The Neural Representation of Force across Grasp Types in Motor Cortex of Humans with Tetraplegia.

Intracortical brain-computer interfaces (iBCIs) have the potential to restore hand grasping and object interaction to individuals with tetraplegia. Optimal grasping and object interaction require simultaneous production of both force and grasp outputs. However, since overlapping neural populations are modulated by both parameters, grasp type could affect how well forces are decoded from motor cortex in a closed-loop force iBCI. Therefore, this work quantified the neural representation and offline decoding performance of discrete hand grasps and force levels in two human participants with tetraplegia. Participants attempted to produce three discrete forces (light, medium, hard) using up to five hand grasp configurations. A two-way Welch ANOVA was implemented on multiunit neural features to assess their modulation to force and grasp Demixed principal component analysis (dPCA) was used to assess for population-level tuning to force and grasp and to predict these parameters from neural activity. Three major findings emerged from this work: (1) force information was neurally represented and could be decoded across multiple hand grasps (and, in one participant, across attempted elbow extension as well); (2) grasp type affected force representation within multiunit neural features and offline force classification accuracy; and (3) grasp was classified more accurately and had greater population-level representation than force. These findings suggest that force and grasp have both independent and interacting representations within cortex, and that incorporating force control into real-time iBCI systems is feasible across multiple hand grasps if the decoder also accounts for grasp type.

Neural Representation of Observed, Imagined, and Attempted Grasping Force in Motor Cortex of Individuals with Chronic Tetraplegia.

Hybrid kinetic and kinematic intracortical brain-computer interfaces (iBCIs) have the potential to restore functional grasping and object interaction capabilities in individuals with tetraplegia. This requires an understanding of how kinetic information is represented in neural activity, and how this representation is affected by non-motor parameters such as volitional state (VoS), namely, whether one observes, imagines, or attempts an action. To this end, this work investigates how motor cortical neural activity changes when three human participants with tetraplegia observe, imagine, and attempt to produce three discrete hand grasping forces with the dominant hand. We show that force representation follows the same VoS-related trends as previously shown for directional arm movements; namely, that attempted force production recruits more neural activity compared to observed or imagined force production. Additionally, VoS-modulated neural activity to a greater extent than grasping force. Neural representation of forces was lower than expected, possibly due to compromised somatosensory pathways in individuals with tetraplegia, which have been shown to influence motor cortical activity. Nevertheless, attempted forces (but not always observed or imagined forces) could be decoded significantly above chance, thereby potentially providing relevant information towards the development of a hybrid kinetic and kinematic iBCI.

Neural ensemble dynamics in dorsal motor cortex during speech in people with paralysis.

Speaking is a sensorimotor behavior whose neural basis is difficult to study with single neuron resolution due to the scarcity of human intracortical measurements. We used electrode arrays to record from the motor cortex 'hand knob' in two people with tetraplegia, an area not previously implicated in speech. Neurons modulated during speaking and during non-speaking movements of the tongue, lips, and jaw. This challenges whether the conventional model of a 'motor homunculus' division by major body regions extends to the single-neuron scale. Spoken words and syllables could be decoded from single trials, demonstrating the potential of intracortical recordings for brain-computer interfaces to restore speech. Two neural population dynamics features previously reported for arm movements were also present during speaking: a component that was mostly invariant across initiating different words, followed by rotatory dynamics during speaking. This suggests that common neural dynamical motifs may underlie movement of arm and speech articulators.

Principled BCI Decoder Design and Parameter Selection Using a Feedback Control Model.

Decoders optimized offline to reconstruct intended movements from neural recordings sometimes fail to achieve optimal performance online when they are used in closed-loop as part of an intracortical brain-computer interface (iBCI). This is because typical decoder calibration routines do not model the emergent interactions between the decoder, the user, and the task parameters (e.g. target size). Here, we investigated the feasibility of simulating online performance to better guide decoder parameter selection and design. Three participants in the BrainGate2 pilot clinical trial controlled a computer cursor using a linear velocity decoder under different gain (speed scaling) and temporal smoothing parameters and acquired targets with different radii and distances. We show that a user-specific iBCI feedback control model can predict how performance changes under these different decoder and task parameters in held-out data. We also used the model to optimize a nonlinear speed scaling function for the decoder. When used online with two participants, it increased the dynamic range of decoded speeds and decreased the time taken to acquire targets (compared to an optimized standard decoder). These results suggest that it is feasible to simulate iBCI performance accurately enough to be useful for quantitative decoder optimization and design.

