Closed-loop stimulation in periods with less epileptiform activity drives improved epilepsy outcomes.

In patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. This therapy, known as closed-loop responsive neurostimulation (RNS), aims to directly halt seizure activity via targeted stimulation of a burgeoning seizure. Rather than immediately stopping seizures as they start, many RNS implants produce slower, long-lasting changes in brain dynamics that better predict clinical outcomes. Here we hypothesize that stimulation during brain states with less epileptiform activity drives long-term changes that restore healthy brain networks. To test this, we quantified stimulation episodes during low- and high-risk brain states-that is, stimulation during periods with a lower or higher risk of generating epileptiform activity-in a cohort of 40 patients treated with RNS. More frequent stimulation in tonic low-risk states and out of rhythmic high-risk states predicted seizure reduction. Additionally, stimulation events were more likely to be phase-locked to prolonged episodes of abnormal activity for intermediate and poor responders when compared to super-responders, consistent with the hypothesis that improved outcomes are driven by stimulation during low-risk states. These results support the hypothesis that stimulation during low-risk periods might underlie the mechanisms of RNS, suggesting a relationship between temporal patterns of neuromodulation and plasticity that facilitates long-term seizure reduction.

Circadian changes in aperiodic activity are correlated with seizure reduction in patients with mesial temporal lobe epilepsy treated with responsive neurostimulation.

OBJECTIVES: Responsive neurostimulation (RNS) is an established therapy for drug-resistant epilepsy that delivers direct electrical brain stimulation in response to detected epileptiform activity. However, despite an overall reduction in seizure frequency, clinical outcomes are variable, and few patients become seizure-free. The aim of this retrospective study was to evaluate aperiodic electrophysiological activity, associated with excitation/inhibition balance, as a novel electrographic biomarker of seizure reduction to aid early prognostication of the clinical response to RNS. METHODS: We identified patients with intractable mesial temporal lobe epilepsy who were implanted with the RNS System between 2015 and 2021 at the University of Utah. We parameterized the neural power spectra from intracranial RNS System recordings during the first 3 months following implantation into aperiodic and periodic components. We then correlated circadian changes in aperiodic and periodic parameters of baseline neural recordings with seizure reduction at the most recent follow-up. RESULTS: Seizure reduction was correlated significantly with a patient's average change in the day/night aperiodic exponent (r = .50, p = .016, n = 23 patients) and oscillatory alpha power (r = .45, p = .042, n = 23 patients) across patients for baseline neural recordings. The aperiodic exponent reached its maximum during nighttime hours (12 a.m. to 6 a.m.) for most responders (i.e., patients with at least a 50% reduction in seizures). SIGNIFICANCE: These findings suggest that circadian modulation of baseline broadband activity is a biomarker of response to RNS early during therapy. This marker has the potential to identify patients who are likely to respond to mesial temporal RNS. Furthermore, we propose that less day/night modulation of the aperiodic exponent may be related to dysfunction in excitation/inhibition balance and its interconnected role in epilepsy, sleep, and memory.

Patient-specific structural connectivity informs outcomes of responsive neurostimulation for temporal lobe epilepsy.

