Benefits and Risks of a Staged-Bilateral VIM Versus Unilateral VIM DBS for Essential Tremor.

Background: Despite over 30 years of clinical experience, high-quality studies on the efficacy of bilateral versus unilateral deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus for medically refractory essential tremor (ET) remain limited. Objectives: To compare benefits and risks of bilateral versus unilateral VIM DBS using the largest ET DBS clinical trial dataset available to date. Methods: Participants from the US St. Jude/Abbott pivotal ET DBS trial who underwent staged-bilateral VIM implantation constituted the primary cohort in this sub-analysis. Their assessments "on" DBS at six months after second-side VIM DBS implantation were compared to the assessments six months after unilateral implantation. Two control cohorts of participants with unilateral implantation only were also used for between-group comparisons. Results: The primary cohort consisted of n = 38 ET patients (22M/16F; age of 65.3 ± 9.5 years). The second side VIM-DBS resulted in a 29.6% additional improvement in the total motor CRST score (P < 0.001), with a 64.1% CRST improvement in the contralateral side (P < 0.001). An added improvement was observed in the axial tremor score (21.4%, P = 0.005), and CRST part B (24.8%, P < 0.001) score. Rate of adverse events was slightly higher after bilateral stimulation. Conclusions: In the largest ET DBS study to date, staged-bilateral VIM DBS was a highly effective treatment for ET with bilateral implantation resulting in greater reduction in total motor tremor scores when compared to unilateral stimulation alone.

Rapid development of an integrated remote programming platform for neuromodulation systems through the biodesign process.

Treating chronic symptoms for pain and movement disorders with neuromodulation therapies involves fine-tuning of programming parameters over several visits to achieve and maintain symptom relief. This, together with challenges in access to trained specialists, has led to a growing need for an integrated wireless remote care platform for neuromodulation devices. In March of 2021, we launched the first neuromodulation device with an integrated remote programming platform. Here, we summarize the biodesign steps taken to identify the unmet patient need, invent, implement, and test the new technology, and finally gain market approval for the remote care platform. Specifically, we illustrate how agile development aligned with the evolving regulatory requirements can enable patient-centric digital health technology in neuromodulation, such as the remote care platform. The three steps of the biodesign process applied for remote care platform development are: (1) Identify, (2) Invent, and (3) Implement. First, we identified the unmet patient needs through market research and voice-of-customer (VOC) process. Next, during the concept generation phase of the invention step, we integrated the results from the VOC into defining requirements for prototype development. Subsequently, in the concept screening phase, ten subjects with PD participated in a clinical pilot study aimed at characterizing the safety of the remote care prototype. Lastly, during the implementation step, lessons learned from the pilot experience were integrated into final product development as new features. Following final product development, we completed usability testing to validate the full remote care system and collected preliminary data from the limited market release experience. The VOC data, during prototype development, helped us identify thresholds for video quality and needs priorities for clinicians and patients. During the pilot study, one subject reported anticipated remote-care-related adverse events that were resolved without sequelae. For usability analysis following final product development, the failure rates for task completion for both user groups were about 1%. Lastly, during the initial 4 weeks of the limited market release experience, a total of 858 remote care sessions were conducted with a 93% success rate. Overall, we developed a remote care platform by adopting a user-centric approach. Although the system intended to address pre-COVID19 challenges associated with disease management, the unforeseen overlap of the study with the pandemic elevated the importance of such a system and an innovative development process enabled us to advance a patient-centric platform to gain regulatory approval and successfully launch the remote care platform to market.

A comprehensive model-based framework for optimal design of biomimetic patterns of electrical stimulation for prosthetic sensation.

OBJECTIVE: Touch and proprioception are essential to motor function as shown by the movement deficits that result from the loss of these senses, e.g. due to neuropathy of sensory nerves. To achieve a high-performance brain-controlled prosthetic arm/hand thus requires the restoration of somatosensation, perhaps through intracortical microstimulation (ICMS) of somatosensory cortex (S1). The challenge is to generate patterns of neuronal activation that evoke interpretable percepts. We present a framework to design optimal spatiotemporal patterns of ICMS (STIM) that evoke naturalistic patterns of neuronal activity and demonstrate performance superior to four previous approaches. APPROACH: We recorded multiunit activity from S1 during a center-out reach task (from proprioceptive neurons in Brodmann's area 2) and during application of skin indentations (from cutaneous neurons in Brodmann's area 1). We implemented a computational model of a cortical hypercolumn and used a genetic algorithm to design STIM that evoked patterns of model neuron activity that mimicked their experimentally-measured counterparts. Finally, from the ICMS patterns, the evoked neuronal activity, and the stimulus parameters that gave rise to it, we trained a recurrent neural network (RNN) to learn the mapping function between the physical stimulus and the biomimetic stimulation pattern, i.e. the sensory encoder to be integrated into a neuroprosthetic device. MAIN RESULTS: We identified ICMS patterns that evoked simulated responses that closely approximated the measured responses for neurons within 50 µm of the electrode tip. The RNN-based sensory encoder generalized well to untrained limb movements or skin indentations. STIM designed using the model-based optimization approach outperformed STIM designed using existing linear and nonlinear mappings. SIGNIFICANCE: The proposed framework produces an encoder that converts limb state or patterns of pressure exerted onto the prosthetic hand into STIM that evoke naturalistic patterns of neuronal activation.