A Comparison of Intention Estimation Methods for Decoder Calibration in Intracortical Brain-Computer Interfaces.

OBJECTIVE: Recent reports indicate that making better assumptions about the user's intended movement can improve the accuracy of decoder calibration for intracortical brain-computer interfaces. Several methods now exist for estimating user intent, including an optimal feedback control model, a piecewise-linear feedback control model, ReFIT, and other heuristics. Which of these methods yields the best decoding performance? METHODS: Using data from the BrainGate2 pilot clinical trial, we measured how a steady-state velocity Kalman filter decoder was affected by the choice of intention estimation method. We examined three separate components of the Kalman filter: dimensionality reduction, temporal smoothing, and output gain (speed scaling). RESULTS: The decoder's dimensionality reduction properties were largely unaffected by the intention estimation method. Decoded velocity vectors differed by <5% in terms of angular error and speed vs. target distance curves across methods. In contrast, the smoothing and gain properties of the decoder were greatly affected (> 50% difference in average values). Since the optimal gain and smoothing properties are task-specific (e.g. lower gains are better for smaller targets but worse for larger targets), no one method was better for all tasks. CONCLUSION: Our results show that, when gain and smoothing differences are accounted for, current intention estimation methods yield nearly equivalent decoders and that simple models of user intent, such as a position error vector (target position minus cursor position), perform comparably to more elaborate models. Our results also highlight that simple differences in gain and smoothing properties have a large effect on online performance and can confound decoder comparisons.

Rapid calibration of an intracortical brain-computer interface for people with tetraplegia.

OBJECTIVE: Brain-computer interfaces (BCIs) can enable individuals with tetraplegia to communicate and control external devices. Though much progress has been made in improving the speed and robustness of neural control provided by intracortical BCIs, little research has been devoted to minimizing the amount of time spent on decoder calibration. APPROACH: We investigated the amount of time users needed to calibrate decoders and achieve performance saturation using two markedly different decoding algorithms: the steady-state Kalman filter, and a novel technique using Gaussian process regression (GP-DKF). MAIN RESULTS: Three people with tetraplegia gained rapid closed-loop neural cursor control and peak, plateaued decoder performance within 3 min of initializing calibration. We also show that a BCI-naïve user (T5) was able to rapidly attain closed-loop neural cursor control with the GP-DKF using self-selected movement imagery on his first-ever day of closed-loop BCI use, acquiring a target 37 s after initiating calibration. SIGNIFICANCE: These results demonstrate the potential for an intracortical BCI to be used immediately after deployment by people with paralysis, without the need for user learning or extensive system calibration.

Restoration of reaching and grasping movements through brain-controlled muscle stimulation in a person with tetraplegia: a proof-of-concept demonstration.