OBJECTIVE: Responsive neurostimulation is an effective therapy for patients with refractory mesial temporal lobe epilepsy. However, clinical outcomes are variable, few patients become seizure-free, and the optimal stimulation location is currently undefined. The aim of this study was to quantify responsive neurostimulation in the mesial temporal lobe, identify stimulation-dependent networks associated with seizure reduction, and determine if stimulation location or stimulation-dependent networks inform outcomes. METHODS: We modeled patient-specific volumes of tissue activated and created probabilistic stimulation maps of local regions of stimulation across a retrospective cohort of 22 patients with mesial temporal lobe epilepsy. We then mapped the network stimulation effects by seeding tractography from the volume of tissue activated with both patient-specific and normative diffusion-weighted imaging. We identified networks associated with seizure reduction across patients using the patient-specific tractography maps and then predicted seizure reduction across the cohort. RESULTS: Patient-specific stimulation-dependent connectivity was correlated with responsive neurostimulation effectiveness after cross-validation (p = .03); however, normative connectivity derived from healthy subjects was not (p = .44). Increased connectivity from the volume of tissue activated to the medial prefrontal cortex, cingulate cortex, and precuneus was associated with greater seizure reduction. SIGNIFICANCE: Overall, our results suggest that the therapeutic effect of responsive neurostimulation may be mediated by specific networks connected to the volume of tissue activated. In addition, patient-specific tractography was required to identify structural networks correlated with outcomes. It is therefore likely that altered connectivity in patients with epilepsy may be associated with the therapeutic effect and that utilizing patient-specific imaging could be important for future studies. The structural networks identified here may be utilized to target stimulation in the mesial temporal lobe and to improve seizure reduction for patients treated with responsive neurostimulation.

Discriminability of multiple cutaneous and proprioceptive hand percepts evoked by intraneural stimulation with Utah slanted electrode arrays in human amputees.

BACKGROUND: Electrical stimulation of residual afferent nerve fibers can evoke sensations from a missing limb after amputation, and bionic arms endowed with artificial sensory feedback have been shown to confer functional and psychological benefits. Here we explore the extent to which artificial sensations can be discriminated based on location, quality, and intensity. METHODS: We implanted Utah Slanted Electrode Arrays (USEAs) in the arm nerves of three transradial amputees and delivered electrical stimulation via different electrodes and frequencies to produce sensations on the missing hand with various locations, qualities, and intensities. Participants performed blind discrimination trials to discriminate among these artificial sensations. RESULTS: Participants successfully discriminated cutaneous and proprioceptive sensations ranging in location, quality and intensity. Performance was significantly greater than chance for all discrimination tasks, including discrimination among up to ten different cutaneous location-intensity combinations (15/30 successes, p < 0.0001) and seven different proprioceptive location-intensity combinations (21/40 successes, p < 0.0001). Variations in the site of stimulation within the nerve, via electrode selection, enabled discrimination among up to five locations and qualities (35/35 successes, p < 0.0001). Variations in the stimulation frequency enabled discrimination among four different intensities at the same location (13/20 successes, p < 0.0005). One participant also discriminated among individual stimulation of two different USEA electrodes, simultaneous stimulation on both electrodes, and interleaved stimulation on both electrodes (20/24 successes, p < 0.0001). CONCLUSION: Electrode location, stimulation frequency, and stimulation pattern can be modulated to evoke functionally discriminable sensations with a range of locations, qualities, and intensities. This rich source of artificial sensory feedback may enhance functional performance and embodiment of bionic arms endowed with a sense of touch.

Activities of daily living with bionic arm improved by combination training and latching filter in prosthesis control comparison.

BACKGROUND: Advanced prostheses can restore function and improve quality of life for individuals with amputations. Unfortunately, most commercial control strategies do not fully utilize the rich control information from residual nerves and musculature. Continuous decoders can provide more intuitive prosthesis control using multi-channel neural or electromyographic recordings. Three components influence continuous decoder performance: the data used to train the algorithm, the algorithm, and smoothing filters on the algorithm's output. Individual groups often focus on a single decoder, so very few studies compare different decoders using otherwise similar experimental conditions. METHODS: We completed a two-phase, head-to-head comparison of 12 continuous decoders using activities of daily living. In phase one, we compared two training types and a smoothing filter with three algorithms (modified Kalman filter, multi-layer perceptron, and convolutional neural network) in a clothespin relocation task. We compared training types that included only individual digit and wrist movements vs. combination movements (e.g., simultaneous grasp and wrist flexion). We also compared raw vs. nonlinearly smoothed algorithm outputs. In phase two, we compared the three algorithms in fragile egg, zipping, pouring, and folding tasks using the combination training and smoothing found beneficial in phase one. In both phases, we collected objective, performance-based (e.g., success rate), and subjective, user-focused (e.g., preference) measures. RESULTS: Phase one showed that combination training improved prosthesis control accuracy and speed, and that the nonlinear smoothing improved accuracy but generally reduced speed. Phase one importantly showed simultaneous movements were used in the task, and that the modified Kalman filter and multi-layer perceptron predicted more simultaneous movements than the convolutional neural network. In phase two, user-focused metrics favored the convolutional neural network and modified Kalman filter, whereas performance-based metrics were generally similar among all algorithms. CONCLUSIONS: These results confirm that state-of-the-art algorithms, whether linear or nonlinear in nature, functionally benefit from training on more complex data and from output smoothing. These studies will be used to select a decoder for a long-term take-home trial with implanted neuromyoelectric devices. Overall, clinical considerations may favor the mKF as it is similar in performance, faster to train, and computationally less expensive than neural networks.

