Thomas J. Foutz

Assessing Tumor Angiogenesis Increased Circulating VE-Cadherin RNA in Patients with Cancer Indicates Viability of Circulating Endothelial Cells

No markers are currently available to indicate the angiogenic profile of a specific malignant disease nor to predict response to antiangiogenic therapies. Nevertheless, many different antiangiogenic drugs are presently being tested in many clinical trials, with an obvious scarcity of useful endpoints for treatment outcome beside survival. By means of a quantitative reverse transcription-PCR approach, we measured VE-cadherin (VE-C), Tie-2, vascular endothelial growth factor receptor 2 and CD133 RNA in the blood of 14 healthy controls, 3 pregnant women, and 84 newly diagnosed (or relapsed) cancer patients. Circulating VE-C RNA was increased in pregnant women and cancer patients (P = 0.0002). VE-C RNA was particularly increased in patients affected by hematological malignancies and decreased to normal values in patients achieving complete remission. Conversely, circulating RNA levels of other endothelial or progenitor cell-specific markers Tie-2, vascular endothelial growth factor receptor 2, and CD133 were not significantly increased in either pregnant women or cancer patients. Comparison of various surrogate angiogenesis markers indicated a switch toward increased plasma vascular endothelial growth factor (VEGF) levels, viable circulating endothelial cells, and circulating VE-C RNA levels in patients affected by hematological malignancies. Taken together, our data indicate that the quantitative evaluation of circulating VE-C RNA is a specific and highly promising tool with which to investigate the angiogenic phenotype of cancer patients.

Evaluation of novel stimulus waveforms for deep brain stimulation

Deep brain stimulation (DBS) is an established therapy for the treatment of a wide range of neurological disorders. Historically, DBS and other neurostimulation technologies have relied on rectangular stimulation waveforms to impose their effects on the nervous system. Recent work has suggested that non-rectangular waveforms may have advantages over the traditional rectangular pulse. Therefore, we used detailed computer models to compare a range of charge-balanced biphasic waveforms with rectangular, exponential, triangular, Gaussian and sinusoidal stimulus pulse shapes. We explored the neural activation energy of these waveforms for both intracellular and extracellular current-controlled stimulation conditions. In the context of extracellular stimulation, we compared their effects on both axonal fibers of passage and projection neurons. Finally, we evaluated the impact of delivering the waveforms through a clinical DBS electrode, as opposed to a theoretical point source. Our results suggest that DBS with a 1 ms centered-triangular pulse can decrease energy consumption by 64% when compared with the standard 100 µs rectangular pulse (energy cost of 48 and 133 nJ, respectively, to stimulate 50% of a distributed population of axons) and can decrease energy consumption by 10% when compared with the most energy efficient rectangular pulse (1.25 ms duration). In turn, there may be measureable energy savings when using appropriately designed non-rectangular pulses in clinical DBS applications, thereby warranting further experimental investigation.

Current steering to activate targeted neural pathways during deep brain stimulation of the subthalamic region

Deep brain stimulation (DBS) has steadily evolved into an established surgical therapy for numerous neurological disorders, most notably Parkinsons disease (PD). Traditional DBS technology relies on voltage-controlled stimulation with a single source; however, recent engineering advances are providing current-controlled devices with multiple independent sources. These new stimulators deliver constant current to the brain tissue, irrespective of impedance changes that occur around the electrode, and enable more specific steering of current towards targeted regions of interest. In this study, we examined the impact of current steering between multiple electrode contacts to directly activate three distinct neural populations in the subthalamic region commonly stimulated for the treatment of PD: projection neurons of the subthalamic nucleus (STN), globus pallidus internus (GPi) fibers of the lenticular fasiculus, and internal capsule (IC) fibers of passage. We used three-dimensional finite element electric field models, along with detailed multicompartment cable models of the three neural populations to determine their activations using a wide range of stimulation parameter settings. Our results indicate that selective activation of neural populations largely depends on the location of the active electrode(s). Greater activation of the GPi and STN populations (without activating any side effect related IC fibers) was achieved by current steering with multiple independent sources, compared to a single current source. Despite this potential advantage, it remains to be seen if these theoretical predictions result in a measurable clinical effect that outweighs the added complexity of the expanded stimulation parameter search space generated by the more flexible technology.

Computational Modeling of Deep Brain Stimulation

Deep brain stimulation (DBS) is an effective clinical treatment for several medically refractory neurological disorders. However, even after decades of clinical success, explicit understanding of the response of neurons to applied electric fields remains limited, and scientific definition of the therapeutic mechanisms of DBS remains elusive. In addition, it is presently unclear which electrode designs and stimulation paradigms are optimal for maximal therapeutic benefit and minimal side-effects with DBS. Detailed computer modeling of DBS has emerged recently as a powerful technique to enhance our understanding of the effects of DBS and to create a virtual testing ground for new stimulation strategies. This chapter summarizes the fundamentals of neurostimulation modeling, presents some scientific contributions of computer models to the field of DBS, and demonstrates the application of DBS modeling tools to augment the clinical utility of DBS.

Energy efficient neural stimulation: coupling circuit design and membrane biophysics.

The delivery of therapeutic levels of electrical current to neural tissue is a well-established treatment for numerous indications such as Parkinson’s disease and chronic pain. While the neuromodulation medical device industry has experienced steady clinical growth over the last two decades, much of the core technology underlying implanted pulse generators remain unchanged. In this study we propose some new methods for achieving increased energy-efficiency during neural stimulation. The first method exploits the biophysical features of excitable tissue through the use of a centered-triangular stimulation waveform. Neural activation with this waveform is achieved with a statistically significant reduction in energy compared to traditional rectangular waveforms. The second method demonstrates energy savings that could be achieved by advanced circuitry design. We show that the traditional practice of using a fixed compliance voltage for constant-current stimulation results in substantial energy loss. A portion of this energy can be recuperated by adjusting the compliance voltage to real-time requirements. Lastly, we demonstrate the potential impact of axon fiber diameter on defining the energy-optimal pulse-width for stimulation. When designing implantable pulse generators for energy efficiency, we propose that the future combination of a variable compliance system, a centered-triangular stimulus waveform, and an axon diameter specific stimulation pulse-width has great potential to reduce energy consumption and prolong battery life in neuromodulation devices.

Successful Treatment of Holmes Tremor With Deep Brain Stimulation of the Prelemniscal Radiations

Holmes tremor (HT) is a rare movement disorder that is typically associated with cerebellar, thalamic or brainstem lesions following a delay. Treatment of HT with deep brain stimulation (DBS) has yielded positive results however; it is unclear which deep brain targets provide optimal therapeutic effects. Here we describe a case report in which a 34 year old man with HT treated successfully with DBS. The ventrointermediate nucleus (VIM) of the thalamus was considered as the initial target. Following electrode placement we determined that the ventral-most electrode contacts were located in the prelemniscal radiations (Raprl). When stimulating from the Raprl contacts, the patient demonstrated robust, stable therapeutic improvements using remarkably low voltages. Our case report corroborates prior evidence suggesting the Raprl as a viable therapeutic target for treating HT with DBS.