BACKGROUND: People with chronic tetraplegia, due to high-cervical spinal cord injury, can regain limb movements through coordinated electrical stimulation of peripheral muscles and nerves, known as functional electrical stimulation (FES). Users typically command FES systems through other preserved, but unrelated and limited in number, volitional movements (eg, facial muscle activity, head movements, shoulder shrugs). We report the findings of an individual with traumatic high-cervical spinal cord injury who coordinated reaching and grasping movements using his own paralysed arm and hand, reanimated through implanted FES, and commanded using his own cortical signals through an intracortical brain-computer interface (iBCI). METHODS: We recruited a participant into the BrainGate2 clinical trial, an ongoing study that obtains safety information regarding an intracortical neural interface device, and investigates the feasibility of people with tetraplegia controlling assistive devices using their cortical signals. Surgical procedures were performed at University Hospitals Cleveland Medical Center (Cleveland, OH, USA). Study procedures and data analyses were performed at Case Western Reserve University (Cleveland, OH, USA) and the US Department of Veterans Affairs, Louis Stokes Cleveland Veterans Affairs Medical Center (Cleveland, OH, USA). The study participant was a 53-year-old man with a spinal cord injury (cervical level 4, American Spinal Injury Association Impairment Scale category A). He received two intracortical microelectrode arrays in the hand area of his motor cortex, and 4 months and 9 months later received a total of 36 implanted percutaneous electrodes in his right upper and lower arm to electrically stimulate his hand, elbow, and shoulder muscles. The participant used a motorised mobile arm support for gravitational assistance and to provide humeral abduction and adduction under cortical control. We assessed the participant's ability to cortically command his paralysed arm to perform simple single-joint arm and hand movements and functionally meaningful multi-joint movements. We compared iBCI control of his paralysed arm with that of a virtual three-dimensional arm. This study is registered with ClinicalTrials.gov, number NCT00912041. FINDINGS: The intracortical implant occurred on Dec 1, 2014, and we are continuing to study the participant. The last session included in this report was Nov 7, 2016. The point-to-point target acquisition sessions began on Oct 8, 2015 (311 days after implant). The participant successfully cortically commanded single-joint and coordinated multi-joint arm movements for point-to-point target acquisitions (80-100% accuracy), using first a virtual arm and second his own arm animated by FES. Using his paralysed arm, the participant volitionally performed self-paced reaches to drink a mug of coffee (successfully completing 11 of 12 attempts within a single session 463 days after implant) and feed himself (717 days after implant). INTERPRETATION: To our knowledge, this is the first report of a combined implanted FES+iBCI neuroprosthesis for restoring both reaching and grasping movements to people with chronic tetraplegia due to spinal cord injury, and represents a major advance, with a clear translational path, for clinically viable neuroprostheses for restoration of reaching and grasping after paralysis. FUNDING: National Institutes of Health, Department of Veterans Affairs.

Signal-independent noise in intracortical brain-computer interfaces causes movement time properties inconsistent with Fitts' law.

OBJECTIVE: Do movements made with an intracortical BCI (iBCI) have the same movement time properties as able-bodied movements? Able-bodied movement times typically obey Fitts' law: [Formula: see text] (where MT is movement time, D is target distance, R is target radius, and [Formula: see text] are parameters). Fitts' law expresses two properties of natural movement that would be ideal for iBCIs to restore: (1) that movement times are insensitive to the absolute scale of the task (since movement time depends only on the ratio [Formula: see text]) and (2) that movements have a large dynamic range of accuracy (since movement time is logarithmically proportional to [Formula: see text]). APPROACH: Two participants in the BrainGate2 pilot clinical trial made cortically controlled cursor movements with a linear velocity decoder and acquired targets by dwelling on them. We investigated whether the movement times were well described by Fitts' law. MAIN RESULTS: We found that movement times were better described by the equation [Formula: see text], which captures how movement time increases sharply as the target radius becomes smaller, independently of distance. In contrast to able-bodied movements, the iBCI movements we studied had a low dynamic range of accuracy (absence of logarithmic proportionality) and were sensitive to the absolute scale of the task (small targets had long movement times regardless of the [Formula: see text] ratio). We argue that this relationship emerges due to noise in the decoder output whose magnitude is largely independent of the user's motor command (signal-independent noise). Signal-independent noise creates a baseline level of variability that cannot be decreased by trying to move slowly or hold still, making targets below a certain size very hard to acquire with a standard decoder. SIGNIFICANCE: The results give new insight into how iBCI movements currently differ from able-bodied movements and suggest that restoring a Fitts' law-like relationship to iBCI movements may require non-linear decoding strategies.

Feedback control policies employed by people using intracortical brain-computer interfaces.

OBJECTIVE: When using an intracortical BCI (iBCI), users modulate their neural population activity to move an effector towards a target, stop accurately, and correct for movement errors. We call the rules that govern this modulation a 'feedback control policy'. A better understanding of these policies may inform the design of higher-performing neural decoders. APPROACH: We studied how three participants in the BrainGate2 pilot clinical trial used an iBCI to control a cursor in a 2D target acquisition task. Participants used a velocity decoder with exponential smoothing dynamics. Through offline analyses, we characterized the users' feedback control policies by modeling their neural activity as a function of cursor state and target position. We also tested whether users could adapt their policy to different decoder dynamics by varying the gain (speed scaling) and temporal smoothing parameters of the iBCI. MAIN RESULTS: We demonstrate that control policy assumptions made in previous studies do not fully describe the policies of our participants. To account for these discrepancies, we propose a new model that captures (1) how the user's neural population activity gradually declines as the cursor approaches the target from afar, then decreases more sharply as the cursor comes into contact with the target, (2) how the user makes constant feedback corrections even when the cursor is on top of the target, and (3) how the user actively accounts for the cursor's current velocity to avoid overshooting the target. Further, we show that users can adapt their control policy to decoder dynamics by attenuating neural modulation when the cursor gain is high and by damping the cursor velocity more strongly when the smoothing dynamics are high. SIGNIFICANCE: Our control policy model may help to build better decoders, understand how neural activity varies during active iBCI control, and produce better simulations of closed-loop iBCI movements.