Selective Decrease in Allodynia With High-Frequency Neuromodulation via High-Electrode-Count Intrafascicular Peripheral Nerve Interface After Brachial Plexus Injury.

OBJECTIVES: Kilohertz high-frequency alternating current (KHFAC) electrical nerve stimulation produces a reversible nerve block in peripheral nerves in human patients with chronic pain pathologies. Although this stimulation methodology has been verified with nonselective extrafascicular electrodes, the effectiveness of producing a selective nerve block with more-selective intrafascicular electrodes has not been well documented. The objective of this study was to examine whether intrafascicular electrodes can block painful stimuli while preserving conduction of other neural activity within the implanted nerve. MATERIALS AND METHODS: We analyzed the effects of various stimulation waveforms delivered through Utah Slanted Electrode Arrays (USEAs) implanted in the median nerve of a male human subject with a left brachial plexus injury. We compared KHFAC stimulation with a sham control. RESULTS: KHFAC stimulation through USEA electrodes produced a reduction in pain sensitivity in the palmar aspect of the left middle finger. KHFAC had limited effects on the patient's ability to feel tactile probing in the same area or move the digits of his left hand. Other tested stimulation parameters either increased or showed no reduction in pain. CONCLUSIONS: KHFAC stimulation in peripheral nerves through intrafascicular electrodes demonstrated a selective reduction in pain sensitivity while preserving other nerve functions. This treatment may benefit patient populations who have chronic pain originating from peripheral nerves, but who do not want to block whole-nerve function in order to preserve sensory and motor function reliant on the implanted nerve. Furthermore, KHFAC may benefit patients who respond negatively to other forms of peripheral nerve stimulation therapy.

Interictal discharge traveling waves recorded from stereoelectroencephalography electrodes.

OBJECTIVE: Interictal epileptiform discharges (IEDs) are intermittent high-amplitude electrical signals that occur between seizures. They have been shown to propagate through the brain as traveling waves when recorded with epicortical grid-type electrodes and small penetrating microelectrode arrays. However, little work has been done to translate experimental IED analyses to more clinically relevant platforms such as stereoelectroencephalography (SEEG). In this pilot study, the authors aimed to define a computational method to identify and characterize IEDs recorded from clinical SEEG electrodes and leverage the directionality of IED traveling waves to localize the seizure onset zone (SOZ). METHODS: Continuous SEEG recordings from 15 patients with medically refractory epilepsy were collected, and IEDs were detected by identifying overlapping peaks of a minimum prominence. IED pathways of propagation were defined and compared to the SOZ location determined by a clinical neurologist based on the ictal recordings. For further analysis of the IED pathways of propagation, IED detections were divided into triplets, defined as a set of 3 consecutive contacts within the same IED detection. Univariate and multivariate linear regression models were employed to associate IED characteristics with colocalization to the SOZ. RESULTS: A median (range) of 22.6 (4.4-183.9) IEDs were detected per hour from 15 patients over a mean of 23.2 hours of recording. Depending on the definition of the SOZ, a median (range) of 20.8% (0.0%-54.5%) to 62.1% (19.2%-99.4%) of IEDs per patient traversed the SOZ. IEDs passing through the SOZ followed discrete pathways that had little overlap with those of the IEDs passing outside the SOZ. Contact triplets that occurred more than once were significantly more likely to be detected in an IED passing through the SOZ (p < 0.001). Per our multivariate model, patients with a greater proportion of IED traveling waves had a significantly greater proportion of IEDs that localized to the SOZ (ß = 0.64, 95% CI 0.01-1.27, p = 0.045). CONCLUSIONS: By using computational methods, IEDs can be meaningfully detected from clinical-grade SEEG recordings of patients with epilepsy. In some patients, a high proportion of IEDs are traveling waves according to multiple metrics that colocalize to the SOZ, offering hope that IED detection, with further refinement, could serve as an alternative method for SOZ localization.

