Designed especially for neurobiologists, FluoRender is an interactive tool for multi-channel fluorescence microscopy data visualization and analysis.
Deep brain stimulation
BrainStimulator is a set of networks that are used in SCIRun to perform simulations of brain stimulation such as transcranial direct current stimulation (tDCS) and magnetic transcranial stimulation (TMS).
Developing software tools for science has always been a central vision of the SCI Institute.

Biomedical Computing

Biomedical computing combines the diagnostic and investigative aspects of biology and medical science with the power and problem-solving capabilities of modern computing. Computers are used to accelerate research learning, simulate patient behavior and visualize complex biological models.


Chris Johnson

Inverse Problems
Computational Electrophysiology

Rob MacLeod

ECG Imaging
Cardiac Disease
Computational Electrophysiology

Jeff Weiss

Computational Biomechanics

Orly Alter

Computational Biology

Tamara Bidone

Computational Models
Simulations of Biological Systems
Multi-Physics Models of Cancer Cells

Centers and Labs:

Funded Research Projects:

Publications in Biomedical Computing:

Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies
V. Vedam-Mai, K. Deisseroth, J. Giordano, G. Lazaro-Munoz, W. Chiong, N. Suthana, J. Langevin, J. Gill, W. Goodman, N. R. Provenza, C. H. Halpern, R. S. Shivacharan, T. N. Cunningham, S. A. Sheth, N. Pouratian, K. W. Scangos, H. S. Mayberg, A. Horn, K. A. Johnson, C. R. Butson, R. Gilron, C. de Hemptinne, R. Wilt, M. Yaroshinsky, S. Little, P. Starr, G. Worrell, P. Shirvalkar, E. Chang, J. Volkmann, M. Muthuraman, S. Groppa, A. A. Kühn, L. Li, M. Johnson, K. J. Otto, R. Raike, S. Goetz, C. Wu, P. Silburn, B. Cheeran, Y. J. Pathak, M. Malekmohammadi, A. Gunduz, J. K. Wong, S. Cernera, A. W. Shukla, A. Ramirez-Zamora, W. Deeb, A. Patterson, K. D. Foote, M. S. Okun. In Frontiers in Human Neuroscience, Vol. 15, pp. 169. 2021.
ISSN: 1662-5161
DOI: 10.3389/fnhum.2021.644593

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer’s disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.

Identification of Deep Brain Stimulation Targets for Neuropathic Pain After Spinal Cord Injury Using Localized Increases in White Matter Fiber Cross‐Section
S. R. Black, A. Janson, M. Mahan, J. Anderson, C. R. Butson. In Neuromodulation: Technology at the Neural Interface, John Wiley & Sons, Inc., 2021.

The spinal cord injury (SCI) patient population is overwhelmingly affected by neuropathic pain (NP), a secondary condition for which therapeutic options are limited and have a low degree of efficacy. The objective of this study was to identify novel deep brain stimulation (DBS) targets that may theoretically benefit those with NP in the SCI patient population. We hypothesize that localized changes in white matter identified in SCI subjects with NP compared to those without NP could be used to develop an evidence‐based approach to DBS target identification.

Materials and Methods
To classify localized neurostructural changes associated with NP in the SCI population, we compared white matter fiber density (FD) and cross‐section (FC) between SCI subjects with NP (N = 17) and SCI subjects without NP (N = 15) using diffusion‐weighted magnetic resonance imaging (MRI). We then identified theoretical target locations for DBS using fiber bundles connected to significantly altered regions of white matter. Finally, we used computational models of DBS to determine if our theoretical target locations could be used to feasibly activate our fiber bundles of interest.
We identified significant increases in FC in the splenium of the corpus callosum in pain subjects when compared to controls. We then isolated five fiber bundles that were directly connected to the affected region of white matter. Our models were able to predict that our fiber bundles of interest can be feasibly activated with DBS at reasonable stimulation amplitudes and with clinically relevant implantation approaches.
Altogether, we identified neuroarchitectural changes associated with NP in the SCI cohort and implemented a novel, evidence‐driven target selection approach for DBS to guide future research in neuromodulation treatment of NP after SCI.

3D Model of Cell Migration and Proliferation in a Tissue Scaffold,
S. H. Campbell, T. Bidone. In Biophysical Journal, Vol. 120, No. 3, Elsevier, pp. 265a. 2021.

