loss were evaluated and quantified for each infusion. RESULTS: All injections (total 22) were successfully placed in the ventral postcommissural putamen nucleus. Four major paths of infusate loss from the putamen were observed: overflow across putamen boundaries, perivascular flow along large blood vessels, backflow along the inserted catheter and catheter tract leakage into the vacated catheter tract upon catheter removal. Overflow loss was observed within the first 30 µl of infusion in all cases. Measurable tracer loss following the path of an artery out of the putamen was observed in 15 cases, and in 8 of these cases, the loss was greater than 10% of infusate. Backflow that exited the putamen was observed in 4 cases and led to large loss of infusate (80% in 1 case) into the corona radiata. Loss into the vacated catheter tract amounted only to a few microliters. CONCLUSIONS: Our analysis demonstrates that after controlling for targeting, catheter type, infusion rate and infusate, the main issues during surgical planning are the identification of appropriate infusate volume that matches the target area, as well as mapping the regional vasculature as it may become a pathway for infusate loss. Most importantly, these results underscore the significance of presurgical planning for catheter placement and infusion, and the value of imaging guidance to ensure targeting accuracy.

Strategies for the delivery of multiple collinear infusion clouds in convection-enhanced delivery in the treatment of Parkinson's disease.

BACKGROUND: Delivery of multiple collinear payloads utilizing convection-enhanced delivery (CED) has historically been performed by retraction of a needle or catheter from the most distal delivery site. Few studies have addressed end-infusion morphology and associated payload reflux in stacked and collinear infusions, and studies comparing the advancement with the retraction mode are lacking. OBJECTIVE: To compare advancement versus retraction mode infusion results. METHODS: Infusion cloud pairs were created with the advancement and retraction technique in agarose gel using both open end-port SmartFlow (SF) and valve tip (VT) catheter infusion systems. Backflow, radius of infusion, and morphology were assessed. RESULTS: Infusions with the SF catheter, in contrast to the VT catheter, exhibited significantly more backflow in retraction mode at the shallow infusion site. Infusion morphology differed with the second infusion after retraction: the infusate at the proximal site first filling the channel left by the retraction and then being convected into gel in a pronouncedly non-spherical shape during the second infusion. CONCLUSIONS: Significant differences in cloud morphology were noted with respect to external catheter geometry with retraction versus penetration between infusions in an agarose gel model of the brain. Further study is warranted to determine optimal protocols for human clinical trials employing CED with multiple collinear payloads.

Deep brain stimulation for medically intractable cluster headache.

Cluster headache is the most severe primary headache disorder known. Ten to 20% of cases are medically intractable. DBS of the posterior hypothalamic area has shown effectiveness for alleviation of cluster headache in many but not all of the 46 reported cases from European centers and the eight cases studied at the University of California, San Francisco. This surgical strategy was based on the finding of increased blood flow in the posterior hypothalamic area on H(2)(15)O PET scanning during spontaneous and nitroglycerin-induced cluster headache attacks. The target point used, 4-5 mm posterior to the mamillothalamic tract, is in the border zone between posterior hypothalamus, anterior periventricular gray matter, and inferior thalamus. Recently, occipital nerve stimulation has shown efficacy, calling in question the use of DBS as a first line surgical therapy. In this report, we review the indications, techniques, and outcomes of DBS for cluster headache.

Long-term measurement of therapeutic electrode impedance in deep brain stimulation.

OBJECTIVE: Deep brain stimulation technology now allows a choice between constant current and constant voltage stimulation, yet clinical trials comparing the two are lacking. Impedance instability would theoretically favor constant current stimulation; however, few publications address this with long-term follow-up. In this report, we review our series for impedance change and discuss our findings and their implications for future study design. MATERIALS AND METHODS: A retrospective chart review was performed of all consecutive patients seen in the outpatient clinic for deep brain stimulation adjustments at the University of Wisconsin-Madison from February 2006 to May 2007. The following data were extracted: Quadrapolar contact selection, frequency, voltage, pulse width, and measured impedance at the therapeutic parameters. Patients were selected if consecutive measurements of therapeutic impedances for the same patient were performed with the same frequency, pulse width, voltage, and configuration of active contacts. RESULTS: A total of 63 patients with 110 electrodes had 301 documented programming visits. From these, 16 patients had 20 consecutive measurements with unchanged parameters in 19 electrodes at a median interval of 68 days and median follow-up of 549 days after implantation. No significant intra-patient intra-electrode therapeutic impedance variability was observed in this study (SD = 105.3 Ω, paired t-test, p= 0.312). In contrast, marked inter-patient variability in impedance was noted. This variability could not be explained by stimulation target, measurement interval, time since implantation, monopolar vs. bipolar stimulation, stimulation voltage, or stimulation frequency. CONCLUSIONS: No significant change in the same electrode therapeutic impedance was identified. Given the assumption that stimulation current is the critical parameter influencing clinical outcomes, these findings would not disadvantage constant voltage stimulation. However, inter-patient variability suggests a possible advantage for constant current stimulation when generalizing experience and comparisons over multiple patients. Further study of the relationship of stimulation efficacy to stimulation mode and impedance change is warranted.