A novel thermoelectric device integrated with a psychophysical paradigm to study pain processing in human subjects.

INTRODUCTION: Cerebral projections of nociceptive stimuli are of great interest as targets for neuromodulation in chronic pain. To study cerebral networks involved in processing noxious stimuli, researchers often rely on thermo-nociception to induce pain. However, various limitations exist in many pain-inducing techniques, such as not accounting for individual variations in pain and trial structure predictability. METHODS: We propose an improved and reliable psychometric experimental method to evaluate human nociceptive processing to overcome some of these limitations. The developed testing paradigm leverages a custom-built, open-source, thermoelectric device (TED). The device construction and hardware are described. A maximum-likelihood adaptive algorithm is integrated into the TED software, facilitating individual psychometric functions representative of both hot and cold pain perception. In addition to testing only hot or cold thresholds, the TED may also be used to induce the thermal grill illusion (TGI), where the bars are set to alternating warm and cool temperatures. RESULTS: Here, we validated the TED's capability to adjust between different temperatures and showed that the device quickly and automatically changes temperature without any experimenter input. We also validated the device and integrated psychometric pain task in 21 healthy human subjects. Hot and cold pain thresholds (HPT, CPT) were determined in human subjects with <1 °C of variation. Thresholds were anticorrelated, meaning a volunteer with a low CPT likely had a high HPT. We also showed how the TED can be used to induce the TGI. CONCLUSION: The TED can induce thermo-nociception and provide probabilistic measures of hot and cold pain thresholds. Based on the findings presented, we discuss how the TED could be used to study thermo-nociceptive cerebral projections if paired with intracranial electrode monitoring.

Characterization of spatiotemporal dynamics of binary and graded tonic pain in humans using intracranial recordings.

Pain is a complex experience involving sensory, emotional, and cognitive aspects, and multiple networks manage its processing in the brain. Examining how pain transforms into a behavioral response can shed light on the networks' relationships and facilitate interventions to treat chronic pain. However, studies using high spatial and temporal resolution methods to investigate the neural encoding of pain and its psychophysical correlates have been limited. We recorded from intracranial stereo-EEG (sEEG) electrodes implanted in sixteen different brain regions of twenty patients who underwent psychophysical pain testing consisting of a tonic thermal stimulus to the hand. Broadband high-frequency local field potential amplitude (HFA; 70-150 Hz) was isolated to investigate the relationship between the ongoing neural activity and the resulting psychophysical pain evaluations. Two different generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. The first model examined the relationship between HFA and whether the patient responded "yes" or "no" to whether the trial was painful. The second model investigated the relationship between HFA and how painful the stimulus was rated on a visual analog scale. GLMEs revealed that HFA in the inferior temporal gyrus (ITG), superior frontal gyrus (SFG), and superior temporal gyrus (STG) predicted painful responses at stimulus onset. An increase in HFA in the orbitofrontal cortex (OFC), SFG, and striatum predicted pain responses at stimulus offset. Numerous regions including the anterior cingulate cortex, hippocampus, IFG, MTG, OFC, and striatum, predicted the pain rating at stimulus onset. However, only the amygdala and fusiform gyrus predicted increased pain ratings at stimulus offset. We characterized the spatiotemporal representations of binary and graded painful responses during tonic pain stimuli. Our study provides evidence from intracranial recordings that the neural encoding of psychophysical pain changes over time during a tonic thermal stimulus, with different brain regions being predictive of pain at the beginning and end of the stimulus.