Tissue scaffolds restore tissue functionality without the limitations of transplants. However, successful tissue growth depends on the interplay between scaffold properties and cell activities. It has been previously reported that scaffold porosity and Young's modulus affect cell migration and tissue generation. However, how the geometrical and mechanical properties of a scaffold exactly interplay with cell processes remain poorly understood and are essential for successful tissue growth. We developed a 3D computational model that simulates cell migration and proliferation on a scaffold. The model generates an adjustable 3D porous scaffold environment with a defined pore size and Young modulus. Cells are treated as explicit spherical particles comparable in size to bone-marrow cells and are initially seeded randomly throughout the scaffold. Cells can create adhesions, proliferate, and independently migrate across pores in a random walk. Cell adhesions during migration follow the molecular-clutch mechanism, where traction force from the cells against the scaffold stiffness reinforces adhesions lifetime up to a threshold. We used the model to test how variations in cell proliferation rate, scaffold Young's modulus, and porosity affect cell migration speed. At a low proliferation rate (1 x 10−7 s−1), the spread of cell speeds is larger than at a high replication rate (1 x 10−6 s−1). A biphasic relation between Young's modulus and cell speed is also observed reflecting the molecular-clutch mechanism at the level of individual adhesions. These observations are consistent with previous reports regarding fibroblast migration on collagen-glycosaminoglycan scaffolds. Additionally, our model shows that similar cell diameters and pore diameter induces a crowding effect decreasing cell speed. The results from our study provide important insights about biophysical mechanisms that govern cell motility on scaffolds with different properties for tissue engineering applications.

Prestin Generates Instantaneous Force in Outer Hair Cell Membranes,
J. Sandhu, T. Bidone, R. D. Rabbitt. In Biophysical Journal, Vol. 120, No. 3, 2021.

Hearing occurs from sound reaching the inner ear cochlea, where electromotile Outer Hair Cells (OHCs) amplify vibrations by elongating and contracting rapidly in response to auditory frequency changes in membrane potential. OHCs can generate force cycle-by-cycle at frequencies exceeding 50kHz, but precisely how this is achieved is unclear. Electromotility requires expression of the transmembrane protein, prestin, which facilitates the electromechanical conversion through action of the Coulomb force acting on the anion Cl- bound at the core of the protein. However, recent experimental data suggests the charge displacement is too slow to support sound amplification at auditory frequencies. As a consequence, prestin electromechanics remain unclear at the molecular level. We hypothesize that prestin instantaneously transmits stress to the membrane, which subsequently drives charge displacement, membrane deformation, and OHC shape changes. To test the hypothesis, we examined the conformational dynamics of prestin and its effects on the motion of lipids under: (1) isometric conditions and (2) constant force conditions in order to mimic different regimes of membrane loading. All-atom molecular dynamics simulations of the prestin dimer embedded in POPC membranes were run and the trajectories analyzed. We discovered that under isometric conditions, the presence of a chloride ion in the electric field increased residue fluctuations. This trend was not observed under constant force conditions, supporting the idea that isometric conditions cause instantaneous force to be generated in the membrane. The analysis allowed us to identify the molecular mechanisms by which prestin allows electromechanical amplification by OHCs in the cochlea.

Computational Model of E-cadherin Clustering under Cortical Tension,
Y. Chen, C. McNabb, T. Bidone. In Biophysical Journal, Vol. 120, No. 3, Elsevier, pp. 236a. 2021.

E-cadherins are adhesion proteins that play a critical role in the formation of cell-cell junctions for several physiological processes, including tissue development and homeostasis. The formation of E-cadherin clusters involves extracellular trans-and cis-associations between cadherin ectodomains and stabilization through intracellular coupling with the contractile actomyosin cortex. The dynamic remodeling of cell-cell junctions largely depends on cortical tension, but previous modeling frameworks did not incorporate this effect. In order to gain insights into the effects of cortical tension on the dynamic properties of E-cadherin clusters, here we developed a computational model based on Brownian dynamics. The model considers individual cadherins as explicit point particles undergoing cycles of lateral diffusion on two parallel surfaces that mimic the membrane of neighboring cells. E-cadherins transit between …

Area Available for Atrial Fibrillation to Propagate Is an Important Determinant of Recurrence After Ablation,
R. Kamali, J. Kump, E. Ghafoori, M. Lange, N. Hu, T. J. Bunch, D. J. Dosdall, R. S. Macleod, R. Ranjan. In JACC: Clinical Electrophysiology, Elsevier, 2021.

This study sought to evaluate atrial fibrillation (AF) ablation outcomes based on scar patterns and contiguous area available for AF wavefronts to propagate.