Long-Term Surface Electrode Impedance Recordings Associated with Gliosis for a Closed-Loop Neurostimulation Device.

BACKGROUND: Closed-loop neurostimulation is a novel alternative therapy for medically intractable focal epilepsy for patients who are not candidates for surgical resection of a seizure focus. Electrodes for this system can be implanted either within the brain parenchyma or in the subdural space. The electrodes then serve the dual role of detecting seizures and delivering an electrical signal aimed at aborting seizure activity. The Responsive Neurostimulation (RNS®) system (Neuropace, Mountain View, CA, USA) is an FDA-approved implantable device designed for this purpose. OBJECTIVE: One of the challenges of the brain machine interface devices is the potential for implanted neurostimulator devices to induce progressive gliosis, apart from that associated with the minimal trauma at implantation. Gliosis has the potential to alter impedances over time, thereby affecting the clinical efficacy of these devices, and also poses a challenge to the prospects of in vivo repositioning of depth electrodes. We present a clinical case with 3-year follow-up and pathology. METHODS: Single-case, retrospective review within a randomized trial with specific minimum follow-up and impedance measurements. RESULTS: Impedance changes in the surface electrode over time were observed. Surgical pathological findings revealed significant gliosis in the leptomeninges of the cortices. CONCLUSION: We report, for the first time, long-term impedance recordings from a surface electrode associated with pathologic findings of gliosis at the Neuropace device-tissue interface in a patient who was enrolled in the multicenter RNS System Pivotal Clinical Investigation. Further study is required to elucidate the temporal relationship of pathological findings over time. Impedance changes were more complex than can be explained by a progressive or transient pathological mechanism. Further effort is required to elucidate the relationship between impedance change and seizure event capture.

Neuromodulation of the cingulum for neuropathic pain after spinal cord injury. Case report.

The authors present a case in which high-frequency electrical stimulation of the cingulum using standard deep brain stimulation (DBS) technology resulted in pain relief similar to that achieved with cingulotomy and superior to that achieved with periventricular gray matter (PVG) stimulation. This patient had a complete spinal cord injury at the C-4 level and suffered from medically refractory neuropathic pain. He underwent placement of bilateral cingulum and unilateral PVG DBS electrodes and a 1-week blinded stimulation trial prior to permanent implantation of a pulse generator. During the stimulation trial, the patient's pain level was assessed using a visual analog scale, and pain medication usage was recorded. During this period the patient was blinded to stimulation parameters. Stimulation of the cingulum provided better pain control than PVG stimulation or medication alone. The authors believe that cingulum stimulation can benefit patients with severe neuropathic pain that is refractory to other treatments. Advantages over cingulotomy include reversibility and the ability to adjust stimulation parameters for optimum efficacy.

Ambulatory Seizure Monitoring: From Concept to Prototype Device.

BACKGROUND: The brain, made up of billions of neurons and synapses, is the marvelous core of human thought, action and memory. However, if neuronal activity manifests into abnormal electrical activity across the brain, neural behavior may exhibit synchronous neural firings known as seizures. If unprovoked seizures occur repeatedly, a patient may be diagnosed with epilepsy. PURPOSE: The scope of this project is to develop an ambulatory seizure monitoring system that can be used away from a hospital, making it possible for the user to stay at home, and primary care personnel to monitor a patient's seizure activity in order to provide deeper analysis of the patient's condition and apply personalized intervention techniques. METHODS: The ambulatory seizure monitoring device is a research device that has been developed with the objective of acquiring a portable, clean electroencephalography (EEG) signal and transmitting it wirelessly to a handheld device for processing and notification. RESULT: This device is comprised of 4 phases: acquisition, transmission, processing and notification. During the acquisition stage, the EEG signal is detected using EEG electrodes; these signals are filtered and amplified before being transmitted in the second stage. The processing stage encompasses the signal processing and seizure prediction. A notification is sent to the patient and designated contacts, given an impending seizure. Each of these phases is comprised of various design components, hardware and software. The experimental findings illustrate that there may be a triggering mechanism through the phase lock value method that enables seizure prediction. CONCLUSION: The device addresses the need for long-term monitoring of the patient's seizure condition in order to provide the clinician a better understanding of the seizure's duration and frequency and ultimately provide the best remedy for the patient.