Neural Networks for Modeling Neural Spiking in S1 Cortex.

Somatosensation is composed of two distinct modalities: touch, arising from sensors in the skin, and proprioception, resulting primarily from sensors in the muscles, combined with these same cutaneous sensors. In contrast to the wealth of information about touch, we know quite less about the nature of the signals giving rise to proprioception at the cortical level. Likewise, while there is considerable interest in developing encoding models of touch-related neurons for application to brain machine interfaces, much less emphasis has been placed on an analogous proprioceptive interface. Here we investigate the use of Artificial Neural Networks (ANNs) to model the relationship between the firing rates of single neurons in area 2, a largely proprioceptive region of somatosensory cortex (S1) and several types of kinematic variables related to arm movement. To gain a better understanding of how these kinematic variables interact to create the proprioceptive responses recorded in our datasets, we train ANNs under different conditions, each involving a different set of input and output variables. We explore the kinematic variables that provide the best network performance, and find that the addition of information about joint angles and/or muscle lengths significantly improves the prediction of neural firing rates. Our results thus provide new insight regarding the complex representations of the limb motion in S1: that the firing rates of neurons in area 2 may be more closely related to the activity of peripheral sensors than it is to extrinsic hand position. In addition, we conduct numerical experiments to determine the sensitivity of ANN models to various choices of training design and hyper-parameters. Our results provide a baseline and new tools for future research that utilizes machine learning to better describe and understand the activity of neurons in S1.

Modern Machine Learning as a Benchmark for Fitting Neural Responses.

Neuroscience has long focused on finding encoding models that effectively ask "what predicts neural spiking?" and generalized linear models (GLMs) are a typical approach. It is often unknown how much of explainable neural activity is captured, or missed, when fitting a model. Here we compared the predictive performance of simple models to three leading machine learning methods: feedforward neural networks, gradient boosted trees (using XGBoost), and stacked ensembles that combine the predictions of several methods. We predicted spike counts in macaque motor (M1) and somatosensory (S1) cortices from standard representations of reaching kinematics, and in rat hippocampal cells from open field location and orientation. Of these methods, XGBoost and the ensemble consistently produced more accurate spike rate predictions and were less sensitive to the preprocessing of features. These methods can thus be applied quickly to detect if feature sets relate to neural activity in a manner not captured by simpler methods. Encoding models built with a machine learning approach accurately predict spike rates and can offer meaningful benchmarks for simpler models.

Methodological considerations for a chronic neural interface with the cuneate nucleus of macaques.

While the response properties of neurons in the somatosensory nerves and anterior parietal cortex have been extensively studied, little is known about the encoding of tactile and proprioceptive information in the cuneate nucleus (CN) or external cuneate nucleus (ECN), the first recipients of upper limb somatosensory afferent signals. The major challenge in characterizing neural coding in CN/ECN has been to record from these tiny, difficult-to-access brain stem structures. Most previous investigations of CN response properties have been carried out in decerebrate or anesthetized animals, thereby eliminating the well-documented top-down signals from cortex, which likely exert a strong influence on CN responses. Seeking to fill this gap in our understanding of somatosensory processing, we describe an approach to chronically implanting arrays of electrodes in the upper limb representation in the brain stem in primates. First, we describe the topography of CN/ECN in rhesus macaques, including its somatotopic organization and the layout of its submodalities (touch and proprioception). Second, we describe the design of electrode arrays and the implantation strategy to obtain stable recordings. Third, we show sample responses of CN/ECN neurons in brain stem obtained from awake, behaving monkeys. With this method, we are in a position to characterize, for the first time, somatosensory representations in CN and ECN of primates.NEW & NOTEWORTHY In primates, the neural basis of touch and of our sense of limb posture and movements has been studied in the peripheral nerves and in somatosensory cortex, but coding in the cuneate and external cuneate nuclei, the first processing stage for these signals in the central nervous system, remains an enigma. We have developed a method to record from these nuclei, thereby paving the way to studying how sensory information from the limb is encoded there.