Electrocardiographic imaging for atrial fibrillation: a perspective from computer models and animal experiments to clinical value
J. Salinet, R. Molero, F. S. Schlindwein, J. Karel, M. Rodrigo, J. L. Rojo-Álvarez, O. Berenfeld, A. M. Climent, B. Zenger, F. Vanheusden, J. G. S. Paredes, R. MacLeod, F. Atienza, M. S. Guillem, M. Cluitmans, P. Bonizzi. In Frontiers in Physiology, Vol. 12, Frontiers Media, April, 2021.
DOI: 10.3389/fphys.2021.653013

Salinet et al. Electrocardiographic Imaging for Atrial Fibrillation treatment guidance (for example, localization of AF triggers and sustaining mechanisms), and we discuss the technological requirements and validation. We address experimental and clinical results, limitations, and future challenges for fruitful application of ECGI for AF understanding and management. We pay attention to existing techniques and clinical application, to computer models and (animal or human) experiments, to challenges of methodological and clinical validation. The overall objective of the study is to provide a consensus on valuable directions that ECGI research may take to provide future improvements in AF characterization and treatment guidance.

Estimation and validation of cardiac conduction velocity and wavefront reconstruction using epicardial and volumetric data
W. W. Good, K. Gillette, B. Zenger, J. Bergquist, L. C. Rupp, J. D. Tate, D. Anderson, M. Gsell, G. Plank, R. S. Macleod. In IEEE Transactions on Biomedical Engineering, IEEE, 2021.
DOI: 10.1109/TBME.2021.3069792

Objective: In this study, we have used whole heart simulations parameterized with large animal experiments to validate three techniques (two from the literature and one novel) for estimating epicardial and volumetric conduction velocity (CV). Methods: We used an eikonal-based simulation model to generate ground truth activation sequences with prescribed CVs. Using the sampling density achieved experimentally we examined the accuracy with which we could reconstruct the wavefront, and then examined the robustness of three CV estimation techniques to reconstruction related error. We examined a triangulation-based, inverse-gradient-based, and streamline-based techniques for estimating CV cross the surface and within the volume of the heart. Results: The reconstructed activation times agreed closely with simulated values, with 50-70% of the volumetric nodes and 97-99% of the epicardial nodes were within 1 ms of the ground truth. We found close agreement between the CVs calculated using reconstructed versus ground truth activation times, with differences in the median estimated CV on the order of 3-5% volumetrically and 1-2% superficially, regardless of what technique was used. Conclusion: Our results indicate that the wavefront reconstruction and CV estimation techniques are accurate, allowing us to examine changes in propagation induced by experimental interventions such as acute ischemia, ectopic pacing, or drugs. Significance: We implemented, validated, and compared the performance of a number of CV estimation techniques. The CV estimation techniques implemented in this study produce accurate, high-resolution CV fields that can be used to study propagation in the heart experimentally and clinically.

Quantifying the spatiotemporal influence of acute myocardial ischemia on volumetric conduction velocity
W. W. Good, B. Zenger, J. A. Bergquist, L. C. Rupp, K. K. Gillette, M. A.F. Gsell, G. Plank, R. S. MacLeod. In Journal of Electrocardiology, Vol. 66, Churchill Livingstone, pp. 86-94. 2021.

Acute myocardial ischemia occurs when coronary perfusion to the heart is inadequate, which can perturb the highly organized electrical activation of the heart and can result in adverse cardiac events including sudden cardiac death. Ischemia is known to influence the ST and repolarization phases of the ECG, but it also has a marked effect on propagation (QRS); however, studies investigating propagation during ischemia have been limited.

We estimated conduction velocity (CV) and ischemic stress prior to and throughout 20 episodes of experimentally induced ischemia in order to quantify the progression and correlation of volumetric conduction changes during ischemia. To estimate volumetric CV, we 1) reconstructed the activation wavefront; 2) calculated the elementwise gradient to approximate propagation direction; and 3) estimated conduction speed (CS) with an inverse-gradient technique.
We found that acute ischemia induces significant conduction slowing, reducing the global median speed by 20 cm/s. We observed a biphasic response in CS (acceleration then deceleration) early in some ischemic episodes. Furthermore, we noted a high temporal correlation between ST-segment changes and CS slowing; however, when comparing these changes over space, we found only moderate correlation (corr. = 0.60).
This study is the first to report volumetric CS changes (acceleration and slowing) during episodes of acute ischemia in the whole heart. We showed that while CS changes progress in a similar time course to ischemic stress (measured by ST-segment shifts), the spatial overlap is complex and variable, showing extreme conduction slowing both in and around regions experiencing severe ischemia.