Obesity and deep brain stimulation: an overview.

Deep brain stimulation (DBS) has been employed to treat a variety of disorders such as Parkinson disease, dystonia, and essential tremor. Newer indications such as epilepsy and obsessive-compulsive disorder have been added to the armamentarium. In this review, we present an initial summary of current methods in the management of obesity and then explore efforts in neuromodulation and DBS as a novel modality in the treatment of obesity disorders.

Wide-bore 1.5 T MRI-guided deep brain stimulation surgery: initial experience and technique comparison.

OBJECT: We report results of the initial experience with magnetic resonance image (MRI)-guided implantation of subthalamic nucleus (STN) deep brain stimulating (DBS) electrodes at the University of Wisconsin after having employed frame-based stereotaxy with previously available MR imaging techniques and microelectrode recording for STN DBS surgeries. METHODS: Ten patients underwent MRI-guided DBS implantation of 20 electrodes between April 2011 and March 2013. The procedure was performed in a purpose-built intraoperative MRI suite configured specifically to allow MRI-guided DBS, using a wide-bore (70 cm) MRI system. Trajectory guidance was accomplished with commercially available system consisting of an MR-visible skull-mounted aiming device and a software guidance system processing intraoperatively acquired iterative MRI scans. RESULTS: A total of 10 patients (5 male, 5 female)-representative of the Parkinson Disease (PD) population-were operated on with standard technique and underwent 20 electrode placements under MRI-guided bilateral STN-targeted DBS placement. All patients completed the procedure with electrodes successfully placed in the STN. Procedure time improved with experience. CONCLUSION: Our initial experience confirms the safety of MRI-guided DBS, setting the stage for future investigations combining physiology and MRI guidance. Further follow-up is required to compare the efficacy of the MRI-guided surgery cohort to that of traditional frame-based stereotaxy.

Image-guided convection-enhanced delivery into agarose gel models of the brain.

Convection-enhanced delivery (CED) has been proposed as a treatment option for a wide range of neurological diseases. Neuroinfusion catheter CED allows for positive pressure bulk flow to deliver greater quantities of therapeutics to an intracranial target than traditional drug delivery methods. The clinical utility of real time MRI guided CED (rCED) lies in the ability to accurately target, monitor therapy, and identify complications. With training, rCED is efficient and complications may be minimized. The agarose gel model of the brain provides an accessible tool for CED testing, research, and training. Simulated brain rCED allows practice of the mock surgery while also providing visual feedback of the infusion. Analysis of infusion allows for calculation of the distribution fraction (Vd/Vi) allowing the trainee to verify the similarity of the model as compared to human brain tissue. This article describes our agarose gel brain phantom and outlines important metrics during a CED infusion and analysis protocols while addressing common pitfalls faced during CED infusion for the treatment of neurological disease.

Investigation of the electrical properties of agarose gel: characterization of concentration using nyquist plot phase angle and the implications of a more comprehensive in vitro model of the brain.

BACKGROUND: The electrical properties of agarose gel, namely impedance and capacitance, are relatively unexplored. Agarose gels are used as in vitro models in studies across numerous disciplines, including imaging, radiotherapy, infusion, and neurosurgery. PURPOSE: In this study, we seek to characterize the impedance response of low concentration agarose gels by relating the gel concentrations to Nyquist Plot phase in order to establish a baseline with which to modify the response of the gel to simulate that of in vivo brain tissue. This information is relevant to areas such as deep brain stimulation, and could have a significant impact on in vitro model design for such studies in the future. METHODS: Ten agarose gels spanning four different concentrations were subjected to impedance spectroscopy using a Model 3387 DBS electrode. Phase angles were calculated and Cartesian Nyquist plots generated from the data. RESULTS: Results suggest that an inverse relationship exists between agarose gel concentration and phase angle. In addition, the results indicate that agarose gel reasonably emulates a constant phase element, which portrays the electrode-electrolyte interface impedance of some equivalent circuit models of brain tissue. CONCLUSION: The data shows that agarose gel is a suitable substrate for a deep brain stimulation in vitro model, but requires modification. In the future, we plan to utilize this data to determine the modifications necessary in the current agarose gel model to make it scientifically applicable to studies of both deep brain stimulation and infusion due to their overlapping variables.

The substitute brain and the potential of the gel model.