Psychophysical pain encoding in the cingulate cortex predicts responsiveness of electrical stimulation.

Background: The anterior cingulate cortex (ACC) plays an important role in the cognitive and emotional processing of pain. Prior studies have used deep brain stimulation (DBS) to treat chronic pain, but results have been inconsistent. This may be due to network adaptation over time and variable causes of chronic pain. Identifying patient-specific pain network features may be necessary to determine patient candidacy for DBS. Hypothesis: Cingulate stimulation would increase patients' hot pain thresholds if non-stimulation 70-150 Hz activity encoded psychophysical pain responses. Methods: In this study, four patients who underwent intracranial monitoring for epilepsy monitoring participated in a pain task. They placed their hand on a device capable of eliciting thermal pain for five seconds and rated their pain. We used these results to determine the individual's thermal pain threshold with and without electrical stimulation. Two different types of generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. Results: The pain threshold for each patient was determined from the psychometric probability density function. Two patients had a higher pain threshold with stimulation than without, while the other two patients had no difference. We also evaluated the relationship between neural activity and pain responses. We found that patients who responded to stimulation had specific time windows where high-frequency activity was associated with increased pain ratings. Conclusion: Stimulation of cingulate regions with increased pain-related neural activity was more effective at modulating pain perception than stimulating non-responsive areas. Personalized evaluation of neural activity biomarkers could help identify the best target for stimulation and predict its effectiveness in future studies evaluating DBS.

Characterization of spatiotemporal dynamics of binary and graded tonic pain in humans using intracranial recordings.

Pain is a complex experience involving sensory, emotional, and cognitive aspects, and multiple networks manage its processing in the brain. Examining how pain transforms into a behavioral response can shed light on the networks' relationships and facilitate interventions to treat chronic pain. However, studies using high spatial and temporal resolution methods to investigate the neural encoding of pain and its psychophysical correlates have been limited. We recorded from intracranial stereo-EEG (sEEG) electrodes implanted in sixteen different brain regions of twenty patients who underwent psychophysical pain testing consisting of a tonic thermal stimulus to the hand. Broadband high-frequency local field potential amplitude (HFA; 70-150 Hz) was isolated to investigate the relationship between the ongoing neural activity and the resulting psychophysical pain evaluations. Two different generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. The first model examined the relationship between HFA and whether the patient responded "yes" or "no" to whether the trial was painful. The second model investigated the relationship between HFA and how painful the stimulus was rated on a visual analog scale. GLMEs revealed that HFA in the inferior temporal gyrus (ITG), superior frontal gyrus (SFG), and superior temporal gyrus (STG) predicted painful responses at stimulus onset. An increase in HFA in the orbitofrontal cortex (OFC), SFG, and striatum predicted pain responses at stimulus offset. Numerous regions, including the anterior cingulate cortex, hippocampus, IFG, MTG, OFC, and striatum, predicted the pain rating at stimulus onset. However, only the amygdala and fusiform gyrus predicted increased pain ratings at stimulus offset. We characterized the spatiotemporal representations of binary and graded painful responses during tonic pain stimuli. Our study provides evidence from intracranial recordings that the neural encoding of psychophysical pain changes over time during a tonic thermal stimulus, with different brain regions being predictive of pain at the beginning and end of the stimulus.

Subsets of cortico-cortical evoked potentials propagate as traveling waves.