Structural connectivity predicts clinical outcomes of deep brain stimulation for Tourette syndrome
K. A. Johnson, G. Duffley, D. Nesterovich Anderson, J. L. Ostrem, M. Welter, J. C. Baldermann, J. Kuhn, D. Huys, V. Visser-Vandewalle, T. Foltynie, L. Zrinzo, M. Hariz, A. F. G. Leentjens, A. Y. Mogilner, M. H. Pourfar, L. Almeida, A. Gunduz, K. D. Foote, M. S. Okun, C. R. Butson. In Brain, July, 2020.
ISSN: 0006-8950
DOI: 10.1093/brain/awaa188

Deep brain stimulation may be an effective therapy for select cases of severe, treatment-refractory Tourette syndrome; however, patient responses are variable, and there are no reliable methods to predict clinical outcomes. The objectives of this retrospective study were to identify the stimulation-dependent structural networks associated with improvements in tics and comorbid obsessive-compulsive behaviour, compare the networks across surgical targets, and determine if connectivity could be used to predict clinical outcomes. Volumes of tissue activated for a large multisite cohort of patients (n = 66) implanted bilaterally in globus pallidus internus (n = 34) or centromedial thalamus (n = 32) were used to generate probabilistic tractography to form a normative structural connectome. The tractography maps were used to identify networks that were correlated with improvement in tics or comorbid obsessive-compulsive behaviour and to predict clinical outcomes across the cohort. The correlated networks were then used to generate ‘reverse’ tractography to parcellate the total volume of stimulation across all patients to identify local regions to target or avoid. The results showed that for globus pallidus internus, connectivity to limbic networks, associative networks, caudate, thalamus, and cerebellum was positively correlated with improvement in tics; the model predicted clinical improvement scores (P = 0.003) and was robust to cross-validation. Regions near the anteromedial pallidum exhibited higher connectivity to the positively correlated networks than posteroventral pallidum, and volume of tissue activated overlap with this map was significantly correlated with tic improvement (P < 0.017). For centromedial thalamus, connectivity to sensorimotor networks, parietal-temporal-occipital networks, putamen, and cerebellum was positively correlated with tic improvement; the model predicted clinical improvement scores (P = 0.012) and was robust to cross-validation. Regions in the anterior/lateral centromedial thalamus exhibited higher connectivity to the positively correlated networks, but volume of tissue activated overlap with this map did not predict improvement (P > 0.23). For obsessive-compulsive behaviour, both targets showed that connectivity to the prefrontal cortex, orbitofrontal cortex, and cingulate cortex was positively correlated with improvement; however, only the centromedial thalamus maps predicted clinical outcomes across the cohort (P = 0.034), but the model was not robust to cross-validation. Collectively, the results demonstrate that the structural connectivity of the site of stimulation are likely important for mediating symptom improvement, and the networks involved in tic improvement may differ across surgical targets. These networks provide important insight on potential mechanisms and could be used to guide lead placement and stimulation parameter selection, as well as refine targets for neuromodulation therapies for Tourette syndrome.

A systematic exploration of parameters affecting evoked intracranial potentials in patients with epilepsy
B. Kundu, T. S. Davis, B. Philip, E. H. Smith, A. Arain, A. Peters, B. Newman, C. R. Butson, J. D. Rolston. In Brain Stimulation, Vol. 13, No. 5, pp. 1232-1244. 2020.

Brain activity is constrained by and evolves over a network of structural and functional connections. Corticocortical evoked potentials (CCEPs) have been used to measure this connectivity and to discern brain areas involved in both brain function and disease. However, how varying stimulation parameters influences the measured CCEP across brain areas has not been well characterized.

To better understand the factors that influence the amplitude of the CCEPs as well as evoked gamma-band power (70–150 Hz) resulting from single-pulse stimulation via cortical surface and depth electrodes.

CCEPs from 4370 stimulation-response channel pairs were recorded across a range of stimulation parameters and brain regions in 11 patients undergoing long-term monitoring for epilepsy. A generalized mixed-effects model was used to model cortical response amplitudes from 5 to 100 ms post-stimulation.