Toward a Proprioceptive Neural Interface that Mimics Natural Cortical Activity.

The dramatic advances in efferent neural interfaces over the past decade are remarkable, with cortical signals used to allow paralyzed patients to control the movement of a prosthetic limb or even their own hand. However, this success has thrown into relief, the relative lack of progress in our ability to restore somatosensation to these same patients. Somatosensation, including proprioception, the sense of limb position and movement, plays a crucial role in even basic motor tasks like reaching and walking. Its loss results in crippling deficits. Historical work dating back decades and even centuries has demonstrated that modality-specific sensations can be elicited by activating the central nervous system electrically. Recent work has focused on the challenge of refining these sensations by stimulating the somatosensory cortex (S1) directly. Animals are able to detect particular patterns of stimulation and even associate those patterns with particular sensory cues. Most of this work has involved areas of the somatosensory cortex that mediate the sense of touch. Very little corresponding work has been done for proprioception. Here we describe the effort to develop afferent neural interfaces through spatiotemporally precise intracortical microstimulation (ICMS). We review what is known of the cortical representation of proprioception, and describe recent work in our lab that demonstrates for the first time, that sensations like those of natural proprioception may be evoked by ICMS in S1. These preliminary findings are an important first step to the development of an afferent cortical interface to restore proprioception.

Effects of posterior distraction forces on anterior column intradiscal pressure in the dual growing rod technique.

BACKGROUND: Little evidence is available addressing biomechanical properties of posterior distraction forces and their effects on anterior spinal column in the growing rod technique. The question is often asked if posterior distraction forces may be kyphogenic. The goal of this study is to determine whether posterior distraction forces transmitted anteriorly through different foundation constructs (i.e., screws vs. hooks) affect intradiscal pressure. METHODS: Six skeletally immature porcine spines were harvested leaving soft tissues and rib heads intact. Pedicle screws served as the lower foundation on a L3-L4 motion segment while pedicle screws and laminar hooks were randomly used at T3-T4 levels. Proximal constructs (hook vs. screw) were switched after initial distraction testing. The dual rod distractor was instrumented with strain gauges and calibrated using a custom force transducer. During distraction, intradiscal pressures immediately inferior to the superior foundation and the level equidistant between foundations were measured using needle pressure transducers. Maximum distraction force and maximum anterior disc pressure change were compared between hook and pedicle screw anchors using one-way ANOVA (p < 0.05). RESULTS: Upper foundations with pedicle screws had significantly greater distraction forces (416 ± 101 N) than those with upper level hooks (349 ± 100 N). There were no significant differences in disc pressures between levels or between upper foundation constructs. Disc pressures adjacent to the upper foundation demonstrated greater reduction (disc expansion) than the level equidistant within the construct. Pedicle screw constructs demonstrated greater endplate separation (distraction) compared to hook constructs. CONCLUSIONS: Posterior distraction forces result in anterior disc separation (distraction) and are distributed across multiple levels rather than delivered to the disc immediately adjacent to a foundation. Constructs with upper foundation hooks had lower distraction forces possibly due to hook motion during distraction. The load distribution at multiple levels may assist with curve control and may affect vertebral growth. The distraction forces may not be kyphogenic as is commonly believed.

Dynamic dominance persists during unsupported reaching.

Previous studies examining lateralization of arm movements focused on supported movements in the horizontal plane, removing the effects of gravity. The authors hypothesized that interlimb differences in free reaching would be consistent with the differences shown during supported reaching. Kinematic and kinetic data were collected for the forearm and upper arm segments in a 3-direction reaching task. Results showed lateralization of coordination, reflected by initial movement direction and trajectory curvature. The nondominant arm showed increased initial direction errors, and path curvature associated with a timing deficit between elbow and shoulder peak torques. These coordination deficits did not disrupt final position accuracy. The authors conclude that nondominant arm coordination deficits are similar to those reported previously for horizontal plane movements.

Biomechanical comparison of kyphoplasty versus a titanium mesh implant with cement for stabilization of vertebral compression fractures.