Contributions of Subsurface Cortical Modulations to Discrimination of Executed and Imagined Grasp Forces through Stereoelectroencephalography.

Stereoelectroencephalographic (SEEG) depth electrodes have the potential to record neural activity from deep brain structures not easily reached with other intracranial recording technologies. SEEG electrodes were placed through deep cortical structures including central sulcus and insular cortex. In order to observe changes in frequency band modulation, participants performed force matching trials at three distinct force levels using two different grasp configurations: a power grasp and a lateral pinch. Signals from these deeper structures were found to contain information useful for distinguishing force from rest trials as well as different force levels in some participants. High frequency components along with alpha and beta bands recorded from electrodes located near the primary motor cortex wall of central sulcus and electrodes passing through sensory cortex were found to be the most useful for classification of force versus rest although one participant did have significant modulation in the insular cortex. This study electrophysiologically corroborates with previous imaging studies that show force-related modulation occurs inside of central sulcus and insular cortex. The results of this work suggest that depth electrodes could be useful tools for investigating the functions of deeper brain structures as well as showing that central sulcus and insular cortex may contain neural signals that could be used for control of a grasp force BMI.

Bilateral Continuous Automated Distraction Osteogenesis: Proof of Principle.

The purpose of this study was to demonstrate that automated, continuous, curvilinear distraction osteogenesis (DO) in a minipig model is effective when performed bilaterally, at rates up to 3 mm/day, to achieve clinically relevant lengthening. A Yucatan minipig in the mixed dentition phase underwent bilaterally, at a continuous DO at a rate of 2 mm/day at the center of rotation; 1.0 and 3.0 mm/day at the superior and inferior regions, respectively. The distraction period was 13 days with no latency period. Vector and rate of distraction were remotely monitored without radiographs, using the device sensor. After fixation and euthanasia, the mandible and digastric muscles were harvested. The ex vivo appearance, stability, and radiodensity of the regenerate were evaluated using a semiquantitative scale. Percent surface area (PSA) occupied by bone, fibrous tissue, cartilage, and hematoma were calculated using histomorphometrics. The effects of DO on the digastric muscles and mandibular condyles were assessed via microscopy, and degenerative changes were quantified. The animal was distracted to 21 mm and 24 mm on the right and left sides, respectively. Clinical appearance, stability, and radiodensity were scored as "3" bilaterally indicating osseous union. The total PSA occupied by bone (right = 75.53 ±â€Š2.19%; left PSA = 73.11 ±â€Š2.18%) approached that of an unoperated mandible (84.67 ±â€Š0.86%). Digastric muscles and condyles showed negligible degenerative or abnormal histologic changes. This proof of principle study is the first report of osseous healing with no ill-effect on associated soft tissue and the mandibular condyle using bilateral, automated, continuous, and curvilinear DO at rates up to 3 mm/day. The model approximates potential human application of continuous automated distraction with a semiburied device.

Assessment of the OsteoMark-Navigation System for Oral and Maxillofacial Surgery.