Stimulation levels <5.5 mA generated variable CCEPs with low amplitude and reduced spatial spread. Stimulation at ≥5.5 mA yielded a reliable and maximal CCEP across stimulation-response pairs over all regions. These findings were similar when examining the evoked gamma-band power. The amplitude of both measures was inversely correlated with distance. CCEPs and evoked gamma power were largest when measured in the hippocampus compared with other areas. Larger CCEP size and evoked gamma power were measured within the seizure onset zone compared with outside this zone.

These results will help guide future stimulation protocols directed at quantifying network connectivity across cognitive and disease states.

Retrospective clinical trial experimentally validates glioblastoma genome-wide pattern of DNA copy-number alterations predictor of survival
S. P. Ponnapalli, M. W. Bradley, K. Devine, J. Bowen, S. E. Coppens, K. M. Leraas, B. A. Milash, F. Li, H. Luo, S. Qiu, K. Wu, H. Yang, C. T. Wittwer, C. A. Palmer, R. L. Jensen, J. M. Gastier-Foster, H. A. Hanson, J. S. Barnholtz-Sloan, O. Alter. In Applied Physics Letters (APL) Bioengineering, Vol. 4, No. 2, May, 2020.

Modeling of genomic profiles from the Cancer Genome Atlas (TCGA) by using recently developed mathematical frameworks has associated a genome-wide pattern of DNA copy-number alterations with a shorter, roughly one-year, median survival time in glioblastoma (GBM) patients. Here, to experimentally test this relationship, we whole-genome sequenced DNA from tumor samples of patients. We show that the patients represent the U.S. adult GBM population in terms of most normal and disease phenotypes. Intratumor heterogeneity affects ≈11% and profiling technology and reference human genome specifics affect <1% of the classifications of the tumors by the pattern, where experimental batch effects normally reduce the reproducibility, i.e., precision, of classifications based upon between one to a few hundred genomic loci by >30%. With a 2.25-year Kaplan–Meier median survival difference, a 3.5 univariate Cox hazard ratio, and a 0.78 concordance index, i.e., accuracy, the pattern predicts survival better than and independent of age at diagnosis, which has been the best indicator since 1950. The prognostic classification by the pattern may, therefore, help to manage GBM pseudoprogression. The diagnostic classification may help drugs progress to regulatory approval. The therapeutic predictions, of previously unrecognized targets that are correlated with survival, may lead to new drugs. Other methods missed this relationship in the roughly 3B-nucleotide genomes of the small, order of magnitude of 100, patient cohorts, e.g., from TCGA. Previous attempts to associate GBM genotypes with patient phenotypes were unsuccessful. This is a proof of principle that the frameworks are uniquely suitable for discovering clinically actionable genotype–phenotype relationships.

Activation robustness with directional leads and multi-lead configurations in deep brain stimulation
A. P. Janson, D. N. Anderson, C. R. Butson. In Journal of Neural Engineering, Vol. 17, No. 2, IOP Publishing, pp. 026012. March, 2020.
DOI: 10.1088/1741-2552/ab7b1d

Objective: Clinical outcomes from deep brain stimulation (DBS) can be highly variable, and two critical factors underlying this variability are the location and type of stimulation. In this study we quantified how robustly DBS activates a target region when taking into account a range of different lead designs and realistic variations in placement. The objective of the study is to assess the likelihood of achieving target activation.

Approach: We performed finite element computational modeling and established a metric of performance robustness to evaluate the ability of directional and multi-lead configurations to activate target fiber pathways while taking into account location variability. A more robust lead configuration produces less variability in activation across all stimulation locations around the target.

Main results: Directional leads demonstrated higher overall performance robustness compared to axisymmetric leads, primarily 1-2 mm outside of the target. Multi-lead configurations demonstrated higher levels of robustness compared to any single lead due to distribution of electrodes in a broader region around the target.

Significance: Robustness measures can be used to evaluate the performance of existing DBS lead designs and aid in the development of novel lead designs to better accommodate known variability in lead location and orientation. This type of analysis may also be useful to understand how DBS clinical outcome variability is influenced by lead location among groups of patients.

Personalized Virtual-heart Technology for Guiding the Ablation of Infarct-related Ventricular Tachycardia,
A. Prakosa, H.J. Arevalo, D. Deng, P.M. Boyle, P.P. Nikolov, H. Ashikaga, J.E. Blauer, E. Ghafoori, C.J. Park, R.C. Blake III, F.T. Han, R.S. MacLeod, H.R. Halperin, D.J. Callans, R. Ranjan, J. Chrispin, S. Nazarian,, N.A. Trayanova. In Nature Biomedical Engineering, Vol. 2, pp. 732–740. 2019.