Emerging evidence suggests that the temporal dynamics of cortico-cortical evoked potentials (CCEPs) may be used to characterize the patterns of information flow between and within brain networks. At present, however, the spatiotemporal dynamics of CCEP propagation cortically and subcortically are incompletely understood. We hypothesized that CCEPs propagate as an evoked traveling wave emanating from the site of stimulation. To elicit CCEPs, we applied single-pulse stimulation to stereoelectroencephalography (SEEG) electrodes implanted in 21 adult patients with intractable epilepsy. For each robust CCEP, we measured the timing of the maximal descent in evoked local field potentials and broadband high-gamma power (70-150 Hz) envelopes relative to the distance between the recording and stimulation contacts using three different metrics (i.e., Euclidean distance, path length, geodesic distance), representing direct, subcortical, and transcortical propagation, respectively. Many evoked responses to single-pulse electrical stimulation appear to propagate as traveling waves (~17-30%), even in the sparsely sampled, three-dimensional SEEG space. These results provide new insights into the spatiotemporal dynamics of CCEP propagation.

Corrigendum: LeGUI: A Fast and Accurate Graphical User Interface for Automated Detection and Anatomical Localization of Intracranial Electrodes.

[This corrects the article DOI: 10.3389/fnins.2021.769872.].

Portable System for Home Use Enables Closed-Loop, Continuous Control of Multi-Degree-of-Freedom Bionic Arm.

Commercial prosthetic hands are frequently abandoned due to unintuitive control methods and a lack of sensory feedback from the prosthesis. Advanced neuromyoelectric prostheses can restore intuitive control and sensory feedback to prosthesis users and potentially reduce abandonment. However, not all advanced prosthetic systems are deployable for home use on portable systems with limited computational power. In this work, we use a commercially available portable neural interface processor (the Ripple Neuro Nomad), and a multi-degree-of-freedom bionic arm (the DEKA LUKE Arm) to create a closed-loop neuromyoelectric prosthesis. The system restores intuitive, independent, continuous control over the arm's six-degrees-of-freedom and provides sensory feedback for up to 288 neural and six vibrotactile channels. Additionally, the large storage capacity of the system enables high-resolution logging of EMG, hand positions, prosthesis sensors, and stimulation parameters. We developed two GUIs enabling wireless, real-time adjustments to motor control and feedback parameters: one with nearly full control over motor control and feedback parameters for investigators, and one with restricted capabilities enabling end-user safety. We verified the system's closed-loop function through a fragile egg task with vibrotactile sensory feedback. We tested the neural stimulation with an amplifier capable of eliciting transcutaneous percepts. This neuromyoelectric prosthetic system will be used for an extended take-home trial that could provide strong clinical justification for advanced, closed-loop prostheses.Clinical Relevance- This work establishes an advanced, intuitive, sensorized prosthesis that can be used in home and clinical settings.

Probabilistic comparison of gray and white matter coverage between depth and surface intracranial electrodes in epilepsy.

In this study, we quantified the coverage of gray and white matter during intracranial electroencephalography in a cohort of epilepsy patients with surface and depth electrodes. We included 65 patients with strip electrodes (n = 12), strip and grid electrodes (n = 24), strip, grid, and depth electrodes (n = 7), or depth electrodes only (n = 22). Patient-specific imaging was used to generate probabilistic gray and white matter maps and atlas segmentations. Gray and white matter coverage was quantified using spherical volumes centered on electrode centroids, with radii ranging from 1 to 15 mm, along with detailed finite element models of local electric fields. Gray matter coverage was highly dependent on the chosen radius of influence (RoI). Using a 2.5 mm RoI, depth electrodes covered more gray matter than surface electrodes; however, surface electrodes covered more gray matter at RoI larger than 4 mm. White matter coverage and amygdala and hippocampal coverage was greatest for depth electrodes at all RoIs. This study provides the first probabilistic analysis to quantify coverage for different intracranial recording configurations. Depth electrodes offer increased coverage of gray matter over other recording strategies if the desired signals are local, while subdural grids and strips sample more gray matter if the desired signals are diffuse.