PURPOSE: To assess the accuracy of a novel navigation system for maxillofacial surgery using human cadavers and a live minipig model. MATERIALS AND METHODS: We tested an electromagnetic tracking system (OsteoMark-Navigation) that uses simple sensors to determine the position and orientation of a hand-held pencil-like marking device. The device can translate 3-dimensional computed tomographic data intraoperatively to allow the surgeon to localize and draw a proposed osteotomy or the resection margins of a tumor on bone. The accuracy of the OsteoMark-Navigation system in locating and marking osteotomies and screw positions in human cadaver heads was assessed. In group 1 (n = 3, 6 sides), OsteoMark-Navigation marked osteotomies and screw positions were compared to virtual treatment plans. In group 2 (n = 3, 6 sides), marked osteotomies and screw positions for distraction osteogenesis devices were compared with those performed using fabricated guide stents. Three metrics were used to document the precision and accuracy. In group 3 (n = 1), the system was tested in a standard operating room environment. RESULTS: For group 1, the mean error between the points was 0.7 mm (horizontal) and 1.7 mm (vertical). Compared with the posterior and inferior mandibular border, the mean error was 1.2 and 1.7 mm, respectively. For group 2, the mean discrepancy between the points marked using the OsteoMark-Navigation system and the surgical guides was 1.9 mm (range 0 to 4.1). The system maintained accuracy on a live minipig in a standard operating room environment. CONCLUSION: Based on this research OsteoMark-Navigation is a potentially powerful tool for clinical use in maxillofacial surgery. It has accuracy and precision comparable to that of existing clinical applications.

Skeletal and soft tissue response to automated, continuous, curvilinear distraction osteogenesis.

PURPOSE: To document the bone formation and soft tissue changes in response to automated, continuous, curvilinear distraction osteogenesis (DO) at rates greater than 1 mm/day in a minipig model. MATERIALS AND METHODS: Two groups of Yucatan minipigs underwent automated, continuous, curvilinear DO of the right mandible: group A, 1.5 mm/day (n = 5); and group B, 3.0 mm/day (n = 5). Each minipig underwent 12 mm of distraction followed by 24 days of fixation. The distracted and contralateral mandibles were harvested at the end of fixation. The percentage of surface area (PSA) of the regenerate occupied by bone, fibrous tissue, cartilage, and hematoma was determined using computerized histomorphometric analysis. The control groups consisted of DO wounds distracted discontinuously at 1 mm/day and the nonoperated contralateral mandible. The ipsilateral and contralateral digastric muscles were harvested and stained for proliferating cell nuclear antigen (PCNA), myogenic differentiation-1 (MyoD), and paired Box 7 protein (PAX7). RESULTS: All 10 minipigs completed the distraction and fixation period. The PSA occupied by bone was similar for groups A (PSA 64.36% ± 5.87%) and B (PSA 63.83% ± 3.37%) and the control group (1 mm/day; PSA 64.89% ± 0.56%) but was less than that on the nonoperated side (PSA 84.67% ± 0.86%). The PSA occupied by cartilage and hematoma in all groups was minimal (<1.1%). The digastric muscles had no abnormal tissue or inflammation, and PAX7, MyoD, and PCNA expression had returned to the baseline levels. CONCLUSIONS: The results of the present study indicate that bone formation in response to automated, continuous, and curvilinear DO at a rate of 1.5 and 3.0 mm/day is nearly identical to that with discontinuous DO at 1 mm/day. In addition, no deleterious effects were found on the digastric muscles.

Automated continuous distraction osteogenesis may allow faster distraction rates: a preliminary study.

PURPOSE: To determine if automated continuous distraction osteogenesis (DO) at rates faster than 1 mm/day results in bone formation by clinical and radiographic criteria, in a minipig model. MATERIALS AND METHODS: An automated, continuous, curvilinear distraction device was placed across a mandibular osteotomy in 10 minipigs. After 12 mm of distraction and 24 days of fixation, the animals were sacrificed and bone healing was evaluated. The continuous distraction rates were 1.5 mm/day (n = 5) and 3 mm/day (n = 5). A semiquantitative scale was used to assess the ex vivo clinical appearance of the distraction gap (3 = osteotomy not visible; 2 = <50% visible; 1 = >50% visible; 0 = 100% visible), stability (3 = no mobility; 2 and 1 = mobility in 1 plane or 2 planes, respectively; 0 = mobility in 3 planes), and radiographic density (4 = 100% of gap opaque; 3 = >75%; 2 = 50% to 75%; 1 = <50%; 0 = radiolucent). Groups of 4 minipigs distracted discontinuously at 1, 2, and 4 mm/day served as controls. RESULTS: Automated, continuous DO at 1.5-mm/day and 3-mm/day had similar bone formation compared to discontinuous DO at 1-mm/day. The continuous DO 1.5-mm/day group had significantly higher scores for appearance and radiographic density compared with the discontinuous 4-mm/day group. The continuous DO 3-mm/day group had significantly higher scores for appearance and radiographic density compared with the discontinuous 4-mm/day group and greater stability compared with the discontinuous 2- and 4-mm/day groups. CONCLUSIONS: Results of this preliminary study indicate that continuous DO at rates of 1.5 and 3.0 mm/day produces better bone formation compared with discontinuous DO at rates faster than 1 mm/day.