Ventricular tachycardia (VT), which can lead to sudden cardiac death, occurs frequently in patients with myocardial infarction. Catheter-based radio-frequency ablation of cardiac tissue has achieved only modest efficacy, owing to the inaccurate identification of ablation targets by current electrical mapping techniques, which can lead to extensive lesions and to a prolonged, poorly tolerated procedure. Here, we show that personalized virtual-heart technology based on cardiac imaging and computational modelling can identify optimal infarct-related VT ablation targets in retrospective animal (five swine) and human studies (21 patients), as well as in a prospective feasibility study (five patients). We first assessed, using retrospective studies (one of which included a proportion of clinical images with artefacts), the capability of the technology to determine the minimum-size ablation targets for eradicating all VTs. In the prospective study, VT sites predicted by the technology were targeted directly, without relying on prior electrical mapping. The approach could improve infarct-related VT ablation guidance, where accurate identification of patient-specific optimal targets could be achieved on a personalized virtual heart before the clinical procedure.

The μDBS: Multiresolution, Directional Deep Brain Stimulation for Improved Targeting of Small Diameter Fibers
D. N. Anderson, C. Anderson, N. Lanka, R. Sharma, C. R. Butson, B. W. Baker, A. D. Dorval. In Frontiers in Neuroscience, Vol. 13, October, 2019.
DOI: 10.3389/fnins.2019.01152

Directional deep brain stimulation (DBS) leads have recently been approved and used in patients, and growing evidence suggests that directional contacts can increase the therapeutic window by redirecting stimulation to the target region while avoiding side-effect-inducing regions. We outline the design, fabrication, and testing of a novel directional DBS lead, theμDBS, which utilizes microscale contacts to increase the spatial resolution of stimulation steering and improve the selectivity in targeting small diameter fibers. We outline the steps of fabrication of theμDBS, from an integrated circuit design to post-processing and validation testing. We tested the onboard digital circuitry for programming fidelity, characterized impedance for a variety of electrode sizes, and demonstrated functionality in a saline bath. In a computational experiment,we determined that reduced electrode sizes focus the stimulation effect on small, nearby fibers. Smaller electrode sizes allow for a relative decrease in small-diameter axon thresholds compared to thresholds of large-diameter fibers, demonstrating a focusing of the stimulation effect within small, and possibly therapeutic, fibers. This principle of selectivity could be useful in further widening the window of therapy. TheμDBS offers a unique, multi resolution design in which any combination of microscale contacts can be used together to function as electrodes of various shapes and sizes. Multiscale electrodes could be useful in selective neural targeting for established neurological targets and in exploring novel treatment targets for new neurological indications.

Which Two-dimensional Radiographic Measurements of Cam Femoroacetabular Impingement Best Describe the Three-dimensional Shape of the Proximal Femur?
P. R. Atkins, Y. Shin, P. Agrawal, S. Y. Elhabian, R. T. Whitaker, J. A. Weiss, S. K. Aoki, C. L. Peters, A. E. Anderson. In Clinical Orthopaedics and Related Research, Vol. 477, No. 1, 2019.


Many two-dimensional (2-D) radiographic views are used to help diagnose cam femoroacetabular impingement (FAI), but there is little consensus as to which view or combination of views is most effective at visualizing the magnitude and extent of the cam lesion (ie, severity). Previous studies have used a single image from a sequence of CT or MR images to serve as a reference standard with which to evaluate the ability of 2-D radiographic views and associated measurements to describe the severity of the cam lesion. However, single images from CT or MRI data may fail to capture the apex of the cam lesion. Thus, it may be more appropriate to use measurements of three-dimensional (3-D) surface reconstructions from CT or MRI data to serve as an anatomic reference standard when evaluating radiographic views and associated measurements used in the diagnosis of cam FAI.


The purpose of this study was to use digitally reconstructed radiographs and 3-D statistical shape modeling to (1) determine the correlation between 2-D radiographic measurements of cam FAI and 3-D metrics of proximal femoral shape; and 2) identify the combination of radiographic measurements from plain film projections that were most effective at predicting the 3-D shape of the proximal femur.