STUDY DESIGN: In vitro biomechanical investigation. OBJECTIVE: To evaluate differences in biomechanical stability of vertebral compression fractures repaired using balloon kyphoplasty versus a titanium mesh implant. SUMMARY OF BACKGROUND DATA: Vertebral compression fractures may be stabilized using an expandable balloon followed by cement injection. There are small but finite risks of endplate fracture and cement extravasation with this procedure. Alternative techniques may affect cement injection volumes, height maintenance, and biomechanical stability but require investigation. METHODS: Four male human cadaveric spines from T2 to L5 were used in this study. After determining bone mineral density, individual vertebral bodies were dissected and inspected for previous fractures or additional exclusion criteria. In the remaining vertebral bodies (n=48) anterior wedge fractures were created using a materials testing machine. Fractured vertebral bodies were systematically randomized to be repaired either with balloon kyphoplasty or with titanium mesh implant and polymethylmethacrylate bone cement, using image intensified fluoroscopy. Anterior vertebral body height (cm) was measured initially, after mechanically creating an anterior wedge fracture, after repairing the compression fracture with either technique, and after recompressing the vertebral body following a 24-hour cement polymerization period. Data for cement injection volume (mL) and height maintained following testing (cm) were compared between repair groups using a 1-way analysis of variance (P<0.05). Data for stiffness (N/mm), yield load (N), and ultimate load (N) were compared between intact bodies and repaired bodies using a 2-way analysis of variance (P<0.05). RESULTS: There was significantly less cement injected (P<0.001) and significantly greater height maintained (P<0.025) with the titanium implant group compared to the kyphoplasty group. There were no significant differences in biomechanical stability between the 2 groups (P>0.05). CONCLUSION: The titanium implant was biomechanically equivalent to the kyphoplasty repair while necessitating less cement and providing greater height maintenance in vitro. Improvements in pain and function could not be specifically addressed in this in vitro study and should be evaluated in a clinical case series.

Pedicle screw surface coatings improve fixation in nonfusion spinal constructs.

STUDY DESIGN: Biomechanical and histologic analysis. OBJECTIVE: To compare the strength of the bone-screw interface of standard uncoated pedicle screws with screws treated with hydroxyapatite (HA), titanium plasma spray (TPS), and a composite HA-TPS coating. SUMMARY OF BACKGROUND DATA: Transpedicular screw fixation has become the gold standard in the treatment of various thoracolumbar spinal conditions. Pedicle screw loosening, however, has been reported, especially in mechanically demanding constructs or in vertebrae with low bone mineral density. METHODS: Six mature porcine were instrumented with 4 types of titanium monoaxial pedicle screws (uncoated, HA-only coated, TPS-only coated, and HA-TPS composite coated) in a systematically varied, single-blinded fashion. After a 3-month survival period, the spines were harvested en-bloc and "time zero" control screws were instrumented in adjacent vertebrae. Screw placement and bone mineral density were evaluated with a postharvest computed tomography, and the strength of the tissue-implant interface was evaluated with a torsional screw extraction analysis (60 screws) and a nondecalcified histologic analysis (16 screws). RESULTS: At 3 months postoperative, peak torque increased for all 3 types of coated screws (increased fixation) and decreased significantly for the uncoated screws (P < 0.001). Although 3-month peak torque was not statistically different between the 3 screw coatings, 4 of 10 TPS-only coated screws had a peak torque that was nearly 0 (<0.1 N m) versus only 1 of 10 HA-only screws and 0 of 10 HA-TPS composite screws. Histologic analysis confirmed the biomechanical findings with improved osseointegration in the HA-only and HA-TPS composite screws. CONCLUSION: Pedicle screw coatings that promote mechanical interlocking, TPS, or direct osteoblast bonding(HA) increased screw fixation in this nonfusion model. More non-HA coated screws, however, were thought to be "loose" with a nearly zero peak extraction torque and fibrous encapsulation. Increased osseointegration with HA may result in a decreased incidence of screw loosening and improved outcomes of transpedicular spinal instrumentation in nonfusion procedures.

Unilateral and bilateral sacropelvic fixation result in similar construct biomechanics.