This purpose of this paper is to review the recent history of the use of agarose gels. Although originally confined to electrophoresis work, agarose gels have proven themselves useful to a number of disciplines in the modern world, which includes brain infusion studies for research involving the treatment of various neurological conditions, such as Parkinson's Disease. In reviewing the relevant research leading up to the modern day, this paper attempts to track agarose gels through their stages of accuracy verification, highlighting why they are useful to the neurosurgery discipline and characterizing the nature of their use. Agarose gels do have significant limitations, which are also discussed, but they have substantial potential as a modifiable medium or as a basis of comparison for even more accurate models in the future.

Ramped-rate vs continuous-rate infusions: An in vitro comparison of convection enhanced delivery protocols.

BACKGROUND: Convection enhanced delivery (CED) is a technique using infusion convection currents to deliver therapeutic agents into targeted regions of the brain. Recently, CED is gaining significant acceptance for use in gene therapy of Parkinson's disease (PD) employing direct infusion into the brain. CED offers advantages in that it targets local areas of the brain, bypasses the blood-brain barrier (BBB), minimizes systemic toxicity of the therapeutics, and allows for delivery of larger molecules that diffusion driven methods cannot achieve. Investigating infusion characteristics such as backflow and morphology is important in developing standard and effective protocols in order to successfully deliver treatments into the brain. Optimizing clinical infusion protocols may reduce backflow, improve final infusion cloud morphology, and maximize infusate penetrance into targeted tissue. PURPOSE: The purpose of the current study was to compare metrics during ramped-rate and continuous-rate infusions using two different catheters in order to optimize current infusion protocols. Occasionally, the infusate refluxes proximally up the catheter tip, known as backflow, and minimizing this can potentially reduce undesirable effects in the clinical setting. Traditionally, infusions are performed at a constant rate throughout the entire duration, and backflow is minimized only by slow infusion rates, which increases the time required to deliver the desired amount of infusate. In this study, we investigate the effects of ramping and various infusion rates on backflow and infusion cloud morphology. The independent parameters in the study are: ramping, maximum infusion rate, time between rate changes, and increments of rate changes. METHODS: Backflow was measured using two methods: i) at the point of pressure stabilization within the catheter, and ii) maximum backflow as shown by video data. Infusion cloud morphology was evaluated based on the height-to-width ratio of each infusion cloud at the end of each experiment. Results were tabulated and statistically analyzed to identify any significant differences between protocols. RESULTS: The experimental results show that CED rampedrate infusion protocols result in smaller backflow distances and more spherical cloud morphologies compared to continuous-rate infusion protocols ending at the same maximum infusion rate. Our results also suggest internal-line pressure measurements can approximate the time-point at which backflow ceases. CONCLUSION: Our findings indicate that ramping CED infusion protocols can potentially minimize backflow and produce more spherical infusion clouds. However, further research is required to determine the strength of this correlation, especially in relation to maximum infusion rates.

Convection enhanced delivery to the Brain: preparing for gene therapy and protein delivery to the Brain for functional and restorative Neurosurgery by understanding low-flow neurocatheter infusions using the Alaris(®) system infusion pump.

BACKGROUND: Convection enhanced delivery (CED) is an emerging form of direct brain infusion therapy employed in human functional and restorative neurosurgery clinical trials delivering protein, viral vectors for gene therapy, and siRNA. PURPOSE: Pressure monitoring has become a vital tool in ensuring infusion safety and success. We report details of this benchmark first trial of the use of a leading syringe infusion pump system capable of low-flow infusions. METHODS: Low-flow infusion performance of the FDA approved Alaris® System syringe pump, commonly used at our institution, was assessed during in vitro and ex vivo CED infusions. In vitro infusion cloud morphology and line pressure were analyzed utilizing a neuroinfusion catheter and delivering volumes and flow rates proposed for a human gene therapy protocol for Parkinson's disease. RESULTS: Pressure monitoring results correlated with previously published in-line pressure monitoring results however the time to peak with catheter occlusion was extended due to the method of pressure monitoring with this device. CONCLUSION: MRI compatible infusion pumps used for brain delivery injectables, pressure monitoring is set to be a guiding instrument for the health care professional employing this emerging form of infusion-to-brain delivery. Further development of infusion pump technology is warranted to allow for infuse/withdraw mode, infusion pressure graphical and numerical display, and pressure monitoring without the need for an inflatable reservoir pressure device. MRI safe infusion systems will need to be available and nursing staff educated to prepare infusions within the high-field environment.

Perioperative brain shift and deep brain stimulating electrode deformation analysis: implications for rigid and non-rigid devices.