Mastoid cavity dimensions and shape: method of measurement and virtual fitting of implantable devices.

Temporal bone implants can be used to electrically stimulate the auditory nerve, to amplify sound, to deliver drugs to the inner ear and potentially for other future applications. The implants require storage space and access to the middle or inner ears. The most acceptable space is the cavity created by a canal wall up mastoidectomy. Detailed knowledge of the available space for implantation and pathways to access the middle and inner ears is necessary for the design of implants and successful implantation. Based on temporal bone CT scans a method for three-dimensional reconstruction of a virtual canal wall up mastoidectomy space is described. Using Amira software the area to be removed during such surgery is marked on axial CT slices, and a three-dimensional model of that space is created. The average volume of 31 reconstructed models is 12.6 cm(3) with standard deviation of 3.69 cm(3), ranging from 7.97 to 23.25 cm(3). Critical distances were measured directly from the model and their averages were calculated: height 3.69 cm, depth 2.43 cm, length above the external auditory canal (EAC) 4.45 cm and length posterior to EAC 3.16 cm. These linear measurements did not correlate well with volume measurements. The shape of the models was variable to a significant extent making the prediction of successful implantation for a given design based on linear and volumetric measurement unreliable. Hence, to assure successful implantation, preoperative assessment should include a virtual fitting of an implant into the intended storage space. The above-mentioned three-dimensional models were exported from Amira to a Solidworks application where virtual fitting was performed. Our results are compared to other temporal bone implant virtual fitting studies. Virtual fitting has been suggested for other human applications.

Zone I flexor tendon injuries.

Zone I flexor tendon injuries entail injuries to the flexor digitorum profundus (FDP) tendon. These injuries occur distal to the superficialis insertion over the middle phalanx or proximal distal phalanx, and as such are isolated injuries to the FDP. The mechanism most commonly is closed avulsion from the distal phalanx or a laceration, but other mechanisms such as open avulsion or crush injury can occur. On physical examination, the cascade of the fingers will be disrupted, and distal interphalangeal (DIP) joint flexion must be isolated to determine if the FDP tendon is continuous, as other mechanisms are present to enable finger flexion at the other joints.

Tissue-specific effect of estradiol on endothelial cell-dependent lymphocyte recruitment.

Estrogen profoundly affects onset and severity of many immune-mediated diseases. In our murine model of drug-induced autoimmunity, female-specific, estrogen-dependent increase in splenic lymphocyte homing was directly implicated in increased disease severity. The present study evaluated the effect of estradiol on microvascular endothelial cells from the spleen compared to endothelial cells from the dermis, which has no disease manifestation in this model. Estradiol increased spleen endothelial cell estrogen receptor (ER) alpha 2.9-fold and decreased estrogen receptor beta 2.1-fold while decreasing both receptors on dermal cells. Estradiol enhanced adhesion of D10 cells to spleen but not dermal endothelial cells 1.53-fold (P < 0.001), an increase that was inhibited by antibodies to VCAM-1 and ICAM-1, and by the estrogen receptor antagonists tamoxifen and ICI 182,780. Estradiol induced greater VCAM-1 expression on spleen than dermal endothelial cells (P < 0.05). Estradiol increased spleen endothelial cell estrogen receptor alpha 2.9-fold and decreased estrogen receptor beta 2.1-fold while decreasing both receptors on the dermal cells. Estrogen specifically and preferentially promoted spleen chemokine protein expression for MCP-1 and MCP-3, while having no effect on dermal protein expression for these chemokines. Estradiol-mediated effects on splenic chemokines were abrogated by tamoxifen and ICI 182,780. The gender-specific increase in lymphocyte homing to spleen may be attributable, at least in part, to tissue-specific estrogen-mediated effects on microvascular endothelial cells.