This study leveraged previously acquired CT images of the femur from a convenience sample of 37 patients (34 males; mean age, 27 years, range, 16-47 years; mean body mass index [BMI], 24.6 kg/m, range, 19.0-30.2 kg/m) diagnosed with cam FAI imaged between February 2005 and January 2016. Patients were diagnosed with cam FAI based on a culmination of clinical examinations, history of hip pain, and imaging findings. The control group consisted of 59 morphologically normal control participants (36 males; mean age, 29 years, range, 15-55 years; mean BMI, 24.4 kg/m, range, 16.3-38.6 kg/m) imaged between April 2008 and September 2014. Of these controls, 30 were cadaveric femurs and 29 were living participants. All controls were screened for evidence of femoral deformities using radiographs. In addition, living control participants had no history of hip pain or previous surgery to the hip or lower limbs. CT images were acquired for each participant and the surface of the proximal femur was segmented and reconstructed. Surfaces were input to our statistical shape modeling pipeline, which objectively calculated 3-D shape scores that described the overall shape of the entire proximal femur and of the region of the femur where the cam lesion is typically located. Digital reconstructions for eight plain film views (AP, Meyer lateral, 45° Dunn, modified 45° Dunn, frog-leg lateral, Espié frog-leg, 90° Dunn, and cross-table lateral) were generated from CT data. For each view, measurements of the α angle and head-neck offset were obtained by two researchers (intraobserver correlation coefficients of 0.80-0.94 for the α angle and 0.42-0.80 for the head-neck offset measurements). The relationships between radiographic measurements from each view and the 3-D shape scores (for the entire proximal femur and for the region specific to the cam lesion) were assessed with linear correlation. Additionally, partial least squares regression was used to determine which combination of views and measurements was the most effective at predicting 3-D shape scores.


Three-dimensional shape scores were most strongly correlated with α angle on the cross-table view when considering the entire proximal femur (r = -0.568; p < 0.001) and on the Meyer lateral view when considering the region of the cam lesion (r = -0.669; p < 0.001). Partial least squares regression demonstrated that measurements from the Meyer lateral and 90° Dunn radiographs produced the optimized regression model for predicting shape scores for the proximal femur (R = 0.405, root mean squared error of prediction [RMSEP] = 1.549) and the region of the cam lesion (R = 0.525, RMSEP = 1.150). Interestingly, views with larger differences in the α angle and head-neck offset between control and cam FAI groups did not have the strongest correlations with 3-D shape.


Considered together, radiographic measurements from the Meyer lateral and 90° Dunn views provided the most effective predictions of 3-D shape of the proximal femur and the region of the cam lesion as determined using shape modeling metrics.


Our results suggest that clinicians should consider using the Meyer lateral and 90° Dunn views to evaluate patients in whom cam FAI is suspected. However, the α angle and head-neck offset measurements from these and other plain film views could describe no more than half of the overall variation in the shape of the proximal femur and cam lesion. Thus, caution should be exercised when evaluating femoral head anatomy using the α angle and head-neck offset measurements from plain film radiographs. Given these findings, we believe there is merit in pursuing research that aims to develop the framework necessary to integrate statistical shape modeling into clinical evaluation, because this could aid in the diagnosis of cam FAI.

Interactive computation and visualization of deep brain stimulation effects using Duality,
J. Vorwerk, D. McCann, J. Krüger, C.R. Butson. In Computer Methods in Biomechanics and Biomedical Engineering: Imaging & Visualization, Taylor & Francis, 2019.

Deep brain stimulation (DBS) is an established treatment for movement disorders such as Parkinson’s disease or essential tremor. Currently, the selection of optimal stimulation settings is performed by iteratively adjusting the stimulation parameters and is a time consuming procedure that requires multiple clinic visits of several hours. Recently, computational models to predict and visualize the effect of DBS have been developed with the goal to simplify and accelerate this procedure by providing visual guidance and such models have been made available also on mobile devices. However, currently available visualization software still either lacks mobility, i.e. it is running on desktop computers and no easily available in clinical praxis, or flexibility, as the simulations that are visualized on mobile devices have to be precomputed. The goal of the pipeline presented in this paper is to close this gap: Using Duality, a newly developed software for the interactive visualization of simulation results, we implemented a pipeline that allows to compute DBS simulations in near-real time and instantaneously visualize the result on a tablet computer. We carry out a performance analysis and present the results of a case study in which the pipeline was applied.