STUDY DESIGN: In vitro biomechanical investigation of lumbosacropelvic spinal instrumentation. OBJECTIVE: Determine whether unilateral iliac fixation, with or without an L6 to S1 interbody graft, provides equivalent biomechanical stability compared with bilateral iliac fixation. SUMMARY OF BACKGROUND DATA: Recent clinical evidence has shown improved clinical outcomes of unilateral iliac fixation compared with bilateral instrumentation that contradicts biomechanical data supporting bilateral instrumentation, although no specific investigation has compared unilateral versus bilateral instrumentation. METHODS: Sixteen porcine spines were instrumented with bilateral segmental pedicle screws from L1 to S1 and 5.5-mm titanium rods. Spines were randomized to either have an intact L6 to S1 disc space (n = 8/group) or a full discectomy and intervertebral cage at L6 to S1 (n = 8/group). Four reflective noncolinear markers were attached to both L6 and S1. Spines were tested with bilateral ilium, unilateral ilium, and sacrum-only fixation in flexion, extension, lateral bending, and axial torsion between +/-7.0 Nm. L6 to S1 range of motion (degrees) and mechanical stiffness (Nmm/degrees) were compared between groups with a 2-way analysis of variance (P < 0.05). RESULTS: No significant differences were found in construct stiffness or L6 to S1 motion between unilateral or bilateral fixation for any test direction and both demonstrated significantly less L6 to S1 motion compared with sacrum-only fixation for all tests (all P values <0.005). Bilateral fixation was significantly stiffer than sacrum-only fixation in flexion and extension (P < 0.0001). The interbody cage significantly decreased construct stiffness in extension, lateral bending, and axial torsion (P < 0.002), and significantly increased L6 to S1 motion in torsion compared with an intact disc (P < 0.03). CONCLUSION: There were no biomechanical differences between bilateral and unilateral iliac screw fixation. Intervertebral cage with full discectomy was significantly less stiff than intact. This study provides biomechanical data to correlate with improved clinical outcomes using unilateral iliac screw fixation, and evidence contraindicating full discectomy with intervertebral cage placement.

Thoracic vertebral screw impingement on the aorta in an in vivo bovine model.

STUDY DESIGN: A bovine model was used to evaluate the effects of thoracic vertebral screw impingement of the aorta. OBJECTIVES: To evaluate the histologic and biomechanical changes in aortic wall tissue that was severely impinged by abutting instrumentation. SUMMARY OF BACKGROUND DATA: Case reports of vascular injury associated with spinal instrumentation generally describe intraoperative injury; some report delayed presentation of large vessel damage. Risks associated with placing instrumentation adjacent to large vessels are largely unknown. METHODS: Six 1-month-old calves underwent left-sided thoracotomies, exposing the anterior thoracic spine and aorta. With the heads removed, screws were inserted in reverse fashion into T6 through T11, leaving the screw tips 1 cm proud and abutting the aorta. After 3, 6, or 12 months (2 calves each), the spines were resected with the adjacent aorta and underwent radiographic, histologic, and biomechanical testing. RESULTS: Computed tomography revealed varying degrees of vessel impingement. Although there were no frank ruptures, 96% of aortic specimens showed histopathologic changes, including 52% with wall thinning; 43% were no longer impinged, yet 60% of these had increased collagen (scar). Biomechanical testing of screw-impinged aortas demonstrated a lower failure stress (1.2 +/- 0.5 N/mm vs. 1.8 +/- 0.4 N/mm, P = 0.016) but no difference in failure strain (42 +/- 9% vs. 32 +/- 10%, P = 0.06) than controls. CONCLUSIONS: Major impingement of vertebral screws on the aorta caused acute and chronic histopathologic and biomechanical changes in the vessel wall. This model represents a severe form of vessel penetration by a screw that confirms such a "worst case" scenario results in marked compromise of the vessel wall integrity. The sequelae of less severe impingement are unknown.

[Changes in the lengths of the gluteus medius and gluteus minimus muscles with trochanteric transfer following pelvic support osteotomy: a biomechanical study]. / Yeni bir pelvik destek osteotomisinde gluteus medius ve minimus kaslarinda meydana gelen uzunluk degisimlerinin incelenmesi: Biyomekanik çalisma.

OBJECTIVES: Using a synthetic bone model, we investigated changes in the muscle length of the gluteus medius and gluteus minimus following trochanteric osteotomy and pelvic support osteotomy (PSO) and compared the results with those of traditional PSO. METHODS: On two pelvises and four femurs, the lengths of the gluteus medius and gluteus minimus were measured in the following circumstances, with the hips in neutral position and in 45 degrees of flexion: (i) alignment of the hip joint with normal congruency; (ii) dislocated hip joint; (iii) following an osteotomy 2.5 cm below the lesser trochanter and stabilization with an angulation of 45 degrees of abduction; (iv) the insertion point was then moved 2 cm distally and 1 cm laterally, simulating a translation osteotomy of the greater trochanter. RESULTS: The muscle lengths increased with PSO compared to those of the dislocated hips (p<0.0001). Following distal and lateral translation osteotomy, the lengths significantly exceeded those obtained with traditional osteotomy (p<0.002), but were significantly less than those in the neutral position (p<0.001). Measurements in 45 degrees of flexion yielded similar results. Normal lengths could not be obtained in any of the procedures. CONCLUSION: Distal and lateral translation osteotomy following traditional PSO seems to increase the length of the abductor moment arm more than that obtained by traditional PSO alone.