LeGUI: A Fast and Accurate Graphical User Interface for Automated Detection and Anatomical Localization of Intracranial Electrodes.

Accurate anatomical localization of intracranial electrodes is important for identifying the seizure foci in patients with epilepsy and for interpreting effects from cognitive studies employing intracranial electroencephalography. Localization is typically performed by coregistering postimplant computed tomography (CT) with preoperative magnetic resonance imaging (MRI). Electrodes are then detected in the CT, and the corresponding brain region is identified using the MRI. Many existing software packages for electrode localization chain together separate preexisting programs or rely on command line instructions to perform the various localization steps, making them difficult to install and operate for a typical user. Further, many packages provide solutions for some, but not all, of the steps needed for confident localization. We have developed software, Locate electrodes Graphical User Interface (LeGUI), that consists of a single interface to perform all steps needed to localize both surface and depth/penetrating intracranial electrodes, including coregistration of the CT to MRI, normalization of the MRI to the Montreal Neurological Institute template, automated electrode detection for multiple types of electrodes, electrode spacing correction and projection to the brain surface, electrode labeling, and anatomical targeting. The software is written in MATLAB, core image processing is performed using the Statistical Parametric Mapping toolbox, and standalone executable binaries are available for Windows, Mac, and Linux platforms. LeGUI was tested and validated on 51 datasets from two universities. The total user and computational time required to process a single dataset was approximately 1 h. Automatic electrode detection correctly identified 4362 of 4695 surface and depth electrodes with only 71 false positives. Anatomical targeting was verified by comparing electrode locations from LeGUI to locations that were assigned by an experienced neuroanatomist. LeGUI showed a 94% match with the 482 neuroanatomist-assigned locations. LeGUI combines all the features needed for fast and accurate anatomical localization of intracranial electrodes into a single interface, making it a valuable tool for intracranial electrophysiology research.

Visual percepts evoked with an intracortical 96-channel microelectrode array inserted in human occipital cortex.

BACKGROUNDA long-held goal of vision therapy is to transfer information directly to the visual cortex of blind individuals, thereby restoring a rudimentary form of sight. However, no clinically available cortical visual prosthesis yet exists.METHODSWe implanted an intracortical microelectrode array consisting of 96 electrodes in the visual cortex of a 57-year-old person with complete blindness for a 6-month period. We measured thresholds and the characteristics of the visual percepts elicited by intracortical microstimulation.RESULTSImplantation and subsequent explantation of intracortical microelectrodes were carried out without complications. The mean stimulation threshold for single electrodes was 66.8 ± 36.5 µA. We consistently obtained high-quality recordings from visually deprived neurons and the stimulation parameters remained stable over time. Simultaneous stimulation via multiple electrodes was associated with a significant reduction in thresholds (P < 0.001, ANOVA) and evoked discriminable phosphene percepts, allowing the blind participant to identify some letters and recognize object boundaries.CONCLUSIONSOur results demonstrate the safety and efficacy of chronic intracortical microstimulation via a large number of electrodes in human visual cortex, showing its high potential for restoring functional vision in the blind.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02983370.FUNDINGThe Spanish Ministerio de Ciencia Innovación y Universidades, the Generalitat Valenciana (Spain), the Europan Union's Horizon 2020 programme, the Bidons Egara Research Chair of the University Miguel Hernández (Spain), and the John Moran Eye Center of the University of Utah.

The Cerebral Localization of Pain: Anatomical and Functional Considerations for Targeted Electrical Therapies.