UNLABELLED: Deep brain stimulation (DBS) efficacy is related to optimal electrode placement. Several authors have quantified brain shift related to surgical targeting; yet, few reports document and discuss the effects of brain shift after insertion. OBJECTIVE: To quantify brain shift and electrode displacement after device insertion. Twelve patients were retrospectively reviewed, and one post-operative MRI and one time-delayed CT were obtained for each patient and their implanted electrodes modeled in 3D. Two competing methods were employed to measure the electrode tip location and deviation from the prototypical linear implant after the resolution of acute surgical changes, such as brain shift and pneumocephalus. In the interim between surgery and a pneumocephalus free postoperative scan, electrode deviation was documented in all patients and all electrodes. Significant shift of the electrode tip was identified in rostral, anterior, and medial directions (p < 0.05). Shift was greatest in the rostral direction, measuring an average of 1.41 mm. Brain shift and subsequent electrode displacement occurs in patients after DBS surgery with the reversal of intraoperative brain shift. Rostral displacement is on the order of the height of one DBS contact. Further investigation into the time course of intraoperative brain shift and its potential effects on procedures performed with rigid and non-rigid devices in supine and semi-sitting surgical positions is needed.

Long-term measurement of impedance in chronically implanted depth and subdural electrodes during responsive neurostimulation in humans.

Long-term stability of the electrode-tissue interface may be required to maintain optimal neural recording with subdural and deep brain implants and to permit appropriate delivery of neuromodulation therapy. Although short-term changes in impedance at the electrode-tissue interface are known to occur, long-term changes in impedance have not previously been examined in detail in humans. To provide further information about short- and long-term impedance changes in chronically implanted electrodes, a dataset from 191 persons with medically intractable epilepsy participating in a trial of an investigational responsive neurostimulation device (the RNS(®) System, NeuroPace, Inc.) was reviewed. Monopolar impedance measurements were available for 391 depth and subdural leads containing a total of 1564 electrodes; measurements were available for median 802 days post-implant (range 28-1634). Although there were statistically significant short-term impedance changes, long-term impedance was stable after one year. Impedances for depth electrodes transiently increased during the third week after lead implantation and impedances for subdural electrodes increased over 12 weeks post-implant, then were stable over the subsequent long-term follow-up. Both depth and subdural electrode impedances demonstrated long-term stability, suggesting that the quality of long-term electrographic recordings (the data used to control responsive brain stimulation) can be maintained over time.

Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue.

BACKGROUND: Convection enhanced delivery (CED) is emerging as a promising infusion toolto facilitate delivery of therapeutic agents into the brain via mechanically controlled pumps. Infusion protocols and catheter design have an important impact on delivery. CED is a valid alternative for systemic administration of agents in clinical trials for cell and gene therapies. Where gel and ex vivo models are not sufficient in modeling the disease, in vivo models allow researchers to better understand the underlying mechanisms of neuron degeneration, which is helpful in finding novel approaches to control the process or reverse the progression. Determining the risks, benefits, and efficacy of new gene therapies introduced via CED will pave a way to enter human clinical trial. PURPOSE: The objective of this study is to compare volume distribution (Vd)/ volume infused (Vi) ratios and backflow measurements following CED infusions in ex vivo versus in vivo non-human primate brain tissue, based on infusion protocols developed in vitro. METHODS: In ex vivo infusions, the first brain received 2 infusions using a balloon catheter at rates of 1 µL/min and 2 µL/min for 30 minutes. The second and third brains received infusions using a valve-tip (VT) catheter at 1 µL/min for 30 minutes. The fourth brain received a total of 45 µL infused at a rate of 1 µL/min for 15 minutes followed by 2 µL/min for 15 minutes. Imaging was performed (SPGR FA34) every 3 minutes. In the in vivo group, 4 subjects received a total of 8 infusions of 50 µL. Subjects 1 and 2 received infusions at 1.0 µL/min using a VT catheter in the left hemisphere and a smart-flow (SF) catheter in the right hemisphere. Subjects 3 and 4 each received 1 infusion in the left and right hemisphere at 1.0 µL/min. RESULTS: MRI calculations of Vd/Vi did not significantly differ from those obtained on post-mortem pathology. The mean measured Vd/Vi of in vivo (5.23 + /-1.67) compared to ex vivo (2.17 + /-1.39) demonstrated a significantly larger Vd/Vi for in vivo by 2.4 times (p = 0.0017). CONCLUSION: We detected higher ratios in the in vivo subjects than in ex vivo. This difference could be explained by the extra cellular space volume fraction. Studies evaluating backflow and morphology use in vivo tissue as a medium are recommended. Further investigation is warranted to evaluate the role blood pressure and heart rate may play in human CED clinical trials.