A retrospective evaluation of automated optimization of deep brain stimulation parameters
J. Vorwerk, A. Brock, D.N. Anderson, J.D. Rolston, C.R. Butson. In Journal of Neural Engineering, 2019.
DOI: 10.1088/1741-2552/ab35b1

Objective: We performed a retrospective analysis of an optimization algorithm for the computation of patient-specific multipolar stimulation configurations employing multiple independent current/voltage sources. We evaluated whether the obtained stimulation configurations align with clinical data and whether the optimized stimulation configurations have the potential to lead to an equal or better stimulation of the target region as manual programming, while reducing the time required for programming sessions. Methods: For three patients (five electrodes) diagnosed with essential tremor, we derived optimized multipolar stimulation configurations using an approach that is suitable for the application in clinical practice. To evaluate the automatically derived stimulation settings, we compared them to the results of the monopolar review. Results: We observe a good agreement between the findings of the monopolar review and the optimized stimulation configurations, with the algorithm assigning the maximal voltage in the optimized multipolar pattern to the contact that was found to lead to the best therapeutic effect in the clinical monopolar review in all cases. Additionally, our simulation results predict that the optimized stimulation settings lead to the activation of an equal or larger volume fraction of the target compared to the manually determined settings in all cases. Conclusions: Our results demonstrate the feasibility of an automatic determination of optimal DBS configurations and motivate a further evaluation of the applied optimization algorithm.

Interleaved deep brain stimulation for dyskinesia management in Parkinson's disease
C. C. Aquino, G. Duffley, D. M. Hedges, J. Vorwerk, P. A. House, H. B. Ferraz, J. D. Rolston, C. R. Butson, L. E. Schrock. In Movement Disorders, 2019.
DOI: 10.1002/mds.27839


In patients with Parkinson's disease, stimulation above the subthalamic nucleus (STN) may engage the pallidofugal fibers and directly suppress dyskinesia.


The objective of this study was to evaluate the effect of interleaving stimulation through a dorsal deep brain stimulation contact above the STN in a cohort of PD patients and to define the volume of tissue activated with antidyskinesia effects.


We analyzed the Core Assessment Program for Surgical Interventional Therapies dyskinesia scale, Unified Parkinson's Disease Rating Scale parts III and IV, and other endpoints in 20 patients with interleaving stimulation for management of dyskinesia. Individual models of volume of tissue activated and heat maps were used to identify stimulation sites with antidyskinesia effects.


The Core Assessment Program for Surgical Interventional Therapies dyskinesia score in the on medication phase improved 70.9 ± 20.6% from baseline with noninterleaved settings (P < 0.003). With interleaved settings, dyskinesia improved 82.0 ± 27.3% from baseline (P < 0.001) and 61.6 ± 39.3% from the noninterleaved phase (P = 0.006). The heat map showed a concentration of volume of tissue activated dorsally to the STN during the interleaved setting with an antidyskinesia effect.


Interleaved deep brain stimulation using the dorsal contacts can directly suppress dyskinesia, probably because of the involvement of the pallidofugal tract, allowing more conservative medication reduction. © 2019 International Parkinson and Movement Disorder Society

Evaluation of methodologies for computing the deep brain stimulation volume of tissue activated
G. Duffley, D. N. Anderson, J. Vorwerk, A. C. Dorval, C. R. Butson. In Journal of Neural Engineering, Aug, 2019.
DOI: 10.1088/1741-2552/ab3c95

Computational models are a popular tool for predicting the effects of deep brain stimulation (DBS) on neural tissue. One commonly used model, the volume of tissue activated (VTA), is computed using multiple methodologies. We quantified differences in the VTAs generated by five methodologies: the traditional axon model method, the electric field norm, and three activating function based approaches - the activating function at each grid point in the tangential direction (AF-Tan) or in the maximally activating direction (AF-3D), and the maximum activating function along the entire length of a tangential fiber (AF-Max).

Approach: We computed the VTA using each method across multiple stimulation settings. The resulting volumes were compared for similarity, and the methodologies were analyzed for their differences in behavior.

Main Results: Activation threshold values for both the electric field norm and the activating function vary with regards to electrode configuration, pulse width, and frequency. All methods produced highly similar volumes for monopolar stimulation. For bipolar electrode configurations, only the maximum activating function along the tangential axon method, AF-Max, produced similar volumes to those produced by the axon model method. Further analysis revealed that both of these methods are biased by their exclusive use of tangential fiber orientations. In contrast, the activating function in the maximally activating direction method, AF-3D, produces a VTA that is free of axon orientation and projection bias.

Significance: Simulating tangentially oriented axons, the standard approach of computing the VTA, is too computationally expensive for widespread implementation and yields results biased by the assumption of tangential fiber orientation. In this work, we show that a computationally efficient method based on the activating function, AF-Max, reliably reproduces the VTAs generated by direct axon modeling. Further, we propose another method, AF-3D as a potentially superior model for representing generic neural tissue activation.