Millions of people in the United States are affected by chronic pain, and the financial cost of pain treatment is weighing on the healthcare system. In some cases, current pharmacological treatments may do more harm than good, as with the United States opioid crisis. Direct electrical stimulation of the brain is one potential non-pharmacological treatment with a long history of investigation. Yet brain stimulation has been far less successful than peripheral or spinal cord stimulation, perhaps because of our limited understanding of the neural circuits involved in pain perception. In this paper, we review the history of using electrical stimulation of the brain to treat pain, as well as contemporary studies identifying the structures involved in pain networks, such as the thalamus, insula, and anterior cingulate. We propose that the thermal grill illusion, an experimental pain model, can facilitate further investigation of these structures. Pairing this model with intracranial recording will provide insight toward disentangling the neural correlates from the described anatomic areas. Finally, the possibility of altering pain perception with brain stimulation in these regions could be highly informative for the development of novel brain stimulation therapies for chronic pain.

Intuitive neuromyoelectric control of a dexterous bionic arm using a modified Kalman filter.

BACKGROUND: Multi-articulate prostheses are capable of performing dexterous hand movements. However, clinically available control strategies fail to provide users with intuitive, independent and proportional control over multiple degrees of freedom (DOFs) in real-time. NEW METHOD: We detail the use of a modified Kalman filter (MKF) to provide intuitive, independent and proportional control over six-DOF prostheses such as the DEKA "LUKE" arm. Input features include neural firing rates recorded from Utah Slanted Electrode Arrays and mean absolute value of intramuscular electromyographic (EMG) recordings. Ad-hoc modifications include thresholds and non-unity gains on the output of a Kalman filter. RESULTS: We demonstrate that both neural and EMG data can be combined effectively. We also highlight that modifications can be optimized to significantly improve performance relative to an unmodified Kalman filter. Thresholds significantly reduced unintended movement and promoted more independent control of the different DOFs. Gains were significantly greater than one and served to ease movement initiation. Optimal modifications can be determined quickly offline and translate to functional improvements online. Using a portable take-home system, participants performed various activities of daily living. COMPARISON WITH EXISTING METHODS: In contrast to pattern recognition, the MKF allows users to continuously modulate their force output, which is critical for fine dexterity. The MKF is also computationally efficient and can be trained in less than five minutes. CONCLUSIONS: The MKF can be used to explore the functional and psychological benefits associated with long-term, at-home control of dexterous prosthetic hands.

Long-term performance of Utah slanted electrode arrays and intramuscular electromyographic leads implanted chronically in human arm nerves and muscles.

OBJECTIVE: We explore the long-term performance and stability of seven percutaneous Utah Slanted Electrode Arrays (USEAs) and intramuscular recording leads (iEMGs) implanted chronically in the residual arm nerves and muscles of three human participants as a means to permanently restore sensorimotor function after transradial amputations. APPROACH: We quantify the number of functional recording and functional stimulating electrodes over time. We also calculate the signal-to-noise ratio (SNR) of USEA and iEMG recordings and quantify the stimulation current necessary to evoke detectable sensory percepts. Furthermore, we quantify the consistency of the sensory modality, receptive field location, and receptive field size of USEA-evoked percepts. MAIN RESULTS: In the most recent subject, involving USEAs with technical improvements, neural recordings persisted for 502 d (entire implant duration) and the number of functional recording electrodes for one USEA increased over time. However, for six out of seven USEAs across the three participants, the number of functional recording electrodes decreased within the first 2 months after implantation. The SNR of neural recordings and electromyographic recordings stayed relatively consistent over time. Sensory percepts were consistently evoked over the span of 14 months, were not significantly different in size, and highlighted the nerves' fascicular organization. The percentage of percepts with consistent modality or consistent receptive field location between sessions (∼1 month apart) varied between 0%-86.2% and 9.1%-100%, respectively. Stimulation thresholds and electrode impedances increased initially but then remained relatively stable over time. SIGNIFICANCE: This work demonstrates improved performance of USEAs, and provides a basis for comparing the longevity and stability of USEAs to that of other neural interfaces. USEAs provide a rich repertoire of neural recordings and sensory percepts. Although their performance still generally declines over time, functionality can persist long-term. Future work should leverage the results presented here to further improve USEA design or to develop adaptive algorithms that can maintain a high